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Oxytocin in psychiatry
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Oxytocin for stress?
A high activity in the oxytocin system attenuates the physiological responses to mental
stress and leads to calmer behaviour. Anatomical studies confirm the presence of
oxytocin-carrying nerve pathways from the hypothalamus to areas of the brain that are
important for stress reactions including the amygdala and locus coeruleus.
A behaviour that generally promotes activity in the oxytocin system can be a viable way
to attenuate mental- and thus physiological stress reactions. The ability of the oxytocin
system to suppress stress responses has probably initially emerged as a supporting
function for mating and breastfeeding. The stress-reducing effect of oxytocin is important
for breastfeeding, where it may provide the necessary sedation of the mother. However,
from having this specific role in reproduction, the ability of oxytocin to reduce stress
reactions in the brain and body has evolved into an important global stress dampening
factor. An increased oxytocin release is therefore now also seen both in physical – this
could be running – and mental stress situations (1). In this context, it is intriguing that
blood levels of oxytocin in the child is comparable to that of the mother during birth (2).
To be born maybe even more stressful than to give birth and this may trigger the
hypothalamus of the child to release a great amount of oxytocin.
A general stress-reducing effect of oxytocin has been observed in mice. It is possible to
completely shut down the oxytocin production by genetically engineering. A greater fear
of moving out into open spaces was observed in such mice (3). On the other hand,
behavioural stress responses could be reduced by the injection of oxytocin directly into
the brain (4) or by stimulating oxytocin-carrying nerve pathways using optogenetic
methods (5). Rats that were bred to be particularly fearful became permanently less
anxious by the sustained introduction of oxytocin into the brain cavities (6).
The attenuation of stress responses by treatment of oxytocin is also reflected by a
reduced CRF reaction. CRF stands for Corticotropin-Releasing Factor, which is a superior
factor in the regulation of both physiological and mental stress. CRF is formed in the
hypothalamus and is transferred to the pituitary gland via a direct local blood vessel
connection. Subsequently, CRF causes the pituitary gland to increase the release of ACTH
(adrenocorticotropic hormone), which in turn promotes the release of cortisol from the
adrenal cortex into the general circulation. Cortisol is a hormone that plays a significant
role in the regulation of both metabolic and immune responses (later). Furthermore, the
regulation of CRF and the sympathetic nervous system are closely interconnected as they
both are influenced by the activity ofthe Locus Coeruleus (7), which is an area of the brain
stem that is closely linked to the hypothalamus.
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CRF production in the hypothalamus has been measured in mice while they were housed
in very limited space. As expected, an increased CRF production was seen, but the
reaction was most pronounced in mice which were made unable to generate oxytocin (8).
The oxytocin system can attenuate the activity of CRF-producing nerve cells in several
ways. One mechanism is based on the fact that oxytocin-releasing magnocellular cells are
mixed with the CHR-producing cells in the same nucleus of the hypothalamus. These CRFproducing
cells are equipped with oxytocin receptors and can, therefore, be influenced
by the oxytocin from the adjacent oxytocin-producing cells (9). Second, the CRFproducing
cells receive input from above, including the amygdala and other parts of the
limbic system (10). As mentioned before, the limbic system consists of several closely
related structures, which are located both basally in the brain but also in areas of the
forebrain (11). The general view is that the activity of the limbic system constitutes the
basis for what we perceive as emotions. Contrary to what is the case for more direct input
from the body to the hypothalamic stress system – this could be acute pain signals – input
from the limbic system may "hang on" for a long time and can, therefore, induce a more
chronic state of stress with a sustained elevated CRF activity. In addition to the
hypothalamus, nerves in the amygdala can also produce CRF, which may influence on
internal brain functions. A hyperactive CRF function of the amygdala is thought to be a
major factor in the development of chronic mental stress disorders (12). However, tracts
of oxytocin-carrying nerves to the limbic system may be capable of attenuating a more
prolonged stress response including the back-feeding from the amygdala to the
hypothalamus.
We do not have the same opportunities to study the impact of oxytocin on stress reactions
in the brain in humans as we do in rats. In humans, we must rely on results from nasally
administered oxytocin to confirm any soothing effect of oxytocin. Such research on
humans is at a very the initial state. However, in one study, the test persons showed an
attenuated stress reaction when they had to speak to a large assembly if they were given
A so-called plus maze,
which is used to test the
degree of fear in small
animals by their liability to
move in open spaces.
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oxytocin (13). But again, the possibility for extrapolation of such experiments is limited
when it comes to the role of oxytocin as a nerve signalling substance in the brain.
Oxytocin for depression?
Oxytocin is thought to have a potential in the treatment of certain depressive disorders,
in part due to its anti-anxiety effect. It is also conceivable that the anhedonic condition
that accompanies the depression could be improved by oxytocin-like substances.
Furthermore, it has been found that oxytocin can promote the activity of the serotonin
system, which is already used as a target for antidepressant treatment.
Depressive disorders reduce the quality of life of many people and can even be directly
debilitating. Depression can be very hard to treat with the types of medication available
today and the most potent drugs can cause serious side effects including severe
disturbances of the heart rhythm (14). The most common agents for relieving depression
and anxiety are the so-called Selective Serotonin Reuptake Inhibitors or SSRIs, which
increase the amount of serotonin in the brain. The serotonin system appears to be
involved in the regulation of our general state of mood. Serotonin is a monoamine like
dopamine, and the structure of serotonin-carrying nerve tracts is somewhat similar to
that of the dopamine system. Both systems originate from nuclei located at the top of the
brainstem and both communicate directly with nucleus accumbens and areas of the
cerebral cortex. However, the serotonin system probably has to do with our general mood
as opposed to the dopamine system, which seems to be mostly engaged with immediate
reward and motivation. Unfortunately, in many cases, SSRIs may be ineffective (15) and
may – upon cessation of the treatment – have worsened the condition of the patient
compared to before its prescription (16). Such treatment may unmask a latent
depression, in case it was initially given against another disorder. Also, SSRI treatment
reduces the desire and ability – as well as the enjoyment – of sex in a very large proportion
of patients, which often makes them tempted to quit the treatment (17).
Thus, there is a true need for the development of better drugs for depression and anxiety,
and here the oxytocin system may be considered a relevant point of attack. To some
extent, rats can be used as a model for depression, since a behaviour similar to what is
seen in depressed people can be induced by stressing the animals in different ways. One
sign of depression in rats is – like in humans – a state of diminished attention and
movement activity. These symptoms can be improved by injecting oxytocin directly into
specific areas of the brain including the hypothalamus (18). An antidepressant effect of
oxytocin may be mediated by the serotonin system since the oxytocin system interacts
closely with this system. Indeed, oxytocin has the potential to increase both serotonin
release and sensitivity (19). Oxytocin-like drugs may, therefore, be a viable way to affect
the serotonin system without patients experiencing the reduced libido that may come
with SSRI treatment.
Reports of trials in humans where oxytocin treatment has been directly aimed at
alleviating depressive symptoms do not yet appear in the literature. As mentioned above,
oxytocin may be capable to attenuate social anxiety also in humans and the substance
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may, therefore, have the potential to prevent anxiety-related depressions. However, men
who already were diagnosed with depression demonstrated exacerbated fear-related
reactions during the trial with oxytocin, despite its effect was confirmed by an improved
ability to interpret facial expressions (20). An explanation for this disappointing result
could be the following: the amygdala is part of a larger nervous network that amplifies
the focus of our consciousness and feelings towards particular characteristics of persons
or things in our vicinity that could be potentially dangerous (21). For instance, if we spot
a snake, we will focus on it and concomitantly a reaction of fear may be triggered. In this
way, the amygdala is involved in conditional learning, not at least concerning anxiety
reactions. This may form the basis for the creation of a hypersensitive amygdala solely
caused by a single strong anxiety-provoking experience and thereby make us respond
with anxiety to stimuli that normally are not anxiety-provoking. In other words, we
develop phobias. Here, it is conceivable that the oxytocin system, by increasing the
salience for social signals also may amplifying the response of the amygdala to such
signals and so, reinforce the phobic reactions in a way that friendly persons unjustly are
being perceived as threatening. Such an adverse effect of oxytocin could be present in
people with a worrisome depressive habitus, which may be complicated by a negative
attitude even towards their loved ones. Considerations about amplifying adverse reaction
patterns have also been made for the treating of autistic people with oxytocin.
As mentioned earlier, a clear association between birth depression and a low oxytocin
level at the end of pregnancy has been shown, while no unambiguous relationship has
been reported with other types of depression (22). However, this does not contradict that
a poorly functioning oxytocin system may predispose for depression in other contexts
than the mother-child relationship. The fact that anxiety and other types of stress
reactions boost the oxytocin system makes a lack of statistical associations between
oxytocin and depression inconclusive. This may be parallel to the fact that high
concentrations of insulin in the blood are certainly not indicative of a well-functioning
insulin system. Neither has a clear association between depression and low serotonin
levels been shown, but this does, indeed, not refrain psychiatrists from using the
serotonin system as a target for antidepressant treatment.
Oxytocin may also be able to counteract depression in other ways than affecting the
serotonin system and reduce anxiety. As previously mentioned, a depressed person can
fall into an anhedonic state where experiences, that healthy people usually enjoy, do not
bring any delight. This can apply both to food, sex, and social activities. Thus, if you are
anhedonic, you are not encouraged to do the things that you would normally do. In the
worst-case scenario, you may fall into complete immobility. Here oxytocin may perhaps,
in some cases, help you get back on track by supporting the reward system in a way that
restores the joyfulness of social activities to some extent. Perhaps this may only break the
vicious circle of depression in patients where their condition is not followed by
discomfort or fear for social interactions. Thus, if it turns out that oxytocin also in humans
can have an antidepressant effect that is applicable for therapeutic purposes, it will
probably never be a simple matter to use the substance for the treatment of depression.
Maybe a detailed mental profile of the patient must be produced before oxytocin can be
prescribed.
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Oxytocin's interaction with the reward system – a possible target against drug
abuse?
Oxytocin seems to be able to reduce the compulsive search for the satisfaction of
euphoric drugs and tasty food. When developing an addiction to drugs – including
alcohol – there is a hijacking of the reward system, so that the stimulation of the
substances replaces the need for other hedonic stimuli. Hereby, the addict loses the
drive for participation in social activities. Oxytocin may have the potential to
counteract this situation and pilot studies have been conducted where alcoholics have
been treated with oxytocin.
Although a high activity in the oxytocin system enhances the reward of sex and social
activities, oxytocin may have the opposite effect on the reward of other stimuli. Many
euphoric substances, including methamphetamine, increase the activity of the nucleus
accumbens and trigger it to stimulate the frontal lobes and structures of the limbic
system, which is perceived by consciousness as pleasure. However, if oxytocin was given
concomitantly with methamphetamine to rats it blunted the response in the nucleus
accumbens to the methamphetamine (23). Accordingly, in another study on mice,
oxytocin reduced the increase in dopamine turnover in nucleus accumbens induced by
methamphetamine (24). In both experiments, oxytocin was also found to counteract the
methamphetamine-triggered hyperactivity. Studies in rats that were allowed to stimulate
themselves with methamphetamine have also demonstrated that if oxytocin was given
directly into the nucleus accumbens by a cannula together with drug, the frequency of
their self-stimulation was reduced (25). This suggests that oxytocin may reduce the
euphoric effect of drugs acting on the dopamine system. The oxytocin system also
appears to be able to reduce the hedonic effect of food, which probably also involves
nucleus accumbens (26). The effect of oxytocin on food intake seems to be predominant
for tasty and especially sweet foods. In this regard, the question may be raised about
whether this may be an explanation for the observations that the pleasure of consuming
such foods is typically the last thing to vanish during the progression of anhedonic
depression, where the oxytocin system may be malfunctioning.
The hedonic response to
sweets is often the last thing
that disappears in depression.
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As mentioned, endorphins are very important signalling agents for reward. This is true
not at least for that associated with eating. Such role has been demonstrated in human
trials, where the administration of a substance that blocks the opioid receptors resulted
in a lower intake of sweets and fatty food without affecting the feeling of hunger (27).
This supports that endorphins promote the hedonic effect of eating. Endorphins also
appear to be important for the pleasure of interacting with other people, as a blockade of
the opioid receptors has been shown to diminish the sense of social cohesion (28).
Regarding sex, it has been reported that opioid blocking was able to attenuate compulsive
sexual behaviour in men (29). On the other hand, men have rated the orgasm during
masturbation to be more intense if an opioid receptor blocker had been given (30). These
two findings are not mutually contradictory but rather emphasize that craving and
pleasure may deploy different hedonic "platforms" which may act partially
independently. Even within the individual hedonic hotspots, such as the nucleus
accumbens, there appear to be anatomically distinct structures that either encodes
craving or pleasure (31). To claim that a neuromodulator such as oxytocin simply affects
the reward system – including its opioid and endocannabinoid systems – in a certain way
would therefore probably be an oversimplification. Thus, oxytocin may very well interact
with opioid systems to enhance the enjoyment of socializing and sex and attenuate pain
while it at the same time may diminish compulsive behaviour related to opioids such as
overeating, excessive use of porn or euphoric drugs.
Euphoric substances such as cocaine, amphetamines, opiates but also alcohol can "hijack"
the reward system so that the drug addict is only seeking reward in the drug instead of
engaging in eating, sex, social activities, and other otherwise rewarding activities (32).
Here, rodent studies have shown that oxytocin has a considerable potential to release the
reward system again so that its sensitivity to social stimuli is restored while the craving
for euphoric drugs is dampened (33). In this context, oxytocin is suggested to mediate the
protection against the urge to abuse euphoric drugs exerted by good social relationships
(34). In particular, an interesting study on pair-forming voles has shown that animals in
a relationship were less likely to search for a cage where they previously had been treated
with amphetamine compared to single voles (35). At the same time, it was found that
treatment with amphetamine led to an increase in the dopamine receptors in the nucleus
accumbens in the singles but not in the voles having a partner. These results suggest that
euphoric agents may enhance their effect by increasing dopamine sensitivity at least in
the nucleus accumbens, but that stable sexual relationships may abolish this mechanism.
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The location of the nucleus accumbens
Unfortunately, persistent substance abuse leads to degeneration of the oxytocin-carrying
nerve cells in several places in the brain, which may contribute to the erosion of the social
skills of drug addicts (36). However, stimulation of the oxytocin system can correct such
damage – not least supported by its self-enhancing potential.
Among the euphoric drugs, alcohol, together with nicotine, is indisputably the drug that
has had the most adverse consequences in the Western world. Although trials of oxytocin
in alcohol-accustomed rats have yielded promising results to the ability of the substance
to reduce spontaneous alcohol intake immediately as well as persistently (37), reports
from similar clinical trials with alcohol-dependent humans are sparse. This is probably
due to the rapid degradation of oxytocin combined with the fact that it must be
administered through the nose. Thus, getting alcoholics to adhere to a regimen with selfadministration
several times a day in order to obtain significant effects may be very
challenging. However, from a single study among a small group of alcoholic men, a
significant reduction in withdrawal symptoms has been reported when contemporarily
treated with oxytocin during the abstaining period (38). Concerning the capacity of
oxytocin to relieve the urge for nicotine, younger smokers indicated in one smaller study
a reduced urge to smoke a cigarette that should be held in their hand when oxytocin was
administered (39). Again, emphasis should be put on the need for the development of
relatively stable compounds that acts on the oxytocin receptors in the brain in an
appropriate manner and that can also be taken by mouth.
Can one become addicted to oxytocin itself? – the substance has, indeed, a euphoric effect
in certain contexts. As a euphoric substance, the effect of oxytocin is preferably present
in combination with sex and other sorts of encounters, but this also applies to several
other euphoric substances including ecstasy. However, some rewarding effect of oxytocin
itself has been demonstrated in an experiment in female rats, where they were allowed
to stimulate themselves with oxytocin by administering the substance into the brain
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cavities each time, they pressed a pedal. Thus, they preferred to press the pedal with
oxytocin rather than a passive pedal, despite that they, in this case, were without any
social stimulation (40). In an Indian medical journal, a single case was reported of a
shepherd who injected himself with oxytocin and thereby achieved a "kick". He had
access to the drug because it was used to facilitate the milking of the cows (41). However,
oxytocin by itself probably never becomes "the new hyped drug" just due to its fast
degradation in the body and the fact that it must be sniffed to work on the brain. However,
it has been revealed that ecstasy, which makes the user very socially engaged, triggers a
strong oxytocin reaction in the brain (42). This property has undoubtedly contributed to
the popularity of ecstasy and other drugs with similar effects. The fact that ecstasy is
called a party drug emphasizes precisely that its effect is greatest in a social context. But
what about the brains own oxytocin – can it be abused, just as is the case for endorphins
when provoked by excessive physical exercise or self-inflicted pain? Yes, it certainly can.
You might first think about people who feel so much about sex that they engage in risky
erotic activities. But what about all the people who relentlessly are seeking for praise and
recognition in their quest for the next social kick?
1. Jong TR, Menon R, Bludau A, Grund T, Biermeier V, Klampfl SM, Jurek B, Bosch OJ,
Hellhammer J, Neumann ID. Salivary oxytocin concentrations in response to
running, sexual self-stimulation, breastfeeding and the TSST: The Regensburg
Oxytocin Challenge (ROC) study. Psychoneuroendocrinology 2015; 62: 381-388.
2. Kumaresan P, Han GS, Anandarangam PB, Vasicka A. Oxytocin in maternal and
fetal blood. Obstetrics and Gynecology 1975; 46(3): 272-274.
3. Amico JA, Mantella RC, Vollmer RR, Li X. Anxiety and stress responses in female
oxytocin deficient mice. Journal of Neuroendocrinology 2004; 16(4): 319-324.
4. Ring RH, Malberg JE, Potestio L, Ping J, Boikess S, Luo B, Schechter LE, Rizzo S,
Rahman Z, Rosenzweig-Lipson S. Anxiolytic-like activity of oxytocin in male mice:
behavioral and autonomic evidence, therapeutic implications.
Psychopharmacology 2006; 185(2): 218-225.
5. Knobloch HS, Charlet A, Hoffmann LC, Eliava M, Khrulev S, Cetin AH, Osten P,
Schwarz MK, Seeburg PH, Stoop R, Grinevich V. Evoked axonal oxytocin release in
the central amygdala attenuates fear response. Neuron 2012; 73(3): 553-566.
Does the urge to meet this
signature have anything to do
with oxytocin?
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6. Slattery DA, Neumann ID. Chronic icv oxytocin attenuates the pathological high
anxiety state of selectively bred Wistar rats. Neuropharmacology 2010; 58(1) 56-
61.
7. Valentino RJ, Van Bockstaele E. Convergent regulation of locus coeruleus activity
as an adaptive response to stress. European Journal of Pharmacology 2008;
583(2-3): 194-203.
8. Nomura M, Saito J, Ueta, Muglia LJ, Pfaff DW, Ogawa S. Enhanced up‐regulation of
corticotropin‐releasing hormone gene expression in response to restraint stress
in the hypothalamic paraventricular nucleus of oxytocin gene‐deficient male mice.
Journal of Neuroendocrinology 2003; 15(11): 1054-1061.
9. Dabrowska J, Hazra R, Ahern TH, Guo JD, McDonald AJ, Mascagni F, Muller JF,
Young LJ, Rainnie DG. Neuroanatomical evidence for reciprocal regulation of the
corticotrophin-releasing factor and oxytocin systems in the hypothalamus and the
bed nucleus of the stria terminalis of the rat: Implications for balancing stress and
affect. Psychoneuroendocrinology 2011; 36(9): 1312-1326.
10. Ulrich-Lai YM, Herman JP. Neural Regulation of Endocrine and Autonomic Stress
Responses. Nature Reviews Neuroscience 2009; 10(6): 397–409.
11. Comte M, Schön D, Coull JT, Reynaud E, Khalfa S, Belzeaux R, Ibrahim EC, Guedj E,
Blin O, Weinberger DR, Fakra E. Dissociating Bottom-Up and Top-Down
Mechanisms in the cortico-limbic system during emotion processing. Cerebral
Cortex 2016; 26(1): 144-155.
12. Flandreau EI, Ressler KJ, Owens MJ, Nemeroff CB. Chronic overexpression of
corticotropin-releasing factor from the central amygdala produces HPA axis
hyperactivity and behavioral anxiety associated with gene-expression changes in
the hippocampus and paraventricular nucleus of the hypothalamus.
Psychoneuroendocrinology 2012; 37(1): 27-38.
13. de Oliveira DC, Zuardi AW, Graeff FG, Queiroz RH, Crippa JA. Anxiolytic-like effect
of oxytocin in the simulated public speaking test. Journal of Psychopharmacology
2012; 26(4): 497-504.
14. Yekehtaz H, Farokhnia M, Akhondzadeh S. Cardiovascular considerations in
antidepressant therapy: an evidence-based review. The Journal of Tehran
University Heart Center 2013; 8(4): 169-176.
15. Linde K, Kriston L, Rücker G, Jamil S, Schumann I, Meissner K, Sigterman K,
Schneider A. Efficacy and acceptability of pharmacological treatments for
depressive disorders in primary care: systematic review and network metaanalysis
The Annals of Family Medicine 2015; 13(1): 69-79.
16. Fava GA, Bernardi M, Tomba E, Rafanelli C. Effects of gradual discontinuation of
selective serotonin reuptake inhibitors in panic disorder with agoraphobia.
International Journal Neuropsychopharmacology 2007; 10(6): 835-835.
17. Higgins A, Nash M, Lynch AM. Antidepressant-associated sexual dysfunction:
impact, effects, and treatment. Drug, Healthcare and Patient Safety 2010; 2: 141-
150.
18. Arletti R, Bertolini A. Oxytocin acts as an antidepressant in two animal models of
depression. Life Science 1987; 41(14): 1725-1730.
19. McQuaid RJ, McInnis OA, Abizaid A, Anisman H. Making room for oxytocin in
understanding depression. Neuroscience & Biobehavioral Reviews 2014; 45: 305-
322.
20. MacDonald K, MacDonald TM, Brüne M, Lamb K, Wilson MP, Golshan S, Feifel D.
Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and
65
subjective effects in males with depression. Psychoneuroendocrinology 2013;
38(12): 2831-2843.
21. Shin LM, Liberzon I. The Neurocircuitry of Fear, Stress, and Anxiety Disorders.
Neuropsychopharmacology 2010; 35(1): 169–191.
22. Massey SH, Backes KA, Schuette S. Plasma oxytocin concentration and depressive
symptoms: A review of current evidence and directions for future research.
Depression and Anxiety 2016; 33(4): 316-322.
23. Carson DS, Hunt GE, Guastella AJ, Barber L, Cornish JL, Arnold JC, Boucher AA,
McGregor IS. Systemically administered oxytocin decreases methamphetamine
activation of the subthalamic nucleus and accumbens core and stimulates
oxytocinergic neurons in the hypothalamus. Addict Biol 2010; 15(4): 448-463.
24. Qi J, Yang JY, Song M, Li Y, Wang F, Wu CF. Inhibition by oxytocin of
methamphetamine-induced hyperactivity related to dopamine turnover in the
mesolimbic region in mice. Naunyn-Schmiedeberg's Archives of Pharmacology
2008; 376(6): 441-448.
25. Baracz SJ, Everett NA, McGregor IS, Cornish JL. Oxytocin in the nucleus accumbens
core reduces reinstatement of methamphetamine-seeking behaviour in rats.
Addiction Biology 2016; 21(2): 316-325.
26. Klockars A, Levine AS, Olszewski PK. Central oxytocin and food intake: focus on
macronutrient-driven reward. Frontiers in Endocrinology 2015; 6: 65.
27. Nogueiras R, Romero-Picó A, Vazquez MJ, Novelle MG, López M, Diéguez C. The
opioid system and food intake: homeostatic and hedonic mechanisms. Obesity
Facts 2012; 5(2): 196-220.
28. Inagaki TK, Ray LA, Irwin MR, Way BM, Eisenberger NI. Opioids and social
bonding: naltrexone reduces feelings of social connection. Social Cognitive and
Affective Neuroscience 2016; 11(5): 728-735.
29. Raymond NC, Grant JE, Coleman E. Augmentation with naltrexone to treat
compulsive sexual behavior: a case series. Annals of Clinical Psychiatry 2010;
22(1): 56-62.
30. Sathe RS, Komisaruk BR, Ladas AK, Godbole SV. Naltrexone-induced augmentation
of sexual response in men. Archives of Medical Research 2001; 32(3): 221-226.
31. Castro DC, Berridge KC. Opioid hedonic hotspot in nucleus accumbens shell: mu,
delta, and kappa maps for enhancement of sweetness "liking" and "wanting".
Journal of Neuroscience 2014; 34(12): 4239-4250.
32. Dackis C, O'Brien C. Neurobiology of addiction: treatment and public policy
ramifications. Nature Neuroscience 2005; 8(11): 1431-1436.
33. Sarnyai Z1, Kovács GL. Oxytocin in learning and addiction: From early discoveries
to the present. 2014; 119: 3-9.
34. Tops M, Koole SL, IJzerman H, Buisman-Pijlman FT. Why social attachment and
oxytocin protect against addiction and stress: Insights from the dynamics between
ventral and dorsal corticostriatal systems. Pharmacology Biochemistry and
Behavior 2014; 119: 39-48.
35. Liu Y, Young KA, Curtis JT, Aragona BJ, Wang Z. Social bonding decreases the
rewarding properties of amphetamine through a dopamine D1 receptor-mediated
mechanism. Journal of Neuroscience 2011; 31(22): 7960-7966.
36. McGregor IS, Bowen MT. Breaking the loop: oxytocin as a potential treatment for
drug addiction. Hormones and Behavior 2012; 61(3): 331-339.
37. Bowen MT, Carson DS, Spiro A, Arnold JC, McGregor IS. Adolescent oxytocin
exposure causes persistent reductions in anxiety and alcohol consumption and
enhances sociability in rats. PLOS ONE 2011; 6(11) e27237.
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38. Pedersen CA, Smedley KL, Leserman J, Jarskog LF, Rau SW, Kampov-Polevoi A,
Casey RL, Fender T, Garbutt JC. Intranasal oxytocin blocks alcohol withdrawal in
human subjects. Alcoholism: Clinical and Experimental Research 2013; 37(3):
484-489.
39. Miller MA1, Bershad A, King AC, Lee R, de Wit H. Intranasal oxytocin dampens cueelicited
cigarette craving in daily smokers: a pilot study. Behavioural
Pharmacology 2016; 27(8): 697-703.
40. Donhoffner ME, Goings SP, Atabaki K, Wood RI. Intracerebroventricular oxytocin
selfadministration in female rats. Journal of Neuroendocrinology 2016; 28(10).
41. Arun P, Chavan BS. Oxytocin abuse: A case report. Indian Journal of Psychiatry
1998; 40(1): 90–91.
42. Thompson MR, Callaghan PD, Hunt GE, Cornish JL, McGregor IS. A role for oxytocin
and 5-HT(1A) receptors in the prosocial effects of 3,4
methylenedioxymethamphetamine ("ecstasy"). Neuroscience 2007; 146(2): 509-
514
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Part II: Oxytocin and soma
Chapter V
Brain & Body
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It has been recognized since ancient times that the brain and thus the mental state plays
a major role in the health of our body, but at that time there was little insight into the
mechanisms at play. However, the latest biological research has made some attempts to
go into it. Clinical research often faces the dilemma that medication with pills which are
supposed to be ineffective may produce statistically significant treatment effects even
comparable with the active medication. This so-called placebo effect is usually regarded
as merely an annoying and costly mental phenomenon, which must be taken into account
when testing new drugs. Placebo effects are, of course, particularly prominent in studies
that examine the effects of medication for mental and pain-related disorders, but they can
also be significant in immune diseases such as allergies and inflammatory conditions.
The established health sciences most often regard the success of alternative medicine as
attributable to such a placebo effect. Therefore, the common standpoint is that an effect
of alternative treatment methods is based on the belief in an effect. In other words, the
consciousness must be convinced that a change in the body has taken place in
contradiction with the facts. The phenomenon is often perceived as suggestion, that is,
the alternative therapist causes the patient to lose his or her critical sense of the
treatment. But why has acupuncture become so popular in veterinary medicine (1) – is
the horse being fool into the perception that it no longer has any back pain?
What if the alternative treatment actually can alter the signalling systems of the brain and
body in a way that has a real biological effect? The touches of a healer may make an allergy
symptomless not because it gives the patient a delusion that he has been cured, nor
because a healing spirit has been evoked as the healer may believe for himself, but
because the sensations combined with mental influences bring the brain into a condition
that causes it to affect the immune system through nerves or hormones. In the case of
acupuncture or massage, consciousness needs not to be involved at all as the basic parts
of the limbic system might solve the problem just in collaboration with the brainstem and
vagus system. Thus, the horse or the allergic patient does not need to believe in anything.
Such mechanisms are very difficult to clarify in placebo-controlled trials – which placebo
treatment should be used for comparison? One must be sure that it does not affect the
basic structures of the brain for instance via a mental impact. Therefore, if such pure
"limbic-dependent" mechanisms are to become a subject for research interest in the
established health sciences and pharmacology, its platform of signalling substances must
be elucidated.
Oxytocin may be an important candidate in this regard. In rats, acupuncture has been
shown to induce an elevated concentration of oxytocin in the brain cavities and the painrelieving
effect of acupuncture could be counteracted by simultaneously providing a
substance that blocks the effect of oxytocin (2). Since the turn of the millennium, research
has revealed more and more surprising effects of oxytocin in the body, which is not only
a result of its actions in the central nervous system but also occurs by its presence in the
blood. Many of the effects that oxytocin has on our tissues and organs appear to be
extremely beneficial, and insights in the mechanisms behind may open up for new
pharmacological preventive and treatment approaches for a variety of diseases. Here I
will try – system by system – to review the most significant of the effects known today.
69
Signalling substances from the brain may explain the healing effect of alternative
treatment.
Chronic stress must be taken seriously
Chronic stress conditions can affect metabolism and blood pressure in such a way that
it increases the risk of thrombosis and cerebral haemorrhage. Among people today, it
is especially bad social relationships that can cause long-term mental and physical
stress reactions. Here, a poorly functioning autonomic nervous system can play a
significant role in the adverse effects. Oxytocin may be an important player in the
regulation of the autonomic nervous system.
Mental stress not only leads to a deteriorating quality of life but puts the body in an alert
that can eventually harm it. Stress is a somewhat diffuse concept, but overall, it can be
regarded as factors that challenge the maintenance of physical and mental balances or
even the existence of the individual. When the senses provide information to the brain
about the environment or the body that something is wrong, signals are sent back to the
body to respond. It can result in a specific behavioural reaction and/or that something
occurs internally in the body. The latter could be an increased heart rate or the
mobilization of fuel for increased physical activity. For the initiation of stress reactions in
the body, the brain uses two signalling systems – the sympathetic nervous system having
noradrenaline and adrenalin (adrenal medulla) as signalling substances and the
glucocorticoid system. The latter acts via the hormone cortisol, which is produced in the
adrenal cortex and is therefore called corticosteroid in daily speech, although it is not the
only steroid hormone that is produced in the adrenal cortex. Both systems are
orchestrated by the hypothalamus and both adrenaline and cortisol are called stress
hormones. The latter is, in fact, a misconception, as both signalling substances are
indispensable in the regulation of the daily household of the body.
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Like the oxytocin system, these systems have adapted during the evolution of animals
towards greater and greater interplay between the individuals. Thus, from merely
engaging in a purely reflex response to environmental threats, the systems are
increasingly being influenced by social signals from other members in the flock. In
humans, social factors have therefore become the main source of stress reactions under
normal conditions. It is well acknowledged, that today, socially stressful conditions at
work or home are the major factors for a persistent harmful state of stress. Here, the
effectiveness of counteracting signalling systems to attenuate such stress response is of
great significance for the degree of harm that stressful factors may inflict on the
individual.
A prolonged stress response is detrimental in many ways. Stress reactions particularly in
the form of anxiety/fear reactions can eventually lead to depression and ultimately to the
development of dementia (4). Regarding physical injury, cardiac arrest is the most wellknown
endpoint. A commonly accepted mechanism is that stress leads to elevated blood
pressure and a risky blood fat profile, which jointly may cause the development of
cardiovascular disease due to atherosclerosis and blood clot formation (thrombosis) (5).
A stressful lifestyle with bad eating habits may exacerbate the damaging impact of the
hormonal arousal. However, other and more direct mechanisms may be involved in the
association between mental stress and cardiac death. Thus, in monkeys, cardiovascular
disease can be provoked by social stress without a concomitant development of
hypertension or metabolic abnormalities (6). Furthermore, a large mixed group of
American men and women have been studied, where their tendency to respond with
anger was associated with the occurrence of subsequent episodes of a heart attack. Here,
it was found that the most bad-tempered men and women had a 3 times greater
likelihood to experience a heart attack, even though they generally had a normal blood
pressure (7).
Poor regulation of the autonomic nervous system enhances the risk that psychological
stress may give rise to catastrophic health events. The autonomic nervous system
constitutes the nervous part of the regulatory systems for the brain to act on the internal
functions of the body. Hence, blood pressure and metabolism are largely regulated via the
autonomic nervous system. In contrast to hormone systems, it can act from second to
second which is necessary for the adjustment of blood pressure for instance when one
gets up. The term autonomous refers to the fact that the system may work independently
of the will. The autonomic nervous system is divided into two subsystems. One system is
the sympathetic nervous system, which already has been mentioned. This subsystem
increases the activity of the bodily functions that respond when the organism is
challenged – it could be increasing the heart rate. The second subsystem is referred to as
the parasympathetic nervous system. This system is primarily responsible for the
"household functions" such as digestion. The two subsystems are mostly working
simultaneously despite that they often act opposite to each other, e.g. parasympathetic
stimulation of the heart lowers its rate and reduces the strength of the beats.
Metaphorically expressed in many textbooks, the sympathetic system constitutes the
accelerator, while the parasympathetic system is the brake. The vagus nerve, which
branches widely into the body, is an essential part of the parasympathetic nervous
system.
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In social animals including humans, it is not only unfortunate social interactions but also
a lack of social stimuli, in general, that may constitute a stress factor that can be healthdamaging.
Thus, in a so-called meta-analysis, using data from some individual studies, it
was found that people with sparse social relationships had a 29% greater risk of
developing cardiovascular disease (8). In most of the studies which were included in the
meta-analysis, factors that may accompany loneliness, including behavioural factors such
as lack of exercise and poor diet, had been considered before calculating the risk effect of
social isolation itself.
Loneliness appears to result in a poorly functioning autonomic nervous system, which
may be an important mediator of its bad health effects. Such a mechanism is supported
by a study of middle-aged women, where individuals who scored low on social
relationships in a questionnaire exhibited a low heart rate variability (HRV) (9). A low
HRV is indicative of a low parasympathetic stimulation of the heart and presumably a
marker of low parasympathetic activity in general. HRV accounts for the variation that
occurs in the intervals between the heartbeats. These intervals vary from stroke to stroke,
partly as a result of breathing, which has a slight second-to-second impact on the blood
pressure receptors. Hereby, signals are transmitted via the vagus nerve to the heart sinus
node which instantaneously changes the heart rate. Thus, a low variation in heart rate is
an indicator of a relatively low potential for the parasympathetic nervous system to affect
the heart. Low HRV has been shown in many studies to be a risk marker for the
development of cardiovascular diseases (10).
Social isolation can also induce a low HRV in social voles. This was seen in an experiment
where the voles were isolated from their siblings in cages (11). However, the response in
HRV to the isolation could be counteracted if they were injected with oxytocin under their
skin every day. Oxytocin, on the other hand, had no effect on HRV in the mice being
allowed to stay with their siblings and therefore basically had a high HRV. Thus, oxytocin
appears to have the potential to alleviate some of the physical adverse effects that
loneliness may cause. Furthermore, an acute increase in HRV following administration of
oxytocin through the nose has been reported in human trials (12). In this case, however,
such an effect was seen only in those individuals who did not feel lonely. This may reflect
that the lonely individuals in this study may have had a poorer functioning oxytocin
system.
Apart from cardiovascular maladies, problems with the oesophagus and stomach is a
frequent result of mental and physical stress. Infection with the Helicobacter pylori
bacteria is the most frequent cause of gastric ulcer development, but a poor mental health
may increase the susceptibly for the disease substantially (13). In rodents, gastric ulcer
can be acutely induced when stressing the animals by water immersion in a restricted
space. In this model, the gastric damages were alleviated if oxytocin was infused into the
ventral tegmental area (14). As described in chapter 3, by sending dopamine carrying
nerve tracts to the nucleus accumbens, this part of the brain is an important part of the
reward system. Very interestingly, the protective effect against the gastric injuries by
oxytocin applied to the ventral tegmental area could be counteracted when a drug which
blocks the effect of dopamine was simultaneously infused into the nucleus accumbens.
This may mean that oxytocin's brain mediated protective mechanisms may share a
72
common neural platform with its pleasure functions. As I will return to, the vagal
signalling may have a pivotal role in the protection of not only the cardiovascular system
but also several other organ systems. Indeed, in the above-mentioned study, the
beneficial effect of oxytocin could also be abolished if lesions had been inflicted on the
dorsal motor nucleus of the vagus which is the major relay station between the brain and
the vagus nerve being situated in the brain stem. In other words, does oxytocin mediated
pleasure activate protective systems by neural avenues from brain to body?
The immune system is involved in cardiovascular disease
Malfunctions of the immune system are a major factor for the accumulating of material
in the walls of the blood vessels that can lead to constriction and thrombosis. Therefore,
a chronic state of inflammation in the vessels is, to a large extent, contributing to
cardiovascular disease.
Atherosclerosis can be perceived as an inflammatory reaction in the vessel wall (15).
There is no pain or redness, but the general elements of an inflammatory reaction are
present including inflow of white blood cells such as neutrophils and monocytes. These
cells, which are found in large quantities in the blood, form a significant part of our
nonspecific immune system. They can kill microorganisms by ejecting very aggressive
substances – the so-called "Reactive Oxygen Substances" or ROS. Monocytes can also eat
microorganisms and other unwanted material after being transformed into macrophages
(16). However, the presence of these cells is a necessary evil, as they can also inflict
substantial damage on our own otherwise healthy cells by exposing them to considerable
oxidative stress. (I will elaborate on ROS and oxidative stress later). Therefore, it is of the
utmost importance that the activity of certain immune cells is kept to the minimum of
what is required to fight unwanted biological activity in the body. For decades, it has been
recognized that oxidative stress is also a major factor in age-related degenerative
phenomena such as atherosclerosis, skin lesions, and type-2 diabetes (17). The activity
of the immune cells is controlled, inter alia, by cytokines, which are signalling agents that
act locally both mutually between the immune cells and between other cell types and the
immune cells (18). The latter communication occurs when immune cells in the blood are
called for from cells in damaged tissue.
In the case of atherosclerosis, the endothelial cells which form the innermost layer of the
blood vessels is disrupted. It may happen if these cells have been subjected to oxidative
stress beforehand. This causes them to call upon the monocytes, which at the same time
transform themselves into macrophages that invade the vessel wall. Before entering the
macrophages, they may have stuffed themselves with fat from the blood which they bring
along. Since this fat cannot just slip out again, it piles up (19). Also, systems that ensure
the coagulation of blood on a broken surface to form wound crusts can be faultily
activated. This creates a solid substance that narrows the blood vessel by thickening the
vessel wall at that site. Eventually, the cell layer toward the bloodstream may burst,
allowing the mass to be released into the blood. Such thrombus may subsequently cling
to narrow vessel sites and stop the blood flow to the tissue that is normally supplied by
the vessel.
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Immune cells are an important element in the development of atherosclerosis and
thrombosis.
The brain regulates the activity of the immune system.
Immune cells are equipped with receptors for a variety of signalling substances that
the brain uses directly and indirectly in its regulation of the body. This allows the brain
to influence immune responses both through nerves and hormones.
There are many indications that a chronic state of low-intensity inflammation
somewhere in the body can activate the immune system in a way that also triggers its
action elsewhere including the blood vessels. This may explain that prolonged
inflammation in the oral cavity increases the risk of cardiovascular disease (20). Such
"cross-reactions" illustrate the importance of an overall management of the immune
system. In this setting, the brain is the "chief executive officer". The immune cells are
controlled from both parts of the autonomic nervous system by being equipped with
receptors for signalling molecules used by both systems (norepinephrine for the
sympathetic and acetylcholine for the parasympathetic) (21). Regarding the
parasympathetic branch, the vagus nerve has been demonstrated in rats to have the
capacity for conveying a strong acute anti-inflammatory signal from the brain to the body
(22). However, the immune cells are also sensitive to hormones by having receptors for
cortisol (23) and oxytocin (24). The brain has therefore multiple options both to turn up
and down the immune activity (25). This applies also during stressful conditions.
Experiments with rhesus monkeys have demonstrated that if placed in socially unstable
groups the activity in the sympathetic nervous system will increase accompanied by
enhanced production of inflammatory cytokines from the immune cells (26). A link
74
between mental stress and immune activity has also been demonstrated in different
studies in humans, including a study on women who have had breast cancer. In this case,
collected immune cells had reduced the production of inflammatory cytokines during
stimulation if the women had participated regularly in yoga sessions over a few months
(27). In another study on hypertensive elderly patients, a reduction in blood pressure
was accompanied by a reduced production of inflammatory cytokines following a week's
stay in a forest with scheduled quiet walks. In contrast, no such effects were observed of
a similar arrangement in a city (28). These results indicate that measures to reduce
mental stress levels can influence the nervous system in a way that attenuates stress
reactions in the immune system.
Therefore, mental stress appears to affect the autonomic nervous system to cause
overactivity in certain functions of the immune system. In this way, immune cells may
inflict augmented oxidative stress on different tissue systems including the walls of the
blood vessels. This is a very plausible mechanism of action whereby mental stress can
lead to heart attacks. However, blood vessels are not the only system in the body that can
be damaged by mental stress in such away. Likely, a mental profile that makes the
individual prone to anxiety or aggressiveness may predispose for variety of other
diseases involving chronic inflammatory conditions including certain arthritis, skin and
bowel disorders, type-2 diabetes, and Alzheimer's.
Stress and metabolism
Chronic mental stress can lead to abnormalities in metabolism – including insulin
resistance – mediated by malfunctions of hormone- and the autonomic nervous
systems. This is an additional mechanism by which such stress can contribute to the
progress of cardiovascular diseases.
In addition to the over-stimulation of the immune function, a hyperactive sympathetic
nervous system may also promote the development of atherosclerosis by causing
metabolic disturbances. All organs of the body involved in fuel storage and mobilization
are controlled by the sympathetic nervous system through various types of receptors for
norepinephrine and adrenaline. This is true for fat, muscle, liver, and pancreas the latter
producing insulin and other metabolic hormones. The supply of these organs with nerve
endings from the sympathetic nervous system – in collaboration with the adrenal medulla
– constitutes an essential part of the control of fuel recruitment for the body. If you face a
dangerous situation, the activity in the sympathetic nervous system increases to ensure
that the muscles have enough fuel to run away from the lion or overcome a rival.
However, in modern society, we are usually not exposed to such a situation, but such
stress reaction is nevertheless preserved. If this state of stress is short-lived, it hardly
harms otherwise healthy individuals, but unfortunately, the sympathetic nervous system
can remain in a state of arousal for a long time if the condition is caused by mental stress.
This may chronically disrupt the management of fuel. Another system that is also
hyperactive during stress is the glucocorticoid system. This system, also being
indispensable for fuel regulation, operates by cortisol as previously mentioned. Increased
75
levels of cortisol are detrimental over time, in part because it accelerates the breakdown
of muscles (29) and bones (30).
Hyperactivity in the sympathetic nervous system and the glucocorticoid system can in
parallel deteriorate the fuel regulation in the body. Such dysfunction may translate into a
condition which is called the metabolic syndrome or insulin resistance syndrome because
it appears to have impaired insulin sensitivity as a focal point (31). Briefly, insulin is
increased in the blood because the pancreas must compensate for the resistance by
producing more insulin. Poor control of blood sugar is particularly revealed after
carbohydrate-rich meals, where blood glucose is elevated for an extended period despite
an increased insulin response. Since insulin also inhibits the release of fat from the fat
cells, abnormal levels of fat in the blood are also a consequence of insulin resistance. This
may amplify the embedding of fat into the walls of the vessels, which, in fact, also directly
suffers from the elevated insulin level. Furthermore, a vicious spiral may be established
as cortisol, in addition to lowering insulin sensitivity, acts on the brain by stimulating
hunger. This can lead to overeating and a dangerous form of obesity with excessive fat
deposits inside the abdominal cavity. From here, the release of fatty acids can directly
affect the liver by accelerating its insulin resistance. Furthermore, abdominal adipose
tissue may release a great number of inflammatory cytokines to the blood and therefore
promote a global state of elevated inflammation and therefore aggravate an already
present inflammation of the blood vessels. In addition to increasing the risk of
cardiovascular disease, insulin resistance can develop into overt type-2 diabetes, where
the insulin-producing cells no longer can cope with the resistance. In this situation, their
ability to perform the hard job may be hampered by attacks from overstimulated immune
cells as insulin-producing cells like endothelial cells are very vulnerable to inflammation.
For further reflection, associations are well established between insulin resistance on the
one hand and impaired liver function, abnormally elevated male sex hormones in women,
certain cancers, and mortality of severe virus infections, on the other.
76
Abdominal obesity can be a consequence of mental stress but can at the same time amplify
the adverse effects of the stress.
It is therefore not without reason that there is a great common awareness about the
adverse consequences of obesity. A rational approach to battle the overweight is
obviously to adjust the diet to prevent its development or to establish a weight loss in an
already overweight person. But in most cases, it probably does not dissolve an underlying
mental state of stress, which may not only have caused the overweight but which, by
itself, may induce insulin resistance (32) and malfunction of the immune system.
Therefore, it is might be appropriate to combat on two fronts, namely, to be conscious
about the diet and to assist the stress-relieving systems of the brain.
Oxytocin attenuates inflammatory reactions
Oxytocin can mitigate inflammatory conditions both via the blood and the
parasympathetic nervous system. Therefore, treatment with oxytocin can not only
attenuate inflammation reactions locally but also on a whole-body level being reflected
by its fever-reducing effect. The anti-inflammatory effect may not at least be important
in the brain, as it would inhibit processes that destroy nerve tissue. With age, this
destruction could otherwise lead to brain dysfunctions and ultimately dementia. In
particular, oxytocin may "leak out" from the production sites into the surrounding
areas of the hypothalamus. Maintaining a high production rate of oxytocin with age
may, therefore, postpone the erosion of important control functions exerted by the
hypothalamus. Many believe that such decay in the regulatory capacity of the brain may
play an important role in the development of age-related morbidities.
Talking about the cardiovascular disease but also other maladies in which chronic
inflammatory conditions are involved, the regulation of the immune system by the brain
plays a significant role. A deficient control caused by stress can, therefore, be an
important predisposing factor for these diseases. The glucocorticoid system has long
been known as an important moderator of immune responses. One of the most prominent
functions of cortisol as a hormone is to enable the brain to counteract an overreaction of
the immune system not a least in connection with infections (33). This is done by
increasing the production of cortisol in the adrenal glands by stimulation by ACTH, whose
secretion from the pituitary gland is, in turn, stimulated by CRF from the hypothalamus,
as previously described. This also means that drugs that mimic the effect of cortisol are
among the most important types of remedies to treat a variety of inflammatory
conditions. However, long-term treatment with such substances can unfortunately cause
side effects in the form of a disturbed metabolism as well as the loss of muscle and bone
mass. However, recent research has documented the presence of an important partner to
cortisol for the brain to control the immune system – namely oxytocin. Oxytocin is
probably an essential feed-back regulator of the nonspecific immune response (34).
Oxytocin activity is increased by elevated blood levels of pro-inflammatory cytokines,
which, in term, is resulting in a feedback effect on immune cells to reduce their production
of these cytokines (35). This can be done by oxytocin acting as a hormone via the blood.
77
However, oxytocin-carrying nerve pathways, in addition to hormonal oxytocin, are also
capable of delivering specific signalling agents that influence inflammatory responses
locally (36). Another nerve signalling pathway involving oxytocin may be via part of the
parasympathetic nervous system including the vagus nerve. The parasympathetic nerve
tracts originate from various nuclei in the brain stem, which receives input from the
oxytocin carrying nerves, as mentioned above (37). Immune cells in the nonspecific
immune system – including neutrophil cells – are equipped with receptors for
acetylcholine and are thus susceptible to signals from the parasympathetic nerve endings
(38).
The fact that oxytocin can attenuate a general inflammatory state of the body has been
demonstrated in humans. In this study, healthy men were exposed to lipopolysaccharide,
which naturally occurs in Coli bacteria and is often used to test inflammatory reactions
(39). This caused a mild global inflammatory response including a mild fever reaction.
However, the fever was reduced if the subjects also were treated with oxytocin into the
bloodstream. Fever is induced by the presence in the blood of some specific cytokines
secreted by immune cells. The response of some of these cytokines was reduced
accordingly during oxytocin administration. The global anti-inflammatory effect of
oxytocin has also been demonstrated in several animal infection models. In one study,
sepsis was introduced by perforation of the gut which led to multiple organ damages
associated with infiltration of immune cells into the different tissue. In this case, oxytocin
treatment was found to be protective with a dampening impact on neutrophils (40).
Oxytocin can also inhibit inflammatory reactions locally. This has been demonstrated in
an experiment with rats by the injection into a blister under the skin of a local irritant
consisting of carbohydrate from seaweed (41). If oxytocin was given together with the
carbohydrate, reduced cytokine response and less outflow of lymph fluid were seen.
The site where the ability of oxytocin to attenuate inflammatory reactions may be of most
importance is perhaps the brain itself. Chronic low-intensity inflammatory conditions in
various areas of the brain are thought to be a major factor in the development of both
depression and dementia disorders including Alzheimer's (42). The brain has its own
system of immune cells, which are made up of the so-called microglial cells, being a
special type of macrophages. These cells most often have a highly branched structure and
are closely connected physically to both bodies and extensions of the nerve cells. As is the
case for the peripheral immune cells, the functions of their counterpart in the brain are
to fight unwanted biological activity both in the form of microorganisms and
malfunctioning cells of the brain itself but also to remove debris. However, also in parallel
with other immune cells, they can cause great damage to healthy cells if they are not
under a strict regimen that prevents them from fostering a chronic low-grade
inflammatory state in the different brain areas. Furthermore, a particular function of the
microglia cells is to assist and regulate the formation and function of the synapses
between the nerve cells. Signal transmission between nerve cells via the synapses is
presumed to constitute the physical platform for learning and other cognitive processes
that I will return to. Therefore, poorly functioning microglia cells having an aberrant
production of inflammatory cytokines, may damage the nerve cells and consequently
different brain functions rather than supporting them (43). Microglia cell function may
be impaired with age, but mental stress may also be a major factor in which elevated
levels of cortisol and noradrenaline produced in the brain can induce overactivity of
microglia cells. Such mechanisms may help explain the relationship between mental
78
stress and the development of depressive states, where not only activity level but also
cognitive functions may be affected.
The brain appears to have been a major regulator of the individual life span of animals up
through the developmental history right down from the worm level, (although it may
disingenuous to speak about the brain of worms)(44). The brain uses exactly its capacity
to control immune functions to perform this assignment. For mammalian research, the
hypothalamus has naturally been addressed on this topic including its regulation of sex
hormones. It has been demonstrated that older mice have increased activity in one of the
signal cascades in the microglia of the hypothalamus which stimulates the production of
various inflammatory cytokines (45). However, if the function of this signalling system
was blocked exclusively in the microglia cells of the hypothalamus it resulted in bettermaintained
brain function – and even more interesting – muscle strength was also better
preserved with age relative to the control mice. At the same time, it was found that the
level of gonadotropin-releasing hormone (GnRH) that is produced in the hypothalamus
and stimulates sex hormone production did not decrease with age in the manipulated
mice, which is otherwise a general phenomenon in mammals. This decline in sex
hormones secondary to an impaired GnRH function may affect muscle and bone function
but more general degenerative processes may also be in play involving an age-dependent
elevation in the global low-intensity inflammation level. This applies not least to changes
that can lead to insulin resistance and type-2 diabetes (46) since the hypothalamus in
collaboration with the pancreas is a key player in the blood sugar regulation.
In mice experiments, prior treatment with oxytocin through the nose has been found to
suppress inflammatory reactions in the frontal lobes provoked by the administration of
lipopolysaccharide into the abdominal cavity (47). In addition to reducing the production
of inflammatory cytokines, the oxytocin counteracted the likelihood of microglia cells to
adopt a shape being characteristic for an activated mode at this location. The same article
reported from experiments in which cultured microglial cells were exposed to
lipopolysaccharide and/or oxytocin. These experiments confirmed the ability of oxytocin
to attenuate the inflammatory cytokine reaction of such cells. Interestingly, oxytocin was
also found to dampen the cell's response to the mitogen-activated protein kinase (MAPK)
signalling cascade. This signalling cascade is an important element in immune cell
inflammatory responses, as its activation ultimately leads to an increased reading of
genes encoding a variety of inflammatory cytokines. (An in-depth explanation of cellular
signal cascades can be found in chapter 10). A possible downgrade of this particular
cascade has gained considerable attention to the development of medical treatment for
dementia (48), and from a recent study, it has been reported that treatment of
Alzheimer's patients with a substance that blocks the MAPK signal cascade improved
their memory (49). However, for good reason just in passing, it should be mentioned that
the effect of oxytocin on this particular signal cascade is a very long story, as oxytocin, in
fact, may stimulate this cascade in other cell types, where it then can result in growth and
regeneration of different tissues. This may be an important mechanism in the activation
of stem cells by oxytocin for instance in the context of muscle regeneration (50).
A nerve-protective effect of oxytocin may, indeed, have the potential to counteract the
progress of the major degenerative brain diseases. In a recent study where dopamine
carrying nerves were poisoned by the neurotoxin MPTP in mice as a model for
79
Parkinson's disease co-administration of oxytocin could reduce the loss of such nerves
and restore normal mobility in the mice (51). However, clinical studies in which oxytocin
has been tested on a long-term basis in an attempt to delay the development of
degenerative brain diseases do not yet appear in the literature. Testing oxytocin on
people with dementia seems to be limited to short-term studies in which the ability to
interpret emotional signals has been investigated. In one of these studies, an
improvement in such functions was observed after one week (52). However, this could
be attributed to the acute psychiatric effects of oxytocin rather than a nerve-protective
effect.
The brain is the most important oxytocin-producing organ, where, as previously
mentioned, oxytocin-carrying nerve tracts expand from the hypothalamus to probably
most corners of the brain. Furthermore, with appropriate stimulation, magnocellular
nerve cells may almost bathe the hypothalamus with oxytocin. Speculation about the
potential of oxytocin as a general brain protector, including the preservation of
hypothalamic resilience may, therefore, be obvious. In this context, the loss of functional
nerve stem cells in the hypothalamus appears to be an important factor in the aging
processes. By accelerating the breakdown of stem cells in the hypothalamus of mice, the
aging processes could be accelerated not only in the brain but also translated into a loss
of muscle strength and a reduced life span (53). Conversely, a general delay of aging was
reported in the same article if nerve stem cells from new-born mice were implanted into
this brain area provided that the cells had been engineered to withstand oxidative stress.
The protecting and stimulating potential of oxytocin on stem cells (see below) may be
tantamount to a restorative capacity of the peptide, not at least concerning the
hypothalamus. However, this remains highly important to be investigated. In any case, a
well-preserved hypothalamus in the elderly may mean that he or she would stay fit into
advanced age. Especially for women, it should be emphasized that oxytocin activity may
decrease by menopause, as estrogen – which stimulates oxytocin production – falls of at
that time. This, in turn, may compromise the GnRH function and further slowdown the
release of estrogen.
With the knowledge of the very close association between the integrity of the
hypothalamus and the general state of health, one could be tempted to propose a
conceptual shift in our understanding of fitness, with a focus on hypothalamic fitness just
as much as cardiovascular fitness – and act accordingly. However, as stated below, effects
on the brain are not the only thing oxytocin has in its repertoire to counteract aging.
1. Litscher G. Ten years evidence-based high-tech acupuncture part 3: A Short
Review of Animal Experiments. Evidence-Based Complementary and Alternative
Medicine 2010; 7(2): 151-155.
2. Uvnäs-Moberg K, Bruzelius G, Alster P, Lundeberg T. The antinociceptive effect of
non-noxious sensory stimulation is mediated partly through oxytocinergic
mechanisms. Acta Physiologica Scandinavica 1993; 149(2): 199-204.
3. Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response.
Annual Review of Physiology 2005; 67: 259–284.
80
4. Johansson L, Guo X, Waern M, Ostling S, Gustafson D, Bengtsson C, Skoog I. Midlife
psychological stress and risk of dementia: a 35-year longitudinal population study.
Brain 2010; 133(Pt 8): 2217-2224.
5. Rosmond R. Role of stress in the pathogenesis of the metabolic syndrome.
Psychoneuroendocrinology 2005; 30(1): 1-10.
6. Kaplan JR, Manuck SB, Clarkson TB, Lusso FM, Taub DM, Miller EW. Social stress
and atherosclerosis in normocholesterolemic monkeys. Science 1983; 220(4598):
733-735.
7. Williams JE, Paton CC, Siegler IC, Eigenbrodt ML, Nieto FJ, Tyroler HA. Anger
proneness predicts coronary heart disease risk: prospective analysis from the
atherosclerosis risk in communities (ARIC) study. Circulation 2000; 101(17):
2034-2039.
8. Valtorta NK, Kanaan M, Gilbody S, Ronzi S, Hanratty B. Loneliness and social
isolation as risk factors for coronary heart disease and stroke: systematic review
and meta-analysis of longitudinal observational studies. Heart 2016; 102(13):
1009-1016.
9. Horsten M, Ericson M, Perski A, Wamala SP, Schenck-Gustafsson K, Orth-Gomér K.
Psychosocial factors and heart rate variability in healthy women. Psychosomatic
Medicine 1999; 61(1): 49-57.
10. Thayer JF, Yamamoto SS, Brosschot JF. The relationship of autonomic imbalance,
heart rate variability and cardiovascular disease risk factors. International Journal
of Cardiology 2010; 141(2): 122-131.
11. Grippo AJ, Trahanas DM, Zimmerman RR, Porges SW, Carter CS. Oxytocin protects
against negative behavioral and autonomic consequences of long-term social
isolation. Psychoneuroendocrinology 2009; 34(10): 1542-1553.
12. Norman GJ, Cacioppo JT, Morris JS, Malarkey WB, Berntson GG, Devries AC.
Oxytocin increases autonomic cardiac control: moderation by loneliness.
Biological Psychology 2011; 86(3): 174-180.
13. Levenstein S, Rosenstock S, Jacobsen RK, Jorgensen T. Psychological stress
increases risk for peptic ulcer, regardless of helicobacter pylori infection or use of
nonsteroidal anti-inflammatory drugs. Clin Gastroenterol Hepatol. 2015; 13(3):
498-506.
14. Leng H, Zhang X, Wang Q, Luan X, Sun X, Guo F, Gao S, Liu X, Xu L. Regulation of
stress-induced gastric ulcers via central oxytocin and a potential mechanism
through the VTA-NAc dopamine pathway. Neurogastroenterol Motil. 2019 31(9):
e13655
15. Chung I. Stress-Induced Atherosclerosis: Clinical evidence and possible
underlying mechanism. Korean Circulation Journal 2005; 35: 101-105.
16. Beutler B. Innate immunity: an overview. Molecular Immunology 2004; 40: 845–
859.
17. Cross CE. Oxygen Radicals and Human Disease. Annals of Internal Medicine. 1987;
107: 526-545.
18. Sokol CL, Luster AD. The Chemokine System in Innate Immunity. Cold Spring
Harbor. Perspectives in Biology. 2015; 7.
19. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell;
145(3): 341-355.
20. Stöllberger C, Finsterer J. Role of infectious and immune factors in coronary and
cerebrovascular arteriosclerosis Clinical and Diagnostic Laboratory Immunology
2002; 9(2): 207-215.
81
21. Kenney MJ1, Ganta CK. Autonomic nervous system and immune system
interactions. Comprehensive Physiology 2014; 4(3): 1177-1200.
22. Borovikova LV, Ivanova S, Nardi D, Zhang M, Yang H, Ombrellino M, Tracey KJ.
2000. Role of vagus nerve signaling in CNI-1493-mediated suppression of acute
inflammation. Autonomic Neuroscience: Basic and clinical 85(1-3): 141-147.
23. Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive
effects of glucocorticoids, recent developments and mechanistic insights
Molecular and Cellular Endocrinology 2011; 335(1): 2-13.
24. Ndiaye K, Poole DH, Pate JL. Expression and regulation of functional oxytocin
receptors in bovine T lymphocytes. Biology of Reproduction 2008; 78(4): 786-
793.
25. Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic antiinflammatory
pathway: a missing link in neuroimmunomodulation. Molecular
Medicine 2003; 9(5-8): 125-134.
26. Capitanio JP, Cole SW. Social instability and immunity in rhesus monkeys: the role
of the sympathetic nervous system. Philosophical Transactions of the Royal
Society of London. Series B, Biological Sciences 2015; 370(1669).
27. Kiecolt-Glaser JK, Bennett JM, Andridge R, Peng J, Shapiro CL, Malarkey WB, Emery
CF, Layman R, Mrozek EE, Glaser R. Yoga's impact on inflammation, mood, and
fatigue in breast cancer survivors: a randomized controlled trial. Journal of Clinical
Oncology 2014; 32(10): 1040-1049.
28. Mao GX, Cao YB, Lan XG, He ZH, Chen ZM, Wang YZ, Hu XL, Lv YD, Wang GF, Yan J.
Therapeutic effect of forest bathing on human hypertension in the elderly. Journal
of Cardiology 2012; 60(6): 495-502.
29. Hasselgren P. Glucocorticoids and muscle catabolism. Current Opinion in Clinical
Nutrition and Metabolic Care 1999; 2(3): 201-205.
30. Raff H, Raff JL, Duthie EH, Wilson CR, Sasse EA, Rudman I, Mattson D. Elevated
salivary cortisol in the evening in healthy elderly men and women: correlation
with bone mineral density. The journals of gerontology. Series A, Biological
sciences and medical sciences 1999; 54(9): M479-483.
31. Kaur J. A Comprehensive Review on Metabolic Syndrome. Cardiology Research
and Practice 2014.
32. Li L, Li X, Zhou W, Messina JL. Acute psychological stress results in the rapid
development of insulin resistance. Journal of Endocrinology 2013; 217(2): 175-
184.
33. Silverman MN, Sternberg EM. Glucocorticoid regulation of inflammation and its
functional correlates: from HPA axis to glucocorticoid receptor dysfunction.
Annals of the New York Academy of Sciences 2012; 1261: 55-63.
34. Li T, Wang P, Wang SC, Wang YF. Approaches Mediating Oxytocin Regulation of
the Immune System. Frontiers in Immunology 2017; 7: 693.
35. Oliveira-Pelegrin GR, Saia RS, Cárnio EC, Rocha MJ. Oxytocin affects nitric oxide
and cytokine production by sepsis-sensitized macrophages.
Neuroimmunomodulation 2013; 20(2): 65-71.
36. Summy-Long JY, Hu S, Long A, Phillips TM. Interleukin-1β release in the SON area
during osmotic stimulation requires neural function. Journal of
Neuroendocrinology 2008; 20(11): 1224–1232.
37. Llewellyn-Smith IJ, Kellett DO, Jordan D, Browning KN, Travagli RA. Oxytocinimmunoreactive
innervation of identified neurons in the rat dorsal vagal complex.
Neurogastroenterology and Motility 2012; 24(3): e136-146.
82
38. de Jonge WJ1, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a
pharmacological target for inflammation. British Journal of Pharmacology 2007;
151(7): 915-929.
39. Clodi M, Vila G, Geyeregger R, Riedl M, Stulnig TM, Struck J, Luger TA, Luger A.
Oxytocin alleviates the neuroendocrine and cytokine response to bacterial
endotoxin in healthy men. American Journal of Physiology. Endocrinology and
Metabolism 2008; 295(3): E686-E91.
40. Işeri SO, Sener G, Saglam B, Gedik N, Ercan F, Yegen BC. Oxytocin protects against
sepsis-induced multiple organ damage: role of neutrophils. Journal of Surgical
Research 2005; 126(1): 73-81.
41. Ghadrdan E, Najafi M, Mirak SM, Eteraf-Oskouei T. Inhibitory effects of oxytocin
on the inflammatory parameters and vascular endothelial growth factor (VEGF)
in the rat air pouch model of inflammation. Physiology and Pharmacology 20
(2016) 48-56.
42. Santos LE, Beckman D, Ferreira ST. Microglial dysfunction connects depression
and Alzheimer's disease. Brain, Behavior, and Immunity 2016; 55: 151-165.
43. Piirainen S, Youssef A, Song C, Kalueff AV, Landreth GE, Malm T, Tian L.
Psychosocial stress on neuroinflammation and cognitive dysfunctions in
Alzheimer's disease: the emerging role for microglia? Neuroscience and
Biobehavioral Reviews 2017; 77: 148-164.
44. Bouchard J, Villeda SA. Aging and brain rejuvenation as systemic events. Journal
of Neurochemistry 2015; 132(1): 5-19.
45. Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D. Hypothalamic
programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 2013;
497(7448): 211-216.
46. Tang Y, Purkayastha S, Cai D. Hypothalamic microinflammation: a common basis
of metabolic syndrome and aging. Trends in Neurosciences 2015; 38(1): 36-44.
47. Yuan L, Liu S, Bai X, Gao Y, Liu G, Wang X, Liu D, Li T, Hao A, Wang Z. Oxytocin
inhibits lipopolysaccharide-induced inflammation in microglial cells and
attenuates microglial activation in lipopolysaccharide-treated mice. Journal of
Neuroinflammation 2016; 13(1): 77.
48. Lee JK, Kim NJ. Recent Advances in the Inhibition of p38 MAPK as a Potential
Strategy for the Treatment of Alzheimer's Disease. Molecules 2017; 22(8): E1287.
49. https://aanddjournal.net/article/S1552-5260(17)33113-8/pdf
50. Elabd C, Cousin W, Upadhyayula P, Chen RY, Chooljian MS, Li J, Kung S, Jiang KP,
Conboy IM. Oxytocin is an age-specific circulating hormone that is necessary for
muscle maintenance and regeneration. Nature Communications 2014; 5: 4082.
51. Almansoub HAMM, Tang H, Wu Y, Wang D-Q, Mahaman YRA, Salissou MTM, Lu Y,
Hu F, Zhou L-T, Almansob YAM, Liu D. Oxytocin Alleviates MPTP-Induced
Neurotoxicity in Mice by Targeting MicroRNA-26a/Death-Associated Protein
Kinase 1 Pathway. J Alzheimers Dis 2020; 74(3): 883-901.
52. Jesso S, Morlog D, Ross S, Pell MD, Pasternak SH, Mitchell DG, Kertesz A, Finger EC.
The effects of oxytocin on social cognition and behaviour in frontotemporal
dementia. Brain 2011; 134(Pt 9): 2493-2501.
53. Zhang Y, Kim MS, Jia B, Yan J, Zuniga-Hertz JP, Han C, Cai D. Hypothalamic stem
cells control ageing speed partly through exosomal miRNAs. Nature 2017;
548(7665): 52-57.
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Chapter VI

hertilhertil
"Would you like to go home with me and differentiate our T lymphocytes?"
Tests of immature immune cells have shown that oxytocin can promote their
differentiation also with regard to the selection for a specific antigen. A wellfunctioning
immune system is vital and characterized by the ability to respond swiftly
and accurately to the antigens we are exposed for.
"Sex is good for the immune system" has become a general mantra, and there is probably
something about it. Although the oxytocin system may, to some extent, attenuate the
nonspecific immune response, it appears to have the potential to enhance the adaptive
immune function. Briefly, the adaptive immune function is the part of the immune
function that is activated only after special immune cells have detected the presence of a
particular antigen – this could be part of a protein on a particular virus. This allows the
immune system to put full sail into the battle against that very invader. The adaptive
immune system consists of two major classes of immune cells: the B-lymphocytes and the
T-lymphocytes. The function of B-lymphocytes is to produce and release antibodies to the
blood. These antibodies make life tough for the invader by binding to it, thereby
preventing it from binding to the surface of our cells. Also, by having antibodies bound to
them the invaders may be made more "delicious" for other types of immune cells that eat
them. The job of T-lymphocytes includes the killing of the body's cells, which have been
infected with a virus as well as cancer cells. Furthermore, they produce cytokines that
invoke other immune cells and stimulate the B-lymphocytes that respond to that antigen.
This causes the B-lymphocytes to divide and produce more antibodies. The adaptive
immune function is also called the acquired immune system because it remembers the
encounter with the specific invader for a long time – in some cases throughout life. This is
what we exploit in vaccinations where we inject harmless antigens from the pathogen
into the blood.
A macrophage engulfing
a pathogenic fungal cell.
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The lymphocytes start their development from stem cells, which are mostly located in the
bone marrow. A stem cell is a cell that is capable to evolve into several different types of
cells by differentiation. Once this has happened, there is usually no going back. The
differentiation into a lymphocyte which is capable of responding to particular antigen
proceeds in several steps. Stem cells, which have the potential to develop into all sorts of
blood cells including red blood cells, initially differentiate into a particular type of blood
cell, this could be a B- or T-lymphocyte (1). From there, the lymphocyte differentiates
toward the specific antigen that the cell is going to target (2). It has been found that Tlymphocytes,
in particular, are well-equipped with oxytocin receptors, even before they
are fully differentiated (3). In this context, a hypothesis is that oxytocin plays an
important role in counteracting the formation of clones of immune cells that attack the
organism itself during fetal development (4). By the way, the ability of oxytocin to
influence the differentiation of various other types of stem cells has been disclosed, which
I will return to. Oxytocin has also been found to promote the growth of cells of different
types, that is, their dividing rate after they have been differentiated. This could very well
also apply to the lymphocytes.
Also, oxytocin may play a role in enhancing the responsiveness of mature lymphocytes to
antigens in adult humans. Phytohemagglutinin – a lectin found in legumes – is often used
to test the ability of immune cells to respond to antigens. This can be done by collecting
the lymphocytes from the blood and then assess to which extent the immune cells are
activated when phytohemagglutinin is added to their medium. Such a test has been done
in an experiment where oxytocin was given to lymphocytes taken from the blood of
healthy women (5). As expected, the phytohemagglutinin stimulated the cells to produce
receptors for interleukin-2 but their response could be amplified by oxytocin.
Interleukin-2 is a cytokine that plays an important role in activating the adaptive immune
response. Immune cells that respond to an antigen become sensitized for interleukin-2
by producing and embedding receptors for interleukin-2 in their cell membrane. The
activated immune cells are stimulated through the interleukin-2 receptor to divide and
form the antibody in question but also to produce more interleukin-2 themselves.
Concomitantly to boost the production of interleukin-2 receptors, oxytocin also appeared
to make a greater number of lymphocytes to go into cell division mode. Hopefully, this
single study will soon be followed by more research that can confirm these results at
other conditions and elucidate whether the effect has a true biological significance which
may be relevant in a pharmacological context. Research on how the immune system can
remain strong throughout life will become increasingly important in a future with more
widespread pandemic virus diseases and pan-resistant bacteria which are particularly
lethal for older people.
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We are programmed to decay
The body is constantly under attack by chemicals that can damage different
components of our cells including the DNA. Furthermore, errors can occur every time
the DNA is copied in connection with cell divisions. If several consecutive errors occur
in a very unfortunate way, it results in malfunction of the cell and, at worst, the cell may
transform into a cancer cell. It is therefore very important that the cells have high
performing DNA repair systems that constantly monitor the DNA. However, eventually,
the damage of the cell proteins and membranes becomes so great that the death of the
cell is the only solution. The destroyed cells may then be replaced by new cells formed
by division. However, normal cells can only divide a certain number of times. This is
because the end of the chromosomes – the so-called telomeres – are shortened each
time the DNA is copied before the division. Therefore, in most tissues, there are
undifferentiated stem cells that, at a certain signal, can differentiate and replace the
worn-out cell lines. However, these stem cells also degenerate as the organism ages
compromising their ability to differentiate. Therefore, postponing such decay of the
stem cells is essential for the delay of the aging processes.
The integrity of tissues and organs is sustained by cell division, replacing dead cells with
new ones. But these cells are, in fact, not entirely new as their DNA has been formed by
copying the DNA of the mother cell. Despite that the cells are equipped with meticulous
proof-readers correcting for errors that might occur during the reading of the DNA, faults
may rarely happen when these incredibly long molecules are manufactured. This may
result in faulty functions of the daughter cell. If such errors occur through several
consecutive cell divisions in a very unfortunate way, we can eventually end up with a
cancer cell. This can happen if some DNA has been affected, that encodes for the control
of cell division processes or communication with the outside world (6). However, in the
vast majority of cases, the cell would have killed itself or have been killed by the immune
system long before it comes so far. However, the potential for self-destruction can also be
impaired and is one of the major characteristics of a cancer cell.
As DNA reading errors can occur every time a cell divides, cells that have been through
many divisions will be at the greatest risk of developing into a cancer cell. Therefore, it is
most often in organs where cell divisions are frequent such as the gut that cancer appears
while bone cancer in at least adult people is very rare. This is believed to be one of the
explanations why elderly people are most prone for developing a cancerous disease as
their cells, on average, have gone through a larger number of divisions.
Cells – dependent on their type – are only able to divide a certain number of times. This is
because the so-called telomeres are truncated each time the DNA strands (chromosomes)
are copied. Telomeres are a specific type of DNA situating at the end of all the
chromosomes which is crucial for their coherence. Therefore, cell divisions cease when
the telomeres have become so short that they can no longer stabilize the chromosomes.
It is believed that the shortening of the telomeres is an important factor in the general
aging of the body because the cells of older people have undergone a greater number of
divisions. Thereby, there should be fewer cells available with their telomeres long enough
88
to divide and thereby keep the stock of functional cells in the tissues straight. However,
some researchers have recently questioned a direct link between the shortening of the
telomeres and the limited lifespan (7).
Certain cell types have enzymes called telomerases which are capable of restoring the
telomeres, so that cell lines in principle achieve immortality. Telomerase activity is a
property that cancer cells can acquire. The so-called HeLa cells, which are still widely
used around the world today in cell cultures for research originate from a cervical cancer
tumour in a patient – Henrietta Lacks – who died in 1951 (8). But stem cells in healthy
individuals also possess telomerase activity to a greater or lesser degree dependent on
stem cell type (9). As I elaborate below, adult stem cells generally serve as a resource for
renewal of cell lines that are no longer viable – perhaps exactly because their telomeres
have become too short. This may explain why the hypothesis of too short telomeres as an
explanation for aging and death does not always hold true.
If, however, the lack of divisible cells is a major explanation for the deterioration of aging
organs – could older people then be treated with telomerases to revitalize their remaining
cells? In this regard, one must make the reservation that, in theory, a cancerous disease
may be provoked by such an effort. Thus, it has been proposed that the last bulwark
against the development of malignancy in a cell line might exactly be the termination of
cell divisions due to short telomeres. Cells in such a cell line may already have divided an
abnormal number of times as their normal suicide mechanisms could be impaired due to
the DNA disturbance (10). If the telomerase activity has not yet been re-established by
further mutations, telomere shortening might be the only thing left to stop such cells. One
hypothesis suggests that complicated multicellular organisms have had to give up on
immortality exactly to keep the development of naughty cells at bay.
The individual cells are aging just like the whole organism that hosts them. Their proteins,
fats, or DNA eventually starts malfunctioning, partly due to the oxidative stress being
exerted on the cells (11). (I explain the concept of oxidative stress later). Fortunately, the
cells are equipped with various enzyme systems, which most often are successful in
repairing various types of damage – not least those on the DNA. This applies to both the
DNA in the cell nucleus and the mitochondria. These systems are constantly monitoring
the state of the DNA, and as soon as a bug is detected, it is repaired by a specific enzyme
capable of handling just that type of irregularity (12). The function of these DNA repair
systems is very crucial for the maintenance of the whole organism as genetic defects in
the systems can cause a marked acceleration in the development of age-degenerative
diseases (13). Also, the activity of the repair systems is regulated by signalling systems
inside the cells which, in turn, are influenced by different signalling substances outside
the cell. Therefore, certain hormones and cytokines have, to some extent, the potential to
influence the maintenance and hence the aging processes of the tissues (hereafter).
89
DNA repair is an intricate process
Eventually, repairing the worn-out cell is no longer useful and it loses its ability to fulfil
its mission satisfactorily. Then it does what is common in the older Japanese culture; it
sacrifices itself for the community. The phenomenon is called apoptosis or programmed
cell death. Often, the cell by itself starts the series of various mutually dependent events
that finally result in its death, but in other cases, it needs help to die from the outside. This
assistance comes from the macrophages constituting an important cell type of the
immune system. The macrophages are in this case invoked by inflammatory cytokines
released from the moribund cells (14). Unfortunately, the apoptosis mechanisms also
happen to be triggered in stressed but otherwise healthy cells. This may worsen the
condition associated with coronary thrombosis in the heart where the muscle cells may
suffer from oxygen shortage.
Thus, in addition to fighting foreign invaders, the immune system must also be able to
keep track of the body's own troops. One problem is that the cells of the immune system
also grow old over time and thus becoming less effective at cleaning up. In this way, the
amount of ineffective so-called senescent cells in the tissues increases. Such senescent
cells may therefore be allowed to dominate the cellular environment by doing nothing
but to stress the remaining well-functioning cells by secreting inflammatory substances
(15). I will leave it up to the reader whether analogies to the society should be drawn
90
here. So, what about the stem cells of the immune system, can't they be recruited to fix
this misery? To a certain extent yes, depending on the type of tissue we are talking about.
But even though stem cells are equipped with telomerase, their telomeres can also
degenerate over time due to oxidative damage. They therefore eventually also lose their
ability to differentiate, divide, and form new cell lines, which I will come back to. Oxytocin
supports the differentiation and growth of different types of stem cells (see below).
Furthermore, it both stimulates antioxidant and inhibits prooxidant systems in the cells
(16). These effects may be very profitable for tissue preservation. Regarding the renewal
function of the macrophages, the ability of oxytocin to stimulate the differentiation of Tlymphocytes
may be advantageous as T-lymphocytes and macrophages work in a close
partnership.
Aging and stem cells
Aggressive substances produced by oxygenation processes impose oxidative stress on
our cells. This is the most important factor in the chemical attack on the cell
components. Stem cells residing in the tissue play a major role in counteracting such
assaults. However, damage to the DNA of the stem cells themselves may compromise
the ability of the tissue to restore the injuries.
As cardiologists and oncologists become better and better at treating the major killer
diseases, the average age and number of citizens with a high age grows significantly. To
prevent a disproportionally large amount of the citizens relying on transfer payments,
the politicians are forced to keep on raising the retirement age. The problem is that the
working skills of the people are not necessarily extended accordingly since the general
decay of the body is not necessarily delayed to the same extent as is death. So, in the
future, we may have a group of citizens between the ages of 65 and 80, who have to
remain in the labour market, although their muscles, bones, and brain may not be suitable
for it anymore. When they finally are allowed to retire, their organ systems are so
degraded that there are hardly left any options for joy. At that time, they may rather look
forward to a long period of maybe 15 years spent in a nursing home with dementia and
bones that relentlessly break until they finally can pass away at the age of 100. Everyone
can see that this is not an optimal scenario. Therefore, we must find ways to delay the
aging processes in the brain, skeletal muscles, bones, and immune system if cancer- and
heart-doctors should be allowed to extend our lives for so long.
91
The major manifestation of aging is a progressive general decline in the ability of the
different body tissues to regenerate. The function of the organs gradually deteriorates:
the strength of the muscles and bones decreases, the elasticity of the skin and its ability
to withstand mechanical impacts and heal itself declines, the potential of the immune
system to defend us crumbles, etc. – etc. All of this is because our cells are becoming less
and less capable to divide and replace those cells that are no longer functioning.
Particularly, a reduced capacity of the stem cells to differentiate can be observed,
whereby the whole foundation for tissue restorage vanishes. The reason for this misery
is probably changed in the stem cells themselves but also their environment (17).
Several hypotheses try to explain why our cells including the stem cells degenerate in
this way, but repeated chemical assaults on their control systems, not at least the DNA,
are considered a pivotal factor (18). Thus, the exposure to oxidative stress may be of
great importance for these injuries on the cells to occur (19).
I have already mentioned stem cells in connection with the immune system, where
oxytocin plays a role in the differentiation of T-lymphocytes, but stem cells are about
many other things than immune cells. The so-called mesenchymal stem cells, found in
almost all kinds of tissue, can differentiate into a lot of different types of cells (20). Stem
cells, as already described, are cells that are not completely differentiated. Therefore, they
do not participate in the daily household of the tissue, but they can take action by
differentiating themselves so new dividing cell lines can be established of the cell type
being currently needed. In this way, most cell systems in the body can renew themselves
to some extent.
As is the case for the formation of T-lymphocytes, any type of cell develops through a
series of cell divisions, with the daughter cells becoming more and more differentiated.
The differentiation can be observed by the cells gradually approximating the targeted
Few people want to spend
their last years in this way.
92
type of cell. This is because they to greater and greater extent form proteins that are
specific for that cell type. This is a result of the genes being read is becoming more and
more focused. For instance, there are cells of different levels of differentiation in the
muscles that can take action and restore the fibres in connection with daily wear or actual
damage (21). In the case of muscle, the final differentiation occurs when cells begin to
form contractible fibre proteins.
Thus, it is possible to determine whether cells of a particular type are present based on
whether mRNA strands appear corresponding to a protein being specific to the given cell
type. The mRNA strands are formed when genes are read in the cell nucleus. The mRNA
strand subsequently passes out into the cytoplasm where it constitute a code for the
protein chain to be produced. The protein production is carried out by enzymes linking
the different amino acids in the order dictated by the mRNA. The cell can regulate its
production of the various proteins by adjusting how much of the actual mRNA that is
formed. When talking about the production activity of a particular protein in a cell
system, it is most often determined by measuring the amount of the corresponding
mRNA.
Which cell type a stem cell differentiates to is determined by several factors. In particular,
it is important what types of cells that there are situated in its environment or perhaps it
has direct contact with. Mesenchymal stem cells from the bone marrow can even find
their way to a damaged heart muscle if they simply are injected into the blood (20). Here,
under appropriate circumstances, they may differentiate into cardiac muscle cells and
thus repair the damage. Stem cells have now, to a great extent, been introduced either
experimentally or as established treatment for several degenerative diseases in the
organs, including the heart, musculoskeletal system, nervous system, pancreas, and
immune system (22).
Human mesenchymal stem cells can differentiate into a variety of cell types
93
In addition to delivering "fresh" cells to the tissues as a replacement for worn-out cells by
differentiation, stem cells also appear to have an equally important function in secreting
cytokines that counteract the degeneration of fully developed cells in their environment.
Attenuating the inflammatory responses of the nearby immune cells is part of this effect
(23).
An increased understanding of the mechanisms that influence the aging of the stem cells
may, therefore, be of great importance. Being essential for the life-long maintenance of
different tissues and thereby the functions of the whole body, the ability of the stem cells
to preserve their capacity to differentiate and divide is a measure for the biological age of
the organism. Although the environment does not place high demands on stem cells
before they are recruited, they have a metabolism and are exposed to various stressors
like other cells. Over time, they therefore also become aged and inferior to renew
themselves. Factors in the stem cell environment, but also innate characteristics of the
stem cells, may, therefore, be decisive for the rate of aging of various tissues and thus for
the whole individual. Accelerated stem cell degeneration is now believed to be a major
factor in progeria diseases, which are characterized by extremely rapid aging (24).
Indeed, as the health of the stem cells plays such a pivotal determining role for the rate of
aging, actions that protect and stimulate these cells are a popular area of research (25).
In this regard, different types of stem cells are sensitive to factors such as behaviour,
environment and, not least, signalling substances in the blood.
As already mentioned, oxidative damage to the telomeres of the stem cells may impair
their capacity to divide and restore the tissue. The telomeres constitute the part of the
chromosomes where the DNAs are most susceptible to oxidative assault and cause them
to be truncated without any cell division. In other words, one journey of a ten-journey
ticket has been used even though one has not been out. Oxidative damage on the
telomeres is likely to contribute to the aging process in all our cells, but especially for the
stem cells, oxidative assaults on the telomeres may impair them from being prolonged by
the telomerases (26). Indeed, a greater risk for developing degenerative disorders such
as cancer, type-2 diabetes, and cardiovascular disease later in life has been found in
middle-aged people with a short telomere length in blood cells (27). Again, this
underlines a preserved capacity to replenish cellular systems as essential for the
prevention of age-related diseases. Possessing stem cells with long telomeres, not at least
those belonging to the immune system, may, therefore, be essential for a healthy old age.
Oxytocin as a youth elixir?
Oxytocin is essential for both bone and muscle to maintain its mass and strength. The
fact that osteoporosis typically develops in women after menopause is probably due to
a decrease in oxytocin, which in turn is due to a reduced oestrogen level. The effect of
oxytocin is by stimulating bone and muscle stem cells to differentiate. Oxytocin has a
potent capacity to promote tissue defence against oxidative stress which comprehends
the strengthening of the stem cells.
94
The blood circulation of two different animals can be joined if it is ensured that there is
no mutual rejection, e.g. the blood types must match. When an old mouse is paired with a
young in a way that blood is shared between them the old mouse begins to exhibit more
youthful features in terms of heart, muscles, nerves, and behaviour (28). Therefore,
factors must be present in the blood of the younger animals having rejuvenating effects.
Although such so-called parabiotic trials have been conducted since the middle of the
19th century, it is remarkable that these kinds of experiments only in recent years have
been granted a place in aging research. Now, of course, there is a great interest in
identifying these rejuvenating substances, as they must have a beneficial effect on the
growth and maintenance of a number of the various cell systems in the body. If fact, a
research program is ongoing to investigate whether the donation of blood plasma
achieved from young people to patients with Alzheimer's can retard the progression of
the disease (29). Here, a single pilot study has been encouraging (30).
Parabiosis experiment
Can oxytocin be among the putative rejuvenating agents by its potential to evoke different
types of stem cells? Oxytocin has not yet been studied with respect to Alzheimer's, but
this has been done pertaining to age-related degeneration of both muscles and bones. In
female mammals, the production of oxytocin in the hypothalamus is dependent on the
level of oestrogens. This may lead to a natural decline in oxytocin activity in women
associated with the menopause. Mice being genetically engineered to be unable to
produce oxytocin demonstrate an accelerated age-associated degeneration of the muscle
mass (31). Also, their muscle stem cells were less capable of differentiating into new
muscle fibres following an applied muscle damage. Both deficits could be overcome by
the administration of oxytocin to replace the lacking intrinsic production. The ability of
oxytocin to stimulate muscle stem cells to differentiate has also been demonstrated in
experiments where isolated stem cells received oxytocin (32). This is a property that the
peptide shares with vasopressin. Furthermore, the muscle-building effect of anabolic
steroids also appears to involve oxytocin, as the treatment of sheep with such steroids
has been shown to boost the number of oxytocin receptors in their skeletal muscles (33).
The muscle-building capacity appears to be particularly potent when it comes to the
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muscle cells of the heart, which has led to considerations if oxytocin can be used as part
of the treatment for heart muscle failure (34).
Loss of muscle strength in the elderly, applying both to cardiac- and skeletal muscles, is a
very serious problem as it is a significant deteriorating factor for the quality of life. Also,
skeletal muscle weakness can result in a lessened ability to maintain balance of the body
resulting in fall injuries encompassing bone fractures due to osteoporosis. This agerelated
muscle degeneration, probably attributable to an impaired ability of the muscle
fibres to regenerate (35) might be counteracted by the maintenance of a high hormonal
level of oxytocin. This could be very interesting since no other safe preventive and
therapeutic measures against muscle weakness in the elderly appears to be known except
for physical exercise. Furthermore, it could be of interest to athletes if oxytocin enhances
the muscle strengthening effect of exercise – hopefully without the hormone being used
as a new doping drug.
Osteoporosis is a disorder that sends a lot of elderly people into nursing homes. The
disease is a consequence of a gradual decline with the age of the embedding of lime
(calcium phosphate)into the bones. The cells responsible for these limescale deposits are
called osteoblasts. But since bones are living tissue, both build-up and breakdown of the
limestone occurs continuously. The cells responsible for the degradation are called
osteoclasts. Thus, it is the balance between the activity of the osteoblasts and the
osteoclasts that determines whether bones are being built up or broken down.
Unfortunately, this balance shifts more and more towards decomposition with age (36).
The activity of both cell types is controlled by a variety of hormones, and here the sex
hormones play a significant role in promoting the activity in the osteoblasts. Unluckily,
the marked decrease in oestrogens associated with menopause causes the bone
breakdown to accelerate especially in older women. And by analogy to the accelerating
muscle weakness, the decline in oxytocin – as a result of the fall in sex hormones – may be
the main offender. Indeed, removing the ovaries from younger mice not only accelerates
muscle breakdown but so – bone breakdown. And again, this can be alleviated by oxytocin
treatment (37). Both osteoblasts and fat cells are formed by the differentiation of
mesenchymal stem cells. Thus, the same article reports from experiments with isolated
and cultured mesenchymal stem cells that the addition of oxytocin caused these stem
cells to differentiate more into osteoblasts rather than fat cells. That oxytocin also is
essential for bone mineralization in humans was supported when women with and
without osteoporosis were compared. Here, significantly lower levels of the hormone
were seen in those suffering from osteoporosis. The potential of oxytocin to increase the
differentiation of mesenchymal stem cells into bone cells at the expense of fat cells
explains why the development of osteoporosis was accompanied by obesity in mice
which were genetically engineered not to produce oxytocin (38). Lack of oxytocin,
therefore, appears both to lead to obesity and a decreased bone mass.
It is not solely concerning the function of stem cells as a source for cell replacement that
the stimulating impact of oxytocin may be of high significance. The peptide also seems to
be able to influence the release of cytokines by stem cells and certain skin cells in such a
manner that it counteracts stress damage (39) and cell aging (40) in the tissues.
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1. Seita J, Weissman IL. Hematopoietic stem cell: self-renewal versus differentiation.
Wiley Interdisciplinary Reviews: Systems Biology and Medicine 2010; 2(6): 640-
653.
2. Fearon DT, Manders P, Wagner SD. Arrested differentiation, the self-renewing
memory lymphocyte, and vaccination. Science 2001; 293(5528): 248-250.
3. Ndiaye K, Poole DH, Pate JL. Expression and regulation of functional oxytocin
receptors in bovine T lymphocytes. Biology of Reproduction 2008; 78(4): 786-
793.
4. Geenen V, Martens H, Brilot F, Renard C, Franchimont D, Kecha O. Thymic
neuroendocrine self-antigens. Role in T-cell development and central T-cell selftolerance.
Annals of the New York Academy of Sciences 2000; 917: 710-723.
5. Macciò A, Madeddu C, Chessa P, Panzone F, Lissoni P, Mantovani G. Oxytocin both
increases proliferative response of peripheral blood lymphomonocytes to
phytohemagglutinin and reverses immunosuppressive estrogen activity. In Vivo
2010; 24(2): 157-163.
6. Bradley D. Preston BD, Albertson TM, Herra AJ. DNA Replication Fidelity and
Cancer. Seminars in Cancer Biology 2010; 20(5): 281–293.
7. Simons MJ. Questioning causal involvement of telomeres in aging. Ageing Research
Reviews 2015; 24(Pt B): 191-196.
8. Skloot R. The Immortal Life of Henrietta Lacks, the Sequel. The New York Times.
March 23, 2013.
9. Shay JW, Wright WE. Telomeres and telomerase in normal and cancer stem cells.
FEBS Letters 2010; 584(17): 3819-3825.
10. Hornsby PJ. Telomerase and the aging process. Experimental Gerontology 2007;
42(7): 575-581.
11. de Almeida AJPO, Ribeiro TP, de Medeiros IA. Aging: Molecular Pathways and
Implications on the Cardiovascular System. Oxidative Medicine and Cellular
Longevity 2017; 2017: 7941563.
12. Iyama T, Wilson DM. DNA repair mechanisms in dividing and non-dividing cells.
DNA Repair 2013; 12(8): 620-636.
13. Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW. DNA repair,
genome stability, and aging. Cell 2005; 120(4): 497-512.
14. Elmore S Apoptosis: a review of programmed cell death. Toxicologic Pathology
2007; 35(4): 495-516.
15. Sagiv A, Krizhanovsky V. Immunosurveillance of senescent cells: the bright side of
the senescence program. Biogerontology 2013; 14(6): 617-628.
16. Rashed LA, Hashem RM, Soliman HM. Oxytocin inhibits NADPH oxidase and P38
MAPK in cisplatin-induced nephrotoxicity. Biomedicine and Pharmacotherapy
2011; 65(7): 474-480.
17. Rando TA. Stem cells, ageing and the quest for immortality. Nature 2006;
441(7097):1080-1086.
18. Freitas AA, de Magalhães JP. A review and appraisal of the DNA damage theory of
ageing. Mutation Research 2011; 728(1-2): 12-22.
19. Kryston TB, Georgiev AB, Pissis P, Georgakilas AG. Role of oxidative stress and
DNA damage in human carcinogenesis. Mutation Research 2011; 711(1-2): 193-
201.
20. Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology,
translational findings, and therapeutic implications for cardiac disease.
Circulation Research 2011; 109(8): 923-940.
97
21. Yin H, Price F, Rudnicki MA. Satellite cells and the muscle stem cell niche.
Physiological Reviews 2013; 93(1): 23-67.
22. Ankrum J, Karp JM. Mesenchymal stem cell therapy: Two steps forward, one step
back. Trends in Molecular Medicine 2010; 16(5): 203-209.
23. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease.
Nature Reviews Immunology 2008; 8(9): 726-736.
24. Compagnucci C, Bertini E. The potential of iPSCs for the treatment of premature
aging disorders. International Journal of Molecular Sciences 2017; 18(11).
25. Jung Y, Brack AS. Cellular mechanisms of somatic stem cell aging. Current Topics
in Developmental Biology 2014; 107: 405-438.
26. Ahmed W, Lingner J. Impact of oxidative stress on telomere biology.
Differentiation 2018; 99: 21-27.
27. Blackburn EH, Epel ES, Lin J. Human telomere biology: A contributory and
interactive factor in aging, disease risks, and protection. Science 2015; 350(6265):
1193-1198.
28. Scudellari M. Blood to blood. Nature 2015; 517: 426-429.
29. Horowitz AM, Villeda SA. Therapeutic potential of systemic brain rejuvenation
strategies for neurodegenerative disease. F1000Research 2017; 6: 1291.
30. Sha SJ, Deutsch GK, Tian L, Richardson K, Coburn M, Gaudioso JL, Marcal T,
Solomon E, Boumis A, Bet A, Mennes M, van Oort E, Beckmann CF, Braithwaite SP,
Jackson S, Nikolich K, Stephens D, Kerchner GA, Wyss-Coray T. Safety, Tolerability,
and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom
Amelioration Study: A Randomized Clinical Trial. JAMA Neurol. 2019;76(1):35-40.
31. Elabd C, Cousin W, Upadhyayula P, Chen RY, Chooljian MS, Li J, Kung S, Jiang KP,
Conboy IM. Oxytocin is an age-specific circulating hormone that is necessary for
muscle maintenance and regeneration. Nature Communications 2014; 5: 4082.
32. Costa A, Rossi E, Scicchitano BM, Coletti D, Moresi V, Adamo S. Neurohypophyseal
Hormones: Novel actors of striated muscle development and homeostasis.
European Journal of Translational Myology 2014; 24(3): 3790.
33. Kongsuwan K, Knox MR, Allingham PG, Pearson R, Dalrymple BP. The effect of
combination treatment with trenbolone acetate and estradiol-17β on skeletal
muscle expression and plasma concentrations of oxytocin in sheep. Domestic
Animal Endocrinology 2012; 43(1): 67-73.
34. Jankowski M, Gonzalez-Reyes A, Noiseux N, Gutkowska J. Oxytocin in the heart
regeneration. Recent Patents on Cardiovascular Drug Discovery 2012; 7(2): 81-
87.
35. Lang T, Streeper T, Cawthon P, Baldwin K, Taaffe DR, Harris TB. Sarcopenia:
etiology, clinical consequences, intervention, and assessment. Osteoporosis
International 2010; 21(4): 543-559.
36. Chan GK, Duque G. Age-related bone loss: old bone, new facts. Gerontology 2002;
48(2): 62-71.
37. Elabd C, Basillais A, Beaupied H, Breuil V, Wagner N, Scheideler M, Zaragosi LE,
Massiéra F, Lemichez E, Trajanoski Z, Carle G, Euller-Ziegler L, Ailhaud G,
Benhamou CL, Dani C, Amri EZ. Oxytocin controls differentiation of human
mesenchymal stem cells and reverses osteoporosis. Stem Cells 2008; 26(9): 2399-
2407.
38. Colaianni G, Sun L, Zaidi M, Zallone A. The "love hormone" oxytocin regulates the
loss and gain of the fat-bone relationship. Frontiers in Endocrinology 2015; 6: 79.
98
39. Noiseux N, Borie M, Desnoyers A, Menaouar A, Stevens LM, Mansour S, Danalache
BA, Roy DC, Jankowski M, Gutkowska J. Preconditioning of stem cells by oxytocin
to improve their therapeutic potential. Endocrinology 2012; 153(11): 5361-5372.
40. Cho SY, Kim AY, Kim J, Choi DH, Son ED, Shin DW. Oxytocin alleviates cellular
senescence through oxytocin receptor-mediated ERK/Nrf2 signalling. British
Journal of Dermatology 2019; 10: 1111.
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Chapter VII
The great protector
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Oxytocin protects the skin and intestine.
The ability of oxytocin to counteract oxidative stress and inflammatory reactions can
also increase the resistance of the skin to sunlight. Furthermore, oxytocin promotes
wound healing and appears to be a factor when mice get a healthier appearance after
being fed a diet that promotes a build-up of lactic acid bacteria in their gut. The gut
itself produces oxytocin, which may support its maintenance. An efficient renewal of
cells in the gut is mandatory due to the massive breakdown of cells taking place in this
organ.
There is much more to tell about the restorative effects of oxytocin. In recent years, the
role of gut bacteria has caught increasingly attention as an important factor for our health
and well-being. It has been shown that substances produced by gut bacteria can affect the
functioning of our immune- and nervous systems in various ways. The so-called gut-skin
axis referring to a putative relationship between the microflora in the intestine and the
propensity to develop inflammatory skin diseases is one example (1). If mice are fed a
diet that promotes the proliferation of certain lactic acid bacteria in their intestines, they
may acquire a healthier appearance including a prettier coat, and at the same time, they
show a greater interest in their cubs. The surface of the body forms the first barrier
against intruders and healthy and intact skin is therefore crucial to withstand physical,
chemical as well as biological attacks. At the same time, healthy skin signals good health
and therefore makes the individual more attractive.
The condition of the skin (and coat) is determined by its ability to repair damage caused
by stresses from the outside, such as solar radiation, but also from the inside in
connection with inflammatory reactions. The regenerative capacity of the skin can be
tested by the infliction of a wound and subsequently follow how fast and perfectly the
wound heals. When skin lesions are repaired, new skin cells are formed from
differentiating stem cells why the stem cell function also is crucial in this case.
Furthermore, inflammatory reactions are present to a greater or lesser extent including
invoked neutrophil cells (2). If this reaction is not adequately controlled, the wound
healing may be compromised because cells that should cover the wound can be subjected
to excessive oxidative stress.
Studies have shown that wounds heal better in mice whose gut flora is enriched with
certain lactic acid bacteria (3). At the same time, these mice have an increased activity of
regulatory T-lymphocytes, which may attenuate the assaults from the neutrophils. As
previously mentioned, oxytocin affects the differentiation of T-lymphocytes, and
interestingly the mice with the enriched gut flora exhibited a higher oxytocin
concentration in their blood. That oxytocin may play a role in this regard was further
indicated by the fact that the beneficial effect of the gut flora enrichment on wound
healing was abolished in mice having their oxytocin system disrupted by genetic
engineering (4). The importance of oxytocin for wound healing has also been
demonstrated in a trial on hamsters where the healing of an applied wound was delayed
in the animals being exposed to stress by confining their space. However, this stress effect
was counteracted if they were allowed to interact with other hamsters but only in animals
with an intact oxytocin system (5). From a study with the treatment of wounds in diabetic
patients, oxytocin was reported to improve the regenerative capacity of the skin- and
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endothelial cells accompanied by a reduction in the necrotic reactions (6). The promoting
effects of oxytocin on wound healing may be exerted by a combined stimulating effect on
the residing stem cells and a suppression of inflammatory reactions in the wound.
The wound healing ability is an indicator of the general health of the skin. The skin is
subjected to life-long oxidative stress leading to damage to the DNA, proteins, and
membranes of the cells (7). Oxidative stress can accelerate the production of
inflammatory cytokines by the skin cells causing a down-regulation in the formation of
the connective tissue strands that provide strength to the skin. As a result, the skin
becomes thinner and less elastic over time. At the same time, its ability to form pigments
is diminished, whilst the bloating of so-called liver spots may appear instead. These spots
consist of fats that have become brown by oxidation – rancid in other words.
Skin becomes thinner and more fragile as you age
Oxytocin appears to play an important role in the skin's defence against oxidative stress.
This has been confirmed by interesting experiments with cultured human skin cells (8).
In cell cultures, the production of a particular protein can be blocked by so-called small
interfering RNA (siRNA). These are small pieces of artificial RNA sequences that can block
the reading of a particular mRNA sequence by attaching to it if they are introduced into
the cytoplasm. In this way, the cells cannot produce the protein encoded for by the actual
mRNA. Which gene having its expression abolished is determined by the sequence of the
siRNA. Cultured skin cells having their production of oxytocin receptors blocked in this
way showed an increased concentration of Reactive Oxygen Substances (ROS) when
exposed to ultraviolet light. This means an increased level of oxidative stress in the cells
(described below). At the same time, this ablation of the oxytocin function led to an
elevated release of inflammatory cytokines from the cells. As no extra oxytocin was added
to the cells during the experiment, it was suggested that a sufficient amount of natural
oxytocin must be present to provide protection against oxidative stress and to attenuate
the inflammatory responses of the cells. Another study on cultured skin cells showed that
oxytocin attenuated their release of inflammatory cytokines when they were placed in a
medium which had been doped with secretions from senescent cells in advance (9). Not
only are skin cells equipped with oxytocin receptors, but they have also been shown to
produce and secrete their own oxytocin. In this way, they can act on themselves and the
immune responses in their vicinity. This is the first time I mention systems outside the
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hypothalamus that can produce oxytocin – but not last. The fact that patients with atopic
eczema display a reduced oxytocin production in the skin (10) further supports that
oxytocin may have a protective effect against chronic inflammatory skin diseases.
The demonstrated protective effect of oxytocin against oxidative stress caused by
ultraviolet light cannot be excluded to mitigate the harmful effects of sunlight. However,
this should not lead to the belief that love can be used as a sunscreen! On the web, you
can find pages with skincare products containing oxytocin. According to the
advertisements, such lotions should be able to fight skin wrinkles. A true effect of such
remedies is very dubious as oxytocin hardly penetrates the skin to a sufficient extent.
Oxytocin is undoubtedly very effective in fighting wrinkles – that means the body's own
oxytocin. On the web, you can find numerous claims that orgasms are good for your skin
and may be used to combat acne. Indeed, this may be true, but the explanations given
including the increased dermal blood flow and the tranquilizing effect of sex may seem
awkward to me with our knowledge about the direct skin protecting effects of oxytocin.
It is often claimed that we have 2 brains -the one in the head and then our intestinal brain.
Depending on how we define a brain this may be correct. The nervous system controlling
the movements of the intestine is extremely complicated and can work autonomously to
some extent. Therefore, it is of no wonder that this intestinal brain also contains oxytocincarrying
nerve pathways that can function autonomously. Also, the cells of the intestinal
mucosa are equipped with oxytocin receptors (11). These cells renew themselves very
fast by cell division, since the wear on the intestinal wall is enormous. Oxytocin may be
of great importance here since the villi of the intestine in mice with knocked-out oxytocin
receptors are very small. Oxytocin causes the stem cells in the crypt between the villi to
differentiate so that they can renew the mucosa. The growth-promoting effect of oxytocin
has also been demonstrated to protect the gut against harmful effects both from
chemicals and from radiation (11). Well-functioning intestinal mucus production is
important as a barrier against bacteria and irritants, which is why a reduced intestinal
mucosal repair is predisposing for inflammatory conditions in the gut.
But the intestinal mucosa is not the only mucosa in our body that oxytocin can enhance
with its growth-stimulating effects. Women often experience dryness and irritation of the
vagina during and after menopause. This is because the mucosa is becoming thinner and
less mucus-producing which is related to the decreasing estrogen level. This condition
can, therefore, be treated with estrogen. However, the application of oxytocin-containing
cream is an alternative to alleviate these problems (12). It could be exciting to investigate
whether such creams also may have a beneficial effect on the oral mucosa in people with
bad gums.
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What is oxidative stress?
Cell structures and functions are constantly attacked by chemically aggressive byproducts
of the respiration that takes place in the mitochondria. These by-products are
referred to as "ROS". Antioxidants from the diet have some protective effect against
ROS, but an adequate functioning of the cell's own protective antioxidant systems can
be of far greater importance. The systems consist of enzymes that break down ROS as
they form. Moreover, different ion channels are found in the mitochondria, which can
uncouple respiration from energy production in a controlled fashion, thereby reducing
their formation of ROS. Senescent and otherwise dysfunctional mitochondria are
believed to have a large production of ROS, which may further damage these very
organelles. Defective mitochondria in the muscles may lead to impaired metabolism
and a reduced working capacity which may add to the general decay with age of the
organism. Since maintenance and renewal mitochondria can be influenced by a variety
of signalling substances, these systems may be promising targets for new drugs.
Oxidative stress appears to be a major factor in the aging of the cells and the whole body.
But what exactly is a phenomenon? The word oxidative is derived from oxygen, the
compound that is a prerequisite for combustion. This also applies to the combustion
going on in our body normally referred to as respiration. It is said that fire is a faithful
servant but a dangerous lord, and so is the substance responsible for the fire. That our
bodies can luxuriate with energy by burning what we eat is because large amounts of
energy are released when oxygen reacts with the fuel. But this is only the case because
oxygen is a highly reactive substance that is constantly on the hunt for electrons. By
stealing or sharing electrons with other atoms, the oxygen atoms can have the so-called
octet rule fulfilled (the reader must read more about the octet rule elsewhere). The
chemists say that atoms or molecules are "oxidized" when they have one or more
electrons "stolen" or if they led electrons to be part of a common electron pair. In the
latter case, a chemical bond is formed as part of a new molecule. The term "oxidized" is
of course also derived from oxygen, although oxygen does not always need to be involved
in oxidative processes.
Exactly because oxygen is a very reactive molecule, it can also react with molecules of the
organisms in an undesirable and extremely harmful way. The first ecological disaster
here on earth occurred as a result of a special kind of bacteria called cyanobacteria which
developed an ability to grow by using water and the CO2 from the air. This process is
known as photosynthesis and has free oxygen (O2) as a by-product. As a result, the oxygen
concentration in the atmosphere eventually raised to a level that was very toxic for life
failing to develop systems that could withstand this highly assaultive substance. But it is
not oxygen itself that is the most aggressive compound but certain other chemicals that
contain oxygen atoms. These molecules are formed in connection with the respiration of
the cells. Such substances are called "Reactive Oxygen Substances" or ROS. Here can be
mentioned superoxide (O2
-) – yes indeed, it is called so – as well as hydrogen peroxide
(H2O2). The latter substance is used to disinfect wounds. Anyone who has tried to get in
skin contact with this stuff knows how nasty it is. The reason that ROS are so aggressive,
is that they are even more determined in their pursuit of electrons than oxygen.
Particularly horrible are the variants that also have an unpaired electron because
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electrons feel like most people to get together in pairs. Such molecules are called free
radicals.
A few other bacteria survived the ravage of the cyanobacteria polluting the atmosphere
with oxygen because they were capable of disarming the oxygen. Among these were the
bacteria that was the precursor for the mitochondria. Thus, the mitochondria are
degenerate bacteria that live inside our cells today and are responsible for the vast
majority of the respiration and therefore energy supply of the body. These bacteria
disarm the oxygen by letting it react with hydrogen ions (H+) and electrons to form water.
Electrons are initially delivered to the inner mitochondrial membrane from the
coenzymes NADH and FADH2, being formed from NAD+ and FAD in advance by the
breakdown of energy-containing nutrients such as fat and carbohydrates. Subsequently,
the electrons migrate through 3 or 4 different protein complexes being attached to the
inner membrane of the mitochondria before they finally are delivered to the oxygen
atoms.
Each time the electrons move through one of the protein complexes, energy is released.
This energy is used by the complex to pump H+-ions into the space between the two
membranes of the mitochondria. This creates an electric voltage difference between the
two sides of the inner membrane with a positively charged outside and a negatively
charged inside. If the H+- ions are now allowed to migrate back, the electrical energy can
be "harvested" by the conversion of ADP into the energy-rich compound ATP. The energy
in ATP is very easily transferable and is therefore used to provide energy for most of the
energy-requiring processes in the cell, including movement. The mitochondria can thus
be regarded as the power plants of the cells, where the energy, in this case, is supplied as
ATP instead of electric current. The electron migration system in the mitochondria is
called the electron transport chain, which together with ATP production is referred to as
oxidative phosphorylation. The overall oxygen-demanding process taking place in the
mitochondria is called respiration.
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Electron transport chain and phosphorylation: Electrons move between 4 different protein
complexes all embedded in the inner membrane of the mitochondria before they react with
H+ and oxygen to form water. Hereby energy is expended to pump hydrogen ions (H+) out
into the space between the membranes. Subsequently, energy is loaded by the
phosphorylation of ADP to ATP when the H+ returns to the mitochondrial matrix.
Occasionally, however, electrons prematurely escape from the electron transport chain.
These electrons then react directly with oxygen to form superoxide instead of water. As
mentioned, superoxide is a very noxious free radical. Therefore, to rapidly degrade the
superoxide, cells are equipped with an enzyme – superoxide dismutase (SOD) – which
promptly converts the superoxide into hydrogen peroxide. Since hydrogen peroxide is
also very dreadful, it is converted to water and oxygen by the enzyme catalase (13).
Unless these ROS'es, which can also be formed by other processes in the cells, are
neutralized, they will attack the different structures of the cell including DNA. This can
cause mutations that can interfere with cell functions and, at worst, lead to cancer. They
can also oxidize the amino acids of the cell's proteins, thereby impairing the activity of
the enzymes and damaging proteins that form the structure of the cell. In the long run,
these oxidative assaults presumably are an important part of the aging process of the
body (14). Also, the ROS can damage the membranes of the cells, where double bonds in
their unsaturated fatty acids are highly vulnerable for theft of electrons. When this
happens, the fatty acids themselves are transformed into free radicals, which, in turn, can
attack a new double bond. By so, a domino effect is established (15). Cells are highly
dependent on the integrity of their membranes as they constitute the boundary and
connection to the outside world. Oxidation of the cell membranes can eventually cause
them to burst resulting in the death of the cell.
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But the ROS can also damage the mitochondria themselves and a relatively new
hypothesis suggests that oxidative damage to the mitochondria is more responsible for
the aging processes associated with oxidative stress than are such stress on other
components of the cells (16). Indeed, the mitochondria can remove free oxygen from the
cells but that occurs on the cost of the formation of small amounts of much more
aggressive by-product during this process. If the electron transport chain functions less
effectively with aging more and more stress by ROS is put on the mitochondria. Mutations
in their DNA may, therefore, occur to a greater and greater extent. The fact that
mitochondrial DNA is less protected against mutations than the DNA in the cell nucleus,
makes it more prone to oxidative damages. A resulting deterioration in the transfer of
electrons through the transport chain will cause more electrons to escape and therefore
increase the ROS production. This will damage the whole cell but not at least the
mitochondria themselves by establishing a vicious spiral. Therefore, it is extremely
important that the enzyme systems of the cells that degrade ROS are functioning properly
to counteract the acceleration of degenerative processes. This must particularly be true
for the mitochondria.
In addition to degradation of the ROS'es by enzymes, the mitochondria also have systems
to avoid their formation particularly during peak loads, where there may be a mismatch
between the number of electrons supplied to the electron transport chain and the
electrons that can be deposited in the formation of water at the end of the chain. Such an
imbalance may be established by the degradation of nutrients and thus an NADH
production that exceeds the need for ATP formation. More H+-ions will, therefore, be
pumped out than would return causing the voltage difference across the membrane
steadily to rise and finally reach a level that cannot be overcome by the complexes of the
electron transport chain. This would force it to a halt but due to the persisting push of
electrons into the chain, they would accumulate. This accumulation of electrons would
cause them to escape from the chain to a greater extent thereby increasing the formation
of superoxide. The existence of such a relationship between a high voltage differential
across the membrane and a strong ROS development has been confirmed in experiments
with isolated mitochondria (17).
So-called uncoupling proteins (UCPs) in the inner mitochondrial membrane are believed
to counteract this situation by allowing H+-ions to pass across the membrane without the
formation of ATP. That this may be so, is confirmed by mitochondria extracted from the
muscles of genetically engineered mice that are unable to produce UCP3. Mitochondria
from these mice exhibit an elevated ROS production during nutrient delivery compared
to those from normal mice (18). Furthermore, some experiments with mitochondria
isolated from different types of tissue have demonstrated that elevated superoxide levels
lead to increased UCP-dependent backflow of H+-ions through the membrane, suggesting
that UCP activity is regulated by the concentration of ROS (19). When we talk about UCP
as a kind of safety valve against electron accumulation, it concerns particularly the UCP2
and UCP3 which are found in a variety of organs, while UCP1 is probably only situated in
brown adipose tissue and permits brown fat cells to produce large amounts of heat. We
will talk about brown adipose tissue later.
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The activity of the UCPs must be strictly regulated as the free passage of H+-ions would
eliminate the voltage difference and therefore make ATP production impossible with
certain death as a consequence. But demands do also prevail for a more fine-tuned UCP
activity in the different cell types. Mitochondrial ROS production in moderate amounts
appears to play a role as signalling agents within the cells not least to regulating the
metabolism but also as a stimulus for the formation of new mitochondria (20). Therefore,
the activity of the UCPs can be part of a control system within the cells via variations in
mitochondrial delivery of ROS.
Certain immune cells, including the macrophages, use ROS discharges to directly kill
invaders mainly bacteria (21). In this context, superoxide is formed not only as a byproduct
of mitochondrial metabolism but also by an enzyme bound to the cell membrane
(NADPH oxidase). This superoxide is a precursor for the production of other ROS'es,
including hydrogen peroxide. However, ROS formed by the mitochondria can also be used
in the immune response. Thus, several studies on rodents have demonstrated an
increased immune capacity in animals where the ability to form UCP2 was abrogated by
genetic engineering. Such animals exhibit stronger responses of inflammatory cytokines
as well as increased resistance to bacterial infections. The other side of the coin is that
they show a greater tendency for the development of degenerative autoimmune
disorders such as atherosclerosis, diabetes, and multiple sclerosis (22). These
experiments clearly illustrate that the immune system is a double-edged sword that may
well kill invading microorganisms by bursts of ROS but, on the other hand, can do serious
harm to the organism's own cells.
Involvement in the function of the immune system is only one example of the fact that the
mitochondria deal with much more than securing the energy supply of the cell. Therefore,
there may be many reasons why malfunctioning mitochondria may be related to poor
health. The mitochondria are also responsible for the initiation of programmed cell death
(apoptosis) (23), which, in some cases, may be the result of oxidative stress (24). This
integration of the mitochondria into some cell functions means that despite the
mitochondria still possess some of their genes, they are completely dependent on
proteins encoded in the genes of the host cell. It is believed that most of the original genes
of the mitochondria have gradually "moved into" the chromosomes of the host cells. The
functions of the mitochondria are therefore perfectly regulated by the cells which they
are a part of. This also means that they are also highly susceptible to the signals coming
to the cells from the outside. In other words, the metabolic functions of mitochondria
being very important for cell survival are regulated by hormones.
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Mitochondria – the structure of the double-membrane can be discerned.
The capacity of the mitochondria to convert the energy contained in oxygen declines with
age. This applies not least to the heart and skeletal muscles and may contribute to the
general decline in the physical performance of elderly people. This can also explain the
generally lower metabolism that comes with age along with the loss of muscle mass.
Furthermore, the decrease in insulin sensitivity of the muscles, also occurring to some
extent in normal-weight seniors, may involve an impaired mitochondrial function. A
study in mice where the oxidative stress was reduced solely in mitochondria has
produced remarkable results in this regard (25). The manipulation of mitochondria was
achieved by increasing the catalase activity exclusively in these organelles via genetic
engineering. Thereby, the hydrogen peroxide formed was more rapidly converted to
water and oxygen. Such genetically engineered mice showed no age-related decrease in
the energy turnover of muscle mitochondria, as otherwise was the case in the mice not
being manipulated. At the same time, whole-body energy turnover as well as the ability
for glucose uptake by the muscles and the entire body remained at the level of the young
mice. Another study reported an average life expectancy of about 20% with similarly
manipulated mice (26). Also, these mice showed a decreased degeneration of their
cardiac muscle. These results point to a decline in the fitness of the mitochondria caused
by oxidative damages as a fundamental mechanism for the corrosion of functions with
age.
Therefore, it is very feasible that a long "health-span" depends on the global ability of the
brain and body to contain and disarm ROS. That is essentially why we have all the talk
about antioxidants in the diet. Dietary antioxidants may prevent other substances from
being oxidized by being oxidized themselves. In this way, they can perform a shielding
against the ROS'es. This is opposed to the mode of action by the antioxidant systems of
the cells, where the ROS'es are enzymatically converted. Nutritional antioxidants include
some vitamins, of which ascorbic acid (vitamin C) is the best known. Ascorbic acid is
naturally found to a large extent in fruits and makes them decompose more slowly, but
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the substance is also used as a preservative in food products. Other antioxidants include
plant polyphenols that taste bitter and are therefore called bitter substances. In most
cases, the intake of foods rich in antioxidants is excellent, although their health potential
may have been overestimated. Clinical studies where the intake of various types of
antioxidants have been tested for its effects on different risk markers for degenerative
diseases have often yielded disappointing results (27). This can be for many reasons. The
mechanisms of how different antioxidants influence the different cellular systems can be
very complex. For instance, do they reach the locations where they could exert some
benefits – not at least the mitochondria? In this context, we have to pay attention to the
fact that the body's antioxidant systems with the enzymatic degradation of the ROS will
always play a superior role in the battle against oxidative stress. Also, the regulation of
UCPs can be of great importance. By its massive signalling, the brain will always be in
charge of these functions down to the mitochondrial level. How, then, can the brain retain
its ability to counteract oxidative stress also into an advanced age? An issue that can be
just as important as how to support health through the diet.
Oxytocin counteracts oxidative stress
Several studies on both animals and humans indicate that neglect and loneliness can
increase the oxidative damage to the DNA of the cells – not least the telomeres. On the
other hand, there has been an independent statistical association between active sex
life and the length of the telomeres. A protective effect of oxytocin may well be an
important explicative factor in both cases. Studies indicate that oxytocin could have a
direct preservative impact on the mitochondria, however, anti-inflammatory effects
may also play a role. In this regard, inflammations increase the production of ROS
where it is formed outside the mitochondria as part of the battle against invaders. In
the long run, a reduction in oxidative stress may delay progressive degradations of cell
structures. However, the anti-inflammatory effect of oxytocin may also save lives in
acute situations where its effect could be potent enough to protect tissue from severe
damage caused by hyperinflammatory conditions. Hence, promoting mechanisms that
reduce the production of damaging molecules and enforces the removal of them,
appears to be important parts of the assignments of oxytocin.
I have already mentioned that oxytocin can counteract skin and intestinal damages
through antioxidant mechanisms. However, the counteracting effect of oxytocin on
oxidative stress is not limited to these parts of the body and appears to involve the
support of several different protective and maintenance systems of the cells including the
activation of the Nrf2 transcription factor (9). Nrf2 is a central factor for the cell's
antioxidative defence as it enhances the activity of enzymes involved the degradation of
ROS (28). The antioxidative impact of oxytocin is therefore exerted on numerous of
different tissue types. Oxytocin may, therefore, be an important player to explain the
relationship between a good social life and good health. In contrast, a lack of care in
childhood and loneliness later in life may be harmful to health. Oxytocin could exert its
protective effect both directly via the bloodstream as a hormone but also indirectly by
dampening brain stress reactions that otherwise could be harmful to the body.
110
If the antioxidant systems of the cells are strengthened, it could have a general protective
effect on the DNA and, in particular, could counteract an accelerated shortening of the
telomeres. Ad discussed above, shortened telomeres impairs the divisions of cells and
therefore their contributions to the renewal of the tissues. Studies have demonstrated
that female rats who were allowed companionship with other female rats for 3 months
had higher levels of oxytocin in the blood compared to similar animals that had been kept
isolated. At the same time, the socializing rats had a higher telomere length in cells
collected from their skin. However, this was not the case if the socializing rats had been
treated with a substance that blocks the effect of oxytocin (29). The presence – also in
humans – of a possible protective effect of oxytocin against corrosion of telomeres has
been supported by a few studies. It has been reported that women who had been
neglected in childhood demonstrated a shorter telomere length in a particular type of Tlymphocytes
compared to a similar group of women having had a normal childhood.
Furthermore, there was an overall positive correlation between telomere length and the
concentration of oxytocin in their blood (30). In another study, a statistical association
between telomere length in lymphocytes and how they had been treated during
childhood was found among younger people. However, this correlation was dependent
on the presence of a particular genetic variant of their oxytocin receptor gene (30). In
other words, the vulnerability of the telomeres for neglect may depend on variations in
the oxytocin system.
An active sexual life may by itself have a protective effect on the telomeres. In one study
on premenopausal women in a stable relationship, the telomere length in different types
of blood cells was tested for statistically associations with age, physical activity, diet,
experienced daily stress, pain, and other malaise, perceived quality of their relationship,
and whether they have had sex over the last week (32). Here, a positive association was
found between telomere length and sexual activity, which was independent of all the
other parameters. Of cause, several population studies with varying designs are needed
to confirm a direct causal relationship being proposed by these results. Can a sexually
active life just be a marker of some health conditions that have not been taken into
account in the study? Can the desire for sex be influenced by signalling substances that,
independently of sexual activity, also have a protective effect on telomeres? Or is it so,
that sexual pleasure by itself induces nerve and/or hormonal activities that prevent the
degradation of telomeres? The answer is currently blowing in the wind, but regardless of
which of these causal factors are most prominent, the involvement of oxytocin is a good
bet.
The protection of the telomeres is far from the only feasible way by which the various
antioxidant mechanisms of oxytocin may have a beneficial effect. Several other avenues
seem far more well-documented which likewise can manifest themselves through
behaviour and social influences. Recent observations support that chronic mental stress
can affect the metabolism of brain cells including the function of their mitochondria in a
very unfortunate way. This may contribute to the development of depressive states (33).
Inflammatory responses in the brain tissue and oxidative stress of the nerve cells can be
crucial interacting factors in the progression of different diseases. In a study where mice
were subjected to mental stress by removing them from the mother 3 hours daily for 14
days, they displayed a depression-like behavioural pattern when tested 60 days after
birth (34). Furthermore, hippocampal tissue samples demonstrated an increased
111
production of inflammatory cytokines accompanied by an increased ROS production in
mitochondria isolated from the samples. However, oxytocin administration into the brain
cavities alleviated the symptoms of depression. Also, the inflammatory activity and ROS
production in the mitochondria was significantly reduced. On the other hand, the
oxytocin treatment had no obvious effects on the mice that had not been exposed to stress
after birth. These results underpin a hypothesis that oxytocin has the potential to
counteract stress-related damage in the brain down to the mitochondrial level.
It is not only via effects on the mitochondria that oxytocin can attenuate cellular stress
caused by ROS and other reactions associated with inflammation. The peptide has been
shown to reduce the NADPH-oxidase activity in the immune cells. This enzyme is used by
immune cells for their ROS production outside the mitochondria. Accordingly, when
treated with oxytocin, both immune cells and cells taken from the walls of blood vessels
demonstrated a decrease in superoxide production while they were stimulated with an
inflammatory cytokine (35). The production of ROS in connection with inflammatory
reactions may be an important factor when it comes to oxidative stress associated with
chronic low-grade inflammatory conditions. However, the ability of oxytocin to
counteract oxidative damage also appears to be very pronounced in acute contexts where
massive inflammatory reactions are involved. Oxytocin has therefore been proposed to
be used in emergency medicine for multiorgan damage in connection with sepsis (36),
severe virus infections (37), and extensive burns (38), where excessive global immune
and oxidative stress reactions can occur.
Indeed, oxidative stress can not only result in a slow-progressing degradation of cells but
may also manifest itself as an acute life-threatening phenomenon, especially in
connection with so-called reperfusion injuries. If tissue has suffered from oxygen
deficiency for some time due to a blocked blood supply, immediate recovery of the bloodand
thus oxygen supply may, in some cases, actually aggravate the situation by increasing
the tissue breakdown. This is explained by the fact that the antioxidant systems of the
cells have been compromised by the lack of oxygen and therefore are unable to respond
adequately when the oxygen reappears. In animal experiments, reperfusion injuries are
associated with a massive ROS formation (39). The greatest consequence of reperfusion
injuries may be when they strike the heart. When a thrombus obstructs one of the
coronary arteries that supplies the heart muscle, that area normally being perfused by
the vessel can be damaged due to oxygen shortage. In the worst case, the thrombosis can
cause muscle tissue to be destroyed in a way that disrupt the impulse system of the heart.
Consequently, the coordination of its contractions is lost and so is its ability to generate
an ejection force. Therefore, the blood supply must be restored as soon as possible.
However, a sudden re-establishing of the oxygen supply can lead to the formation of large
amounts of ROS, which, in turn, causes further destruction of the musculature by
triggering the heart cells to kill themselves. This may be accompanied by a violent
inflammatory reaction in the heart tissue, which amplifies the cell death (40).
Experiments with rodents, where part of the blood supply to the heart muscle is squeezed
and then reopened after some time are frequently used as a model for damages inflicted
by thrombosis. If oxytocin is given in conjunction with such interventions, the reperfusion
damage may be diminished. Moreover, the degree of oxidation of fatty acids in the tissue
112
as a measure of over-all oxidative damage is reduced. Finally, the cardiac arrhythmias
that could otherwise be observed during the reperfusion are eliminated. These effects of
oxytocin could be abolished by drugs that block its action (41).
Reperfusion study on mouse heart
The survival of cells during oxygen deprivation depends on the ability of their metabolism
to adapt to the reduced oxygen supply. In this context, the resilience of mitochondria is
essential. Activation of a channel structure in the inner mitochondrial membrane – the
mitochondrial ATP-sensitive potassium channel – has been proposed to play an important
role in counteracting an overload of the mitochondria during oxygen shortage, so that
ROS production can be limited (42). The protective effect of oxytocin against reperfusion
injury appears to involve this channel (43). Although the channel increases the passage
of K+ ions instead of H+ ions, it may have a function that is similar to that of the UCPs. This
is because the K+ ion is also positively electrically charged and therefore will reduce the
membrane potential if it passes through the mitochondrial membrane in the same
direction as H+. The antioxidant effect of oxytocin after oxygen deprivation is likely to
occur in conjunction with other signalling agents such as a nitric oxide (NO)(43). The fact
that oxytocin can have a direct antioxidant effect on the heart muscle cells themselves is
supported by the observations that delivery of the peptide to isolated heart cells can
reduce the release of ROS during an alternating oxygen supply to the incubation fluid
(44). By the way, heart muscle cells can produce oxytocin themselves (more on this later).
The protective effect of oxytocin against reperfusion injuries has also been demonstrated
in other organs, including the urinary bladder (45), kidney (46), and liver (47).
Furthermore, oxytocin may additionally exert protective effects against coronary
thrombosis by effects mediated via the brain. The exitance of such mechanisms is
supported by an experiment where rats were injected with oxytocin into the brain before
the heart was removed and the blood supply was blocked to part of its musculature (48).
This way of oxytocin administration also reduced the damage to the heart, despite that
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there was no increase of oxytocin in the blood. The researchers, therefore, concluded that
the oxytocin treatment may have affected the brain in a way that protected the heart. This
might have been mediated by a nerve-related mechanism. As previously discussed, the
brainstem is tightly provided with oxytocin-carrying nerve endings which also applies to
the part that controls the heart. That the heart is strongly influenced by oxytocin via the
brainstem is demonstrated by observations that the exercise-induced increase in heart
rate can be diminished by administration of oxytocin at this location (49).
Correspondingly, oxytocin blockade increased the heart rate during exercise. The
protective effect of oxytocin against reperfusion injuries has also been demonstrated in
other organs, including the bladder.
1. Szántó M, Dózsa A, Antal D, Szabó K, Kemény L, Bai P: Targeting the Gut-Skin axisProbiotics
as New Tools for Skin Disorder Management? Experimental
Dermatology Exp Dermatol. 2019; 28(11):1210-1218.
2. Guo S, DiPietro LA. Factors Affecting Wound Healing. Journal of Dental Research
2010; 89(3): 219–229.
3. Erdman SE, Poutahidis T. Probiotic 'glow of health': it's more than skin deep.
Beneficial Microbes 2014; 5(2): 109-119.
4. Poutahidis T, Kearney SM, Levkovich T, Qi P, Varian BJ, Lakritz JR, Ibrahim YM,
Chatzigiagkos A, Alm EJ, Erdman SE. Microbial symbionts accelerate wound
healing via the neuropeptide hormone oxytocin. PLoS One 2013; 8(10): e78898.
5. Detillion CE, Craft TK, Glasper ER, Prendergast BJ, DeVries AC. Social facilitation of
wound healing. Psychoneuroendocrinology 2004; 29(8): 1004-1011.
6. Gavrilenko VG, Esipov VK, Sivozhelezov KG. Morfologiia. Morphological
characteristic of wound healing process in patients with diabetic purulentnecrotic
foot lesion treated with oxytocin 2003; 124(5): 24-27.
7. Poljšak B1, Dahmane RG, Godić A. Intrinsic skin aging: the role of oxidative stress.
Acta Dermatovenerologica Alpina, Pannonica et Adriatica 2012; 21(2): 33-36.
8. DeingV, Roggenkamp D, Kühnl J, GruschkaA, Stäb F, Wenck H, Bürkle A, Neufang
G. Oxytocin modulates proliferation and stress responses of human skin cells:
implications for atopic dermatitis. Experimental Dermatology 2013; 22(6): 399-
405.
9. Cho SY, Kim AY, Kim J, Choi DH, Son ED, Shin DW. Oxytocin alleviates cellular
senescence through oxytocin receptor-mediated ERK/Nrf2 signalling. British
Journal of Dermatology 2019; 10: 1111.
10. Deing V, Roggenkamp D, Kühnl J, Gruschka A, Stäb F, Wenck H, Neufang G. A new
role of the oxytocin system in human skin stress responses and implications for
atopic dermatitis. Brain, Behavior, and Immunity 2013; 29:(Suppl 15) S11.
11. Chen D, Zhao J, Wang H, An N, Zhou Y, Fan J, Luo J, Su W, Liu C, Li J. Oxytocin evokes
a pulsatile PGE2 release from ileum mucosa and is required for repair of intestinal
epithelium after injury. Scientific Reports 2015; 5: 11731.
12. Al-Saqi SH, Uvnäs-Moberg K Jonasson AF. Intravaginally applied oxytocin
improves post-menopausal vaginal atrophy. Post Reproductive Health 2015;
21(3): 88–97.
13. Scheibmeir HD, Christensen K, Whitaker SH, Jegaethesan J, Clancy R, Pierce JD. A
review of free radicals and antioxidants for critical care nurses. Intensive and
Critical Care Nursing 2005; 21(1): 24-28.
114
14. Cannizzo ES, Clement CC, Sahu R, Follo C, Santambrogio L. Oxidative stress,
inflamm-aging and immunosenescence. Journal of Proteomics 2011; 74(11):
2313-2323.
15. Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional
foods: Impact on human health. Pharmacognosy Reviews 2010; 4(8): 118-126.
16. Dai DF, Chiao YA, Marcinek DJ, Szeto HH, Rabinovitch PS. Mitochondrial oxidative
stress in aging and healthspan. Longevity and Healthspan 2014; 3: 6
17. Korshunov SS, Skulachev VP, Starkov AA. High protonic potential actuates a
mechanism of production of reactive oxygen species in mitochondria. FEBS
Letters 1997; 416(1): 15-18.
18. Toime LJ, Brand MD. Uncoupling protein-3 lowers reactive oxygen species
production in isolated mitochondria. Free Radical Biology and Medicine 2010;
49(4): 606-611.
19. Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, Harper JA,
Roebuck SJ, Morrison A, Pickering S, Clapham JC, Brand MD. Superoxide activates
mitochondrial uncoupling proteins. Nature. 2002; 415(6867): 96-99.
20. Shadel GS, Horvath TL. Mitochondrial ROS signaling in organismal homeostasis.
Cell 2015; 163(3): 560-569.
21. Slauch JM. How does the oxidative burst of macrophages kill bacteria? Still an open
question. Molecular Microbiology 2011; 80(3): 580-583.
22. Emre Y, Nübel T. Uncoupling protein UCP2: when mitochondrial activity meets
immunity. FEBS Letters 2010; 584(8): 1437-1442.
23. Spierings D, McStay G, Saleh M, Bender C, Chipuk J, Maurer U, Green DR. Connected
to death: the (unexpurgated) mitochondrial pathway of apoptosis. Science 2005;
310(5745): 66-67.
24. Kannan K, Jain SK. Oxidative stress and apoptosis. Pathophysiology 2000; 7(3),
153–163.
25. Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, Zhang D, Woo
DK, Shadel GS, Ladiges W, Rabinovitch PS, Santos JH, Petersen KF, Samuel VT,
Shulman GI. Targeted expression of catalase to mitochondria prevents ageassociated
reductions in mitochondrial function and insulin resistance. Cell
Metabolism 2010; 12(6): 668-674.
26. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE,
Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS. Extension of
murine life span by overexpression of catalase targeted to mitochondria. Science
2005; 308(5730): 1909-1911.
27. Conti V, Izzo V, Corbi G, Russomanno G, Manzo V, De Lise F, Di Donato A, Filippelli
A. Antioxidant Supplementation in the Treatment of Aging-Associated Diseases.
Frontiers in Pharmacology 2016; 7: 24.
28. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annual Review of Pharmacology
and Toxicology 2013; 53: 401-426
29. Faraji J, Karimi M, Soltanpour N, Moharrerie A, Rouhzadeh Z, Lotfi H, Hosseini SA,
Jafari SY, Roudaki S, Moeeini R, Metz GA. Oxytocin-mediated social enrichment
promotes longer telomeres and novelty seeking. Elife 2018; 7: e40262.
30. Boeck C, Krause S, Karabatsiakis A, Schury K, Gündel H, Waller C, Kolassa IT.
History of child maltreatment and telomere length in immune cell subsets:
Associations with stress- and attachment-related hormones. Development and
Psychopathology 2018; 30(2): 539-551.
115
31. Smearman EL, Yu T, Brody GH. Variation in the oxytocin receptor gene moderates
the protective effects of a family-based prevention program on telomere length.
Brain and Behavior 2016; 6(2): e00423.
32. Cabeza de Baca T, Epel ES, Robles TF, Coccia M, Gilbert A, Puterman E, Prather AA.
Sexual intimacy in couples is associated with longer telomere length.
Psychoneuroendocrinology 2017; 81: 46-51.
33. Gardnera A, Bolesb RG. Beyond the serotonin hypothesis: Mitochondria,
inflammation and neurodegeneration in major depression and affective spectrum
disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry
2011; 35(3): 730-743.
34. Amini-Khoei H, Mohammadi-Asl A, Amiri S, Hosseini MJ, Momeny M, Hassanipour
M, Rastegar M, Haj-Mirzaian A, Mirzaian AH, Sanjarimoghaddam H, Mehr SE,
Dehpour AR. Oxytocin mitigated the depressive-like behaviors of maternal
separation stress through modulating mitochondrial function and
neuroinflammation. Progress in Neuro-Psychopharmacology and Biological
Psychiatry 2017; 76: 169-178.
35. Szeto A, Nation DA, Mendez AJ, Dominguez-Bendala J, Brooks LG, Schneiderman N,
McCabe PM. Oxytocin attenuates NADPH-dependent superoxide activity and IL-6
secretion in macrophages and vascular cells. American Journal of PhysiologyEndocrinology
and Metabolism 2008; 295(6): E1495-1501.
36. Işeri SO, Sener G, Saglam B, Gedik N, Ercan F, Yegen BC. Oxytocin protects against
sepsis-induced multiple organ damage: role of neutrophils Journal of Surgical
Research 2005; 126(1): 73-81.
37. Soumier A, Sirigu A. Oxytocin as a potential defence against Covid-19? Medical
Hypotheses 2020; 140: 109785.
38. Işeri SO, Gedik IE, Erzik C, Uslu B, Arbak S, Gedik N, Yeğen BC. Oxytocin ameliorates
skin damage and oxidant gastric injury in rats with thermal trauma. Burns 2008;
34(3): 361-369.
39. Granger DN, Kvietys PR. Reperfusion injury and reactive oxygen species: The
evolution of a concept. Redox Biology 2015; 6: 524-551.
40. Frangogiannis NG. The inflammatory response in myocardial injury, repair and
remodeling. Nature Reviews Cardiology 2014; 11(5): 255–265.
41. Alizadeh AM, Faghihi M, Sadeghipour HR, Mohammadghasemi F, Imani A,
Houshmand F, Khori V. Oxytocin protects rat heart against ischemia-reperfusion
injury via pathway involving mitochondrial ATP-dependent potassium channel.
Peptides 2010; 31(7): 1341-1345.
42. Laskowski M, Augustynek B, Kulawiak B, Koprowski P, Bednarczyk P,
Jarmuszkiewicz W, Szewczyk A. What do we not know about mitochondrial
potassium channels? Biochimica et Biophysica Acta2016; 1857(8): 1247-1257.
43. Faghihi M, Alizadeh AM, Khori V, Latifpour M, Khodayari S. The role of nitric oxide,
reactive oxygen species, and protein kinase C in oxytocin-induced
cardioprotection in ischemic rat heart. Peptides 2012; 37(2): 314-319.
44. Gonzalez-Reyes A, Menaouar A, Yip D, Danalache B, Plante E, Noiseux N,
Gutkowska J, Jankowski M. Molecular mechanisms underlying oxytocin-induced
cardiomyocyte protection from simulated ischemia-reperfusion. Molecular and
Cellular Endocrinology 2015; 412: 170-181.
45. Erkanli Senturk G, Erkanli K, Aydin U, Yucel D, Isiksacan N, Ercan F, Arbak S. The
protective effect of oxytocin on ischemia/reperfusion injury in rat urinary
bladder. Peptides 2013; 40: 82-88.
116
46. Tuğtepe H, Sener G, Biyikli NK, Yüksel M, Cetinel S, Gedik N, Yeğen BC 2007. The
Protective effect of oxytocin on renal ischemia/reperfusion injury in rats.
Regulatory Peptides 2007; 140(3):101-108.
47. Düşünceli F, Işeri SO, Ercan F, Gedik N, Yeğen C, Yeğen BC. Oxytocin alleviates
hepatic ischemia-reperfusion injury in rats. Peptides 2008; 29(7):1216-1222.
48. Moghimian M, Faghihi M, Karimian SM, Imani A, Houshmand F, Azizi Y. Role of
central oxytocin in stress-induced cardioprotection in ischemic-reperfused heart
model. Journal of Cardiology 2013; 61(1): 79-86.
49. Michelini LC. Oxytocin in the NTS. A new modulator of cardiovascular control
during exercise. Annals of the New York Academy of Sciences 2001; 940:206-220.
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Chapter VIII
Oxytocin and metabolism
118
Can oxytocin prevent impaired insulin function?
Impaired insulin function both related to overweight and old age is a consequence of a
reduced insulin sensitivity, for example in the muscles often accompanied by a reduced
capacity of the pancreas to produce insulin. In both cases, inflammatory reactions and
oxidative damages – increasing with age – play a role. Trials in rodents underpin the
potential of oxytocin to retard such a development. In addition, oxytocin has acute
effects on metabolism, which also enhance insulin function.
As mentioned above, the counteracting effect of oxytocin on oxidative damage can occur
both in the short and long run. Therefore, the peptide may exert a general slowing effect
on age-degenerative mechanisms comprising a DNA protective effect. Among the agerelated
diseases, I have already mentioned atherosclerosis, muscle weakness, and
osteoporosis, but type-2 diabetes (onset diabetes), is another devastating age-associated
disorder. However, in recent years, this disease has unfortunately become more frequent
also among the younger generations as more and more people develop excessive obesity.
When insulin-responsive cells are acted on by this hormone, some signalling mechanisms
are initiated, which ultimately results in an increased uptake of glucose from the blood.
As blood glucose rises, the pancreas produces more insulin so that the glucose in excess
can be cleared from the blood. But with age, the capacity of pancreatic cells that are
responsible for insulin production appears to decline. This makes it more difficult to meet
the increased requirement for the release of insulin brought about by a dwindling insulin
sensitivity which also comes with age, not at least if the individual becomes overweight.
With age, deposits of amyloid develop in the insulin-producing cells, and this amyloid
accumulation is thought to be a major factor in the progression of type-2 diabetes.
Amyloid deposits are formed by damaged proteins pairing with each other in a network
within the cells. The accumulation of amyloid is also seen in the brain tissue of
Alzheimer's patients, and concordantly Alzheimer's occurs far more frequently in type-2
diabetes patients (1). There are several hypotheses to explain this relationship, and it has
been suggested that low levels of sex hormones may be a common determinant. Oxidative
stress is presumably an essential common factor in amyloid formation (2) why a
generally low antioxidative defence may be a prominent risk factor.
Oxytocin has been shown to enhance insulin release from the pancreas under normal
circumstances. Thus, in healthy men, an elevated insulin response was observed to the
ingestion of a sugar solution if oxytocin had been given in advance by nose spray (3).
Consequently, the peak concentration of blood glucose was lowered. This insulinstimulating
effect of oxytocin appears to be mediated via parasympathetic nerves to the
pancreas, as a similar effect in rats can be abolished by giving atropine which blocks the
action of acetylcholine (4).
But an improved insulin release is just one kind of artillery that oxytocin has in its
possession to fight a poor insulin function. Obviously, a reduced insulin sensitivity is a
consequence of the organs that respond to insulin become less receptive. This is the case
for muscles and adipose tissue, which are responsible for the clearance of blood glucose
and the liver, which must stop releasing glucose to the blood. A decreased insulin
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sensitivity may manifest itself as elevated blood glucose during fasting and as an
increased and sustained rise in blood glucose following the meals. In this regard, oxytocin
can, to some extent, enhance the capacity of insulin to stimulate the uptake of blood
glucose in the muscles (5) and to shut down the release of glucose by the liver (3).
Elevated levels of fatty acids directly obstruct the insulin signalling pathways in the cells
(6), which is why increased concentrations of fatty acids in the blood are considered to
be a major factor in the development of resistance to insulin in overweight people.
Therefore, a possible stimulating effect of oxytocin on fat metabolism and thus the
removal of fatty acids may be an important mechanism for this peptide to increase insulin
sensitivity. Indeed, oxytocin may increase the ability of adipose tissue to retain the fat not
being metabolized right away. In this context, rats treated with oxytocin have been
reported to develop a large number of small effective fat cells (7). This could be explained
by an increased formation of the transcription factor PPAR-γ. Transcription factors are
proteins that are formed and function within the cells and regulate the reading of certain
targeted genes and, by so, influence the production of particular proteins. In this case,
PPAR-γ is a transcription factor that stimulates the division of fat cells.
To the prevention and treatment of insulin resistance and type-2 diabetes, tools are called
for that counteract the progressive deterioration of insulin-responsive organs. Aging is a
factor by itself for this development, but some factors strongly amplify it – including
obesity, as already mentioned. Aged rats, like aged humans, generally have reduced
insulin sensitivity, and just as in humans, their fat mass typically increases with age.
However, it has been reported that old rats that received oxytocin injected into the
abdomen each day for 5 days showed a response in blood glucose to the injection of
glucose that was similar to that of the young rats (8). Also, comparing values of insulin
and glucose in the blood revealed an increased insulin sensitivity in the old rats having
had oxytocin compared to the old rats which did not. No such effect of oxytocin was seen
in the young rats which already had a high insulin sensitivity. The beneficial effect of
oxytocin on insulin sensitivity in the old rats was not a consequence of weight loss as this
did not occur to a significant extent. The phenomenon, on the other hand, could be
attributable to an anti-inflammatory effect of oxytocin. Thus, the old untreated rats
exhibited markedly higher concentrations in the blood of several different inflammatory
cytokines compared to the young. Accordingly, there was a marked increase in the
production of these cytokines in samples taken from both adipose tissue and a thigh
muscle in the old rats. Also, these samples showed higher levels of malondialdehyde,
which is a marker of oxidative stress. All these parameters were brought down to a level
similar to that seen in the younger animals if the old rats had been given oxytocin. This
was also true for TNF-α, which is a cytokine that is notorious for its ability to disrupt
insulin functions. The study nor found any convincing effects of oxytocin treatment on
these parameters in the young rats.
Oxidative stress thus appears to be a significant factor in the development of insulin
resistance. The reason for this is probably obstruction of the signalling function within
the insulin-responsive cells. The skeletal muscles are very crucial as carbohydrate
storage and therefore essential for the clearance of blood glucose. In this regard, several
laboratory experiments have shown that oxidative stress of muscles leads to a reduction
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in insulin sensitivity (9). As the diabetic state by itself leads to oxidative stress, an evil
spiral can be established.
However, as mentioned, the insulin-producing cells in the pancreas may also be damaged
by oxidative stress, which may cause insulin resistance to progress into true diabetes. In
this regard, treatment with antioxidants particularly targeting the mitochondria has been
shown to improve the function of isolated insulin-producing cells after being exposed to
oxidatively reactive substances similar to those formed at high blood sugar levels (10). In
this context, oxytocin may again get on the field. Thus, it has been demonstrated in mice
made diabetic by treatment with streptozotocin that the insulin-producing ability of the
pancreas was partially restored if they received oxytocin along with the streptozotocin
(11). Streptozotocin is knocking out the insulin-producing cells by subjecting them to
massive oxidative stress. Oxytocin also appears to be able to inhibit the development of
other diabetic-induced degenerative conditions, such as nerve damages which is a
frequently manifesting co-morbidity of diabetes (12).
Isles of insulin-producing cells in the pancreas with red staining for insulin. To the right in
a diabetic inflammatory condition with increased infiltration of macrophages (in black).
So, an elevated level of aggressive by-products of glucose metabolism can predispose –
and exacerbate diabetes. Dietary changes aimed at avoiding large fluctuations in blood
glucose is therefore an appropriate measure to alleviate the consequences of diabetes.
Also, an increased accumulation of a body of fat with age may add to the enhanced
inflammatory cytokines activity in the elderly. Thus, a lifelong high level of physical
activity combined with the forsaking of energy-dense foods is a pertinent remedy to
defend an effective insulin function.
But there is a joker in the game – namely the brains impact on the immune system. This
might also, to some extent, be influenced by such lifestyle approaches. However, the
brain-immune axis is also susceptible to other actions not a least those that directly target
the limbic system. In this regard, reinforcement of the oxytocin system may directly and
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via the autonomic nervous system have a moderating impact on the prevailing immune
activity. This may damp a persistent low-grade inflammatory state (13) which otherwise
is accelerating age-generative processes including those harming the insulin function.
Moreover, a direct preserving effect by oxytocin on the skeletal muscles may retard their
decay with age and make it easier to be physically active throughout the last decades of
life.
Oxytocin affects the energy balance
Oxytocin probably plays an important role in regulating our food intake. Oxytocin can
affect the perception of sensory signals from the body – in this case, not from the
genitals – but the gastrointestinal tract. Also, by acting on parts of our reward system
oxytocin can influence the urge and pleasure associated with food consumption – in a
repressing rather than enhancing way. Animal studies support that oxytocin influences
food intake in a close interaction with other signalling agents supposed to be essential
for appetite regulation. Oxytocin also has the potential to stimulate both the
combustion of fat and the total energy turnover of the body, which may support the
establishment of a transitional negative energy balance.
Should an attractive mare come into sight, by whom it might be a good idea to share some
DNA, the stallion must prioritize, now the opportunity arises. In other words, it does not
help that it remains immersed in its grazing. In this context, it could be logical if oxytocin
has developed a hunger-suppressing effect. On the other hand, it may seem contradictory
that oxytocin inhibits hunger in the nursing female. However, it may be appropriate that
the mother's urge for seeking food does not reach a level where the child may be
neglected. Other signalling systems may, in this case, go in and counteract the attenuating
effect of oxytocin on hunger, so that she does not suffer from food shortages.
Much attention has already been paid to the effects of oxytocin on food intake and energy
balance, as research on prevention and treatment of obesity is a major area of focus
worldwide for good reasons. Many rodent trials have demonstrated that meals are
shortened while the intervals between the meals are increased when oxytocin is injected
into the brain cavities (14). One of the mechanisms of action may be that oxytocin
attenuates the reward associated with eating. Thus, mice having their oxytocin function
knocked out, demonstrated a greatly increased intake of a freely available sugar solution.
However, this was not the case, if they were given an ordinary and not very tasty diet
(15). Conversely, the urge for sugar was reported to be reduced in normal rats if they
were given oxytocin directly into the ventral tegmental area by an introduced cannula
(16). When normal-weight men were given oxytocin as a nasal spray, no effect was
detected on how much food they consumed from a breakfast buffet, however, the intake
of tasty snacks after the meal was reduced (17). In a more recent study, it was found that
the inhibitory effect of oxytocin on food intake was most pronounced in obese subjects
whose consumption from the breakfast buffet also was reduced (18). Also, it has been
reported that oxytocin attenuated the response in the ventral tegmental area – assessed
by fMRI – to photographs of energy-rich dishes (19). This indicates a decreased sensitivity
of the reward system to food-related stimuli. These results confirm the thesis that
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oxytocin diminishes the hedonic aspects of the urge to eat rather than affects hunger
itself. Such inhibition by oxytocin on the hedonic response to food may be so persistent
in humans that it may cause a weight loss. An average weight loss of about 9 kg over 8
weeks has been reported in a small preliminary study on obese patients, with the
administration of oxytocin four times a day as the only intervention. No weight loss was
seen in a control group receiving an inactive nasal spray (11).
The regulation of food intake is very complicated and involves the limbic system
including the hypothalamus, motivation-related areas of the cerebral cortex, and the
brainstem. Thus, the nucleus tractus solitarius which is situated in the brainstem may be
an important part of the hunger regulation system as it comprehends a relay station for
upward and downward signals transmitted via the vagus nerve. Sensory signals from the
stomach can be enhanced by input from oxytocin-carrying nerves when passing this
nucleus on their way to higher brain centres. This is somewhat like what can happen with
sensory signals from the genitals. An extended stomach can, therefore, be perceived with
greater intensity, causing the feeling of satiation to occur earlier. Also, oxytocin-carrying
nerves may affect nerve signals from the brainstem to the stomach reducing its motor
activity, so that it remains extended for a longer period (14). Finally, some sensory vagus
nerve endings in the gut which are responsive to hunger attenuating substances such as
leptin and CCK can also be stimulated by oxytocin (20). This means that oxytocin present
in the blood or being released in vicinity of these nerve ending may contribute to a satiety
signal sent from the gut to the brain by the vagus nerve.
Different nuclei in the hypothalamus receive signals which inform about conditions in the
stomach, intestine, liver, and adipose tissue via nerve pathways but also via hormones
secreted by these organs. This influences the activity in the brain of different nerve
systems each using one or few of the numerous different signalling substances – of which
oxytocin is just one of them. By interacting with each other these systems ultimately
decide whether to eat or not – and maybe also – what to eat. This is probably one of the
reasons why the development of a medicine that can effectively prevent and treat obesity
Oxytocin must be given as a
nasal spray to achieve a direct
effect on the brain.
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is a very complicated matter. Such medicine must neither cause unacceptable side effects
nor have an effect which is too small because it targets a signal system that can be
overridden by other signal systems.
The melanocortin system brain should be mentioned as a possible target point for
affecting energy balance of the body because it appears to constitute an intermediary
between incoming signals about energy status of the body including insulin- and leptin
levels and outgoing signals that can affect food intake as well as the amount of nutrient
combustion in the body (21). Oxytocin appears to be one of the important messengers of
its outbound signals. This is indicated by observation that the reduction of food intake
induced by stimulation of certain parts of the melanocortin system can be counteracted
by concomitant administration of a substance that blocked the effect of oxytocin (22).
Should a drug be developed with an effective anti-obesity effect that is targeting the
melanocortin system, one should, therefore, be aware that it would hardly work without
oxytocin as a partner.
The oxytocin system can influence the energy balance of the body not only by reducing
nutrient intake but also by increasing nutrient combustion. A weight loss has been
reported in rats during prolonged treatment with oxytocin, although no sustained
reduction in energy intake could be detected in that experiment. Concordantly, rodents
were reported to become obese if their oxytocin system was knocked out by genetic
manipulation despite that their food intake was unaffected (23). Conversely, rhesus
monkeys who had been made obese by having free access to soft drinks lost weight
during a 4 week period while they received injections of oxytocin into the blood twice
daily but still had free access to the same diet. The monkeys had their food intake
recorded and their combustion measured. The weight loss could only be explained by a
combination of reduced food intake and increased combustion, particularly at night (24).
Given that oxytocin has an immediate half-life in the blood of a few minutes, it must be
questioned how 2 daily injections of the drug into the blood can affect eating behaviour
and combustion throughout the entire day. However, some oxytocin may accumulate in
the tissue to being subsequently released. Alternatively, the phenomenon might be
explained by short-term high concentrations of oxytocin in the blood enhancing the
oxytocin system. This could applicable both to the release of – and sensitivity to – oxytocin.
Such a reinforcement may also be of significance to the sexual response, birth,
breastfeeding, and relationships as previously discussed.
The oxytocin system may increase energy turnover by communicating with nerve
pathways in the sympathetic nervous system, which stimulates the combustion. This
encompasses nervous stimulation of the brown adipose tissue. Brown adipose tissue is
made up of transformed fat cells being dedicated to producing heat. In this regard,
oxytocin is important for the ability of small mammals to stimulate combustion when
exposed to cold (25) and nerve endings in the brown adipose tissue has been traced back
to oxytocin-producing areas of the hypothalamus (26). Small mammals rely heavily on
brown adipose tissue to keep warm under cold conditions. In adult large mammals such
as humans, however, the amount of brown adipose tissue is usually limited and normally,
its role in the overall energy turnover appears to be insignificant. However, oxytocin can
stimulate the conversion of normal fat cells into brown fat cells via a hormone called atrial
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natriuretic peptide (ANP) (27) – more about this hormone later. The ability of oxytocin to
increase combustion makes sense when it comes to nursing since the mother thereby
better can manage to keep her cubs warm.
Brown fat cells
But in addition to increasing energy turnover in the body, a study in fasting healthy men
has demonstrated that they burned more fat compared to carbohydrates after they have
had oxytocin by a nasal spray (28). The ratio of fat to carbohydrate being combusted can
be calculated from assessments of the person's oxygen uptake and CO2 production
measured in their ventilation. Interventions that increase the combustion of fat in favour
of carbohydrates are believed to have the potential for weight loss. This is because a
shortage in carbohydrate storage particularly in the liver may elicit hunger. If more fat is
combusted less carbohydrate would be needed from its deposits and it will, therefore,
take longer before they reach a level that triggers an urge to eat. Also, the size of the meals
may tend to be reduced.
Thus, oxytocin seems to affect metabolism in numerous ways and there are many
possible explanations that this peptide may increase fat burning. Experiments with
isolated cells have demonstrated that oxytocin can activate the transcription factor PPAR-
α (29). PPAR-α stimulates the reading of a variety of genes that encode enzymes
responsible for the mobilization, degradation, and combustion of fat. Furthermore, the
researchers reported that the application of oxytocin into the brain cavities in rats
reduced the fat content of the blood and increased the number of enzymes in the adipose
tissue that degrades fat. This may mean a greater global fat metabolism in the body.
Although the oxytocin was given into the brain, the effects could also have been hormonal,
as its blood concentration also increased. On the other hand, the increased fat combustion
with oxytocin in the aforementioned human experiment must have been nerve-mediated,
as there was no effect on the blood level of oxytocin by the nasal administration. The
activation by oxytocin of specific pathways in the sympathetic nervous system extending
to the adipose tissue may be one explanation in this case. Indeed, fat cells can be
125
stimulated via such nerve pathways to release fatty acids into the blood (30), which then
will "compete" with carbohydrates to be used as fuel.
It should also be mentioned that the increase in insulin sensitivity caused by oxytocin also
may affect the ratio of fat to carbohydrates being combusted. Despite that insulin directly
stimulates carbohydrate combustion, increased sensitivity to insulin – at least when
provided through physical exercise – appears to be linked to an improved capacity to
mobilize fat for combustion in situations where a long time has passed since the last meal
(31). The fact that oxytocin has developed an ability to support the mobilization and
combustion of fat may be a consequence of the mother being required to supply a waste
amount of fuel to the offspring through the milk and therefore easily comes into an energy
deficit where she has to rely on her fat depots.
1. Asih PR, Tegg ML, Sohrabi H, Carruthers M, Gandy SE, Saad F, Verdile G, Ittner LM,
Martins RN. Multiple Mechanisms Linking Type 2 Diabetes and Alzheimer's
Disease: Testosterone as a Modifier. Journal of Alzheimer's Disease 2017; 59(2):
445-466.
2. Mao P, Reddy PH. Aging and amyloid beta-induced oxidative DNA damage and
mitochondrial dysfunction in Alzheimer's disease: implications for early
intervention and therapeutics. Biochimica et Biophysica Acta 2011; 1812(11):
1359-1370.
3. Klement J, Ott V, Rapp K, Brede S, Piccinini F, Cobelli C, Lehnert H, Hallschmid M.
Oxytocin Improves β-Cell Responsivity and Glucose Tolerance in Healthy Men.
Diabetes 2017; 66(2): 264-271.
4. Björkstrand E, Eriksson M, Uvnäs-Moberg K. Evidence of a peripheral and a central
effect of oxytocin on pancreatic hormone release in rats. Neuroendocrinology
1996; 63(4): 377-383.
5. Lee ES, Uhm KO, Lee YM, Kwon J, Park SH, Soo KH. Oxytocin stimulates glucose
uptake in skeletal muscle cells through the calcium-CaMKK-AMPK pathway.
Regulatory Peptides 2008; 151(1-3): 71-74.
6. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in
human muscle is associated with changes in diacylglycerol, protein kinase C, and
IkappaB-alpha. Diabetes 2002; 51(7): 2005-2011.
7. Eckertova M, Ondrejcakova M, Krskova K, Zorad S, Jezova D. Subchronic treatment
of rats with oxytocin results in improved adipocyte differentiation and increased
gene expression of factors involved in adipogenesis. British Journal of
Pharmacology. 2011;162(2):452-463.
8. Abood AM, Alghamdi BS. Oxytocin supplementation alleviates age-related insulin
resistance through down regulation of pro-inflammatory cytokine gene
expression. Biomedical Research 2017; 28(5): 2209-2215.
9. Henriksen EJ, Diamond-Stanic MK, Marchionne EM. Oxidative stress and the
etiology of insulin resistance and type 2 diabetes. Free Radical Biology and
Medicine 2011; 51(5): 993-999.
10. Lim S, Rashid MA, Jang M, Kim Y, Won H, Lee J, Woo JT, Kim YS, Murphy MP, Ali L,
Ha J, Kim SS. Mitochondria-targeted antioxidants protect pancreatic β -cells
against oxidative stress and improve insulin secretion in glucotoxicity and
glucolipotoxicity. Cellular Physiology and Biochemistry 2011; 28(5): 873-886.
126
11. Zhang H, Wu C, Chen Q, Chen X, Xu Z, Wu J, Cai D. Treatment of obesity and diabetes
using oxytocin or analogs in patients and mouse models. PLoS One 2013; 8(5):
e61477.
12. Erbas O, Taşkıran D, Oltulu F, Yavaşoğlu A, Bora S, Bilge O, Çınar BP, Peker G.
Oxytocin provides protection against diabetic polyneuropathy in rats.
Neurological Research 2017; 39(1): 45-53.
13. Fulop T, Le Page A, Fortin C, Witkowski JM, Dupuis G, Larbi A. Cellular signaling in
the aging immune system. Current Opinion in Immunology 2014; 29: 105-111.
14. Sabatier N, Leng G, Menzies J. Oytocin, feeding, and satiety. Frontiers in
Endocrinology 2013; 4: 35.
15. Amico JA, Vollmer RR, Cai HM, Miedlar JA, Rinaman L. Enhanced initial and
sustained intake of sucrose solution in mice with an oxytocin gene deletion.
American Journal of Physiology-Regulatory, Integrative and Comparative
Physiology 2005; 289(6): R1798-1806.
16. Mullis K, Kay K, Williams DL. Oxytocin action in the ventral tegmental area affects
sucrose intake. Brain Research 2013; 1513: 85-91.
17. Ott V, Finlayson G, Lehnert H, Heitmann B, Heinrichs M, Born J, Hallschmid M.
Oxytocin reduces reward-driven food intake in humans. Diabetes 2013; 62(10):
3418-3425.
18. Thienel M, Fritsche A, Heinrichs M, Peter A, Ewers M, Lehnert H, Born J, Hallschmid
M. Oxytocin's inhibitory effect on food intake is stronger in obese than normalweight
men. International Journal of Obesity 2016; 40(11): 1707-1714.
19. Plessow F, Marengi D, Perry SK, Felicione JM, Franklin R, Holmes TM, Holsen LM5,
Makris N6, Deckersbach T, Lawson EA. Effects of intranasal oxytocin on the blood
oxygenation level-dependent signal in food motivation and cognitive control
pathways in overweight and obese men. Neuropsychopharmacology. 2018; 43(3):
638-645.
20. Iwasaki Y, Maejima Y, Suyama S, Yoshida M, Arai T, Katsurada K, Kumari P,
Nakabayashi H, Kakei M, Yada T. Peripheral oxytocin activates vagal afferent
neurons to suppress feeding in normal and leptin-resistant mice: a route for
ameliorating hyperphagia and obesity. American Journal Physiology. Regulatory
Integrative Comparative Physiology 2015; 308(5): R360-369.
21. Kim JD, Leyva S, Diano S. Hormonal regulation of the hypothalamic melanocortin
system. Frontiers in Physiology 2014; 5: 480.
22. Yosten GL, Samson WK. The anorexigenic and hypertensive effects of nesfatin-1
are reversed by pretreatment with an oxytocin receptor antagonist. American
journal of physiology. Regulatory, integrative and comparative physiology 2010;
298(6): R1642-1647.
23. Takayanagi Y, Kasahara Y, Onaka T, Takahashi N, Kawada T, Nishimori K. Oxytocin
receptor-deficient mice developed late-onset obesity. Neuroreport 2008; 19(9):
951-955.
24. Blevins JE, Graham JL, Morton GJ, Bales KL, Schwartz MW, Baskin DG, Havel PJ.
Chronic oxytocin administration inhibits food intake, increases energy
expenditure, and produces weight loss in fructose-fed obese rhesus monkeys.
American journal of physiology. Regulatory, integrative and comparative
physiology 2015; 308(5): R431-R438.
25. Kasahara Y, Takayanagi Y, Kawada T, Itoi K, Nishimori K. Impaired
thermoregulatory ability of oxytocin-deficient mice during cold-exposure.
Bioscience, Biotechnology, and Biochemistry 2007; 71(12):3122-3126.
127
26. Oldfield BJ, Giles ME, Watson A, Anderson C, Colvill LM, McKinley MJ. The
neurochemical characterisation of hypothalamic pathways projecting
polysynaptically to brown adipose tissue in the rat. Neuroscience 2002;
110(3):515-526.
27. Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessì-Fulgheri P, Zhang C, Takahashi N,
Sarzani R, Collins S. Cardiac natriuretic peptides act via p38 MAPK to induce the
brown fat thermogenic program in mouse and human adipocytes. Journal of
Clinical Investigation 2012; 122(3): 1022-1036.
28. Lawson EA, Marengi DA, DeSanti RL, Holmes TM, Schoenfeld DA, Tolley CJ.
Oxytocin reduces caloric intake in men. Obesity 2015; 23(5):950-956.
29. Deblon N, Veyrat-Durebex C, Bourgoin L, Caillon A, Bussier AL, Petrosino S,
Piscitelli F, Legros JJ, Geenen V, Foti M, Wahli W, Di Marzo V, Rohner-Jeanrenaud
F. Mechanisms of the anti-obesity effects of oxytocin in diet-induced obese rats.
PLoS One 2011; 6(9):e25565.
30. Bartness TJ, Shrestha YB, Vaughan CH, Schwartz GJ, Song CK. Sensory and
sympathetic nervous system control of white adipose tissue lipolysis. Molecular
and Cellular Endocrinology 2010; 318(1-2): 34-43.
31. Goodpaster BH, Katsiaras A, Kelley DE. Enhanced fat oxidation through physical
activity is associated with improvements in insulin sensitivity in obesity. Diabetes
2003; 52(9): 2191-2197.
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Chapter IX
Heart and brain
129
Oxytocin as a heart protector
Oxytocin plays an important role in blood pressure regulation. This involves both the
autonomic nervous system and hormonal effects. Apart from being able to lower blood
pressure, oxytocin can stimulate fat metabolism in such a way as to counteract fat and
cholesterol accumulation in the walls of the blood vessels. However, sustained
inhibition of inflammatory reactions in the vessels may be of even greater significance
for the protection of the heart. Should the heart be exposed to unhealthy stress, for
example, by prolonged periods with hypertension, oxytocin may counteract the
formation of injuries which otherwise may reduce its pumping power. The latter effect
of oxytocin may involve its ability to protect and activate stem cells.
Cardiovascular diseases at mid-life do not only cause the early death of many people, they
are also guilty of the loss of a great many years with a good quality of life. Therefore, it is
not without reason that general health recommendations in Western societies are
directed towards the prevention of these diseases including more physical activity. But
had it been possible, we would certainly have been recommended to breastfeed every
day – young as old, women as men. Thus, several population studies have confirmed that
breastfeeding has a significant preventive effect on the development of cardiovascular
disorders. To mention, a large US study on postmenopausal women has shown that even
at this age, a preventive effect of the previous breastfeeding could be traced so that
mothers who had breastfed their children for more than 12 months in total had a slightly
lower frequency of cardiovascular disease compared to mothers who had never breastfed
(1). Such an observation can have many explanations, for instance, that women with a
high social status may be more motivated to breastfeed or that a high level of stress may
lead to giving up breastfeeding. Also, breastfeeding can cause a reduction in weight gain
that is often seen after pregnancy.
However, such factors that relate statistically both with cardiovascular diseases and
breast-feeding do not appear to be the whole explanation. In a study on menopausal
mothers which likewise compared those who had breastfed to those who had not, one
assessed the risk factors for developing cardiovascular diseases such as high blood fat
concentration, poor blood glucose control, high waist circumference, and hypertension
(2). In this case, it was found that the mothers who had breastfed had a lower propensity
to exhibit a risk profile, even after possible interacting factors such as Body Mass Index
(BMI), smoking, physical activity, and social status statistically were taken into account.
Furthermore, the longer the mothers had breastfed, the smaller was the tendency to be
at risk for cardiovascular disease. A third similar study found that middle-aged mothers
who had breast-fed demonstrated a markedly lower frequency of signs of atherosclerosis
in the major arteries even after social and lifestyle factors were taken into account (3).
These results indicate that breastfeeding, by itself, protects against cardiovascular
disease later in life. Such an effect may be contingent upon hormonal changes associated
with breastfeeding. Two hormones are markedly increased in breastfeeding; prolactin,
which is responsible for milk production, and oxytocin, which, as mentioned, is necessary
for milk expulsion. The fact that these beneficial effects of breastfeeding can be detected
for many years could be speculated to involve epigenetic effects on the oxytocin system
or other systems being important for metabolism and inflammatory reactions.
130
That a high oxytocin activity may prevent cardiovascular disease from developing with
fatal consequences can be argued on several levels. I have already mentioned the ability
of oxytocin to attenuate inflammatory reactions and oxidative attacks on the vessel walls,
which, by itself, could reduce the risk of blood vessel constrictions and thrombosis. Also,
I have mentioned that the antioxidative properties of oxytocin may be potent enough to
have a protective effect on the heart muscle – should an event of coronary thrombosis
occur. Furthermore, trials indicate that treatment with oxytocin actually can improve
blood fat profile, also in humans, by reducing the amount of total cholesterol and lowdensity
lipoprotein (4). Elevated blood concentrations of these lipid components are
significant risk factors for cardiovascular disease. The beneficial effects on blood lipids
are not necessarily dependent on any weight loss since an acute drop in blood triglyceride
concentration has been reported in women after a single oxytocin injection (5). The fact
that oxytocin has such an effect must be attributable to its ability to stimulate fat
metabolism.
However, oxytocin seems to have even more ace to play when it comes to protecting the
heart and circulation. Few people know that the heart is also an endocrine gland, but it is
quite naturally that the organ which generates the blood pressure also participates in
regulating it. This is mainly executed by the right atrium producing and secreting a
hormone called Atrial Natriuretic Peptide (ANP). ANP has a blood pressure-lowering
effect by reducing the blood and fluid volume in the body. This is carried out when ANP
reduces the retention of sodium ions and consequently water in the kidneys resulting in
increased urinary excretion (6). ANP is activated as follows: ANP release from the right
atrium is directly stimulated when the atrium is extended. An increased extension occurs
when the return of blood to the heart is increased. This is sensed by stretch receptors in
the muscle tissue, causing them to send a signal to release more ANP (7). Since an
elevated blood volume results in increased blood flow to the heart, ANP can act as a
feedback regulator for the blood volume.
However, some nervous and hormonal factors participate in the regulation of the ANP
secretion by the heart. Stretch receptors in the carotid artery supplying the brain are
essential for immediate blood pressure regulation by sending signals up to the brain
stem. From here, the signals are sent directly back to the heart but also further on to the
hypothalamus. The hypothalamus can then respond by releasing hormones that affect the
heart including oxytocin. Thus, the right atrium is densely equipped with oxytocin
receptors which enable it to respond to the hormone with an increased release of ANP
(8). This mechanism reminds a little of what happens during childbirth, where it also is a
nerve signal produced by stretch receptors that cause the hypothalamus to release
oxytocin to the blood.
ANP is an extremely potent hormone when it comes to increasing the urine production
(9), which most people have faced by the urge to pass water when exposed to cold
conditions (10). In this case, the diminished blood supply to the skin causes a temporarily
increased inflow to the heart. The large amounts of highly diluted urine produced by
some women during sexual stimulation (11) may therefore be explained by an oxytocininduced
ANP release. In addition to increasing urinary output, ANP also reduces the fluid
131
volume of the body by inhibiting thirst and the urge for salt (12). Remarkable, oxytocin
itself has a slight reducing effect on urinary excretion, due to its slight similarity with
vasopressin and can therefore also act on the vasopressin receptors to some extent (13).
However, regulating blood pressure by changing blood volume only makes sense if a
blood pressure being too high or too low is caused by a too high or too low blood volume,
respectively. The latter can be attributable to the loss of fluid by a large sweat production.
If the derangement of blood pressure is due to other factors than deviations in blood
volume, blood pressure can be regulated directly by controlling the pumping activity of
the heart or by the resistance of the minor arteries. In the latter case, arterial resistance
is increased when the diameter of the vessel is decreased by contraction of the small
muscles encircling it. In both cases, these adjustments can be performed second-bysecond
by being mediated through nerves. Such regulation is imperative as we otherwise
would pass out when we get up from a lying to an upright position. Both parts of the
autonomic nervous system are involved in this regulation, where the sympathetic part
raises blood pressure while the parasympathetic lowers it.
Oxytocin has been shown to affect the heart in such a way that both the rate and
contraction power is reduced. As previously mentioned, this effect may be exerted by
oxytocin carrying nerves acting on heart regulating centres in the brainstem. However,
oxytocin may also influence heart activity by hormonal routes. In isolated rat hearts, it
has been demonstrated that a suppressing impact on the heart by oxytocin could be
blocked by atropine, suggesting that the responsiveness of parasympathetic nerve
endings in the heart appears to be enhanced by oxytocin (14). This is a textbook example
of oxytocin acting as a neuromodulator. In this case, it does so, as a hormone.
Blood pressure is determined not only by the pumping activity of the heart but also by
the overall resistance in the bloodstream, which is why much of the medicine given for
hypertension has a muscle-relaxing impact on the blood vessels. Nitric oxide (NO) is
produced by the endothelial cells forming the inside lining of the blood vessels. In this
context, NO plays an important role as a regulator of the vessel diameter by diffusing into
the musculature of the vessel wall, where it induces a relaxation (15). NO is a small,
unstable fat-soluble molecule that readily passes through cellular structures. Therefore,
it can be used in very short-lived signalling mechanisms between neighbouring cells of
different types.
Conversely, the signal substances adrenaline and noradrenalin activate the calcium ion
release inside muscle cells, thereby causing them to contract. This is an important
mechanism when reducing the diameter of blood vessels to maintain blood pressure.
When you become pale in the face by rage, this is caused by a constriction of the blood
vessels in your skin when their musculature becomes directly stimulated by neural
noradrenaline increasing the concentration of calcium ions inside the muscle cells. But in
contrast, the blood supply to different other organs, including skeletal muscles may
concomitantly be increased when you are going into a "flight or fight" mode. For these
organs, stimulation by the sympathetic nerve pathways must therefore rather lead to
blood vessel extension. Here, it is to a greater extent the endothelial cells that are
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stimulated by the noradrenalin. This also leads to a rise of the calcium ions inside these
cells, but in this case, it prompts them to release NO instead. This NO then reaches the
muscle cells of the vessels, causing them to relax. Therefore, whether stimulation by
sympathetic nerves promotes or decreases blood supply to an organ depends on the
balance of stimulation between the muscle and the endothelial cells of the vessels (16),
which in turn can be determined by how the cells are equipped by the various receptors
for adrenaline and noradrenalin.
What about the calcium ion-releasing effect of oxytocin on the different cells of the blood
vessels? Its overall capacity to stimulate calcium ion release inside the cells is certainly
not exerted unnoticed when it torments the smooth muscle of the uterus during
childbirth. Can oxytocin also affect the blood vessels smooth muscle? In this regard,
oxytocin receptors have been found in the endothelial cells of certain blood vessels where
they can be stimulated to produce NO by oxytocin by calcium ion-dependent response
(17). That oxytocin has such a vasodilatory effect conditioned by NO-release is supported
by a study on dogs. Here, it was found that an increase in blood flow into the brain induced
by oxytocin administration could be blocked by a substance that counteracted NO
synthesis (18). Thus, a general vasodilatory effect of oxytocin via stimulation of NO
production in the blood vessels may well contribute to the blood pressure-lowering effect
of oxytocin. The NO-mediated vasodilatation is also targeted by drugs with a β3-
adrenoceptor stimulating effect that is used for the treatment of hypertension (19).
Oxytocin differs with its vasodilating effect from its sister hormone vasopressin, which
generally has a marked constricting effect on the blood vessels (hence the name of this
hormone). Moreover, the increased NO production in the endothelium may constitute a
protective effect against atherosclerosis by inhibiting inflammatory reactions in the
vessel wall at the same time. This has been demonstrated in experiments with rats (20).
The term cardioprotective is used for drugs that protect the heart from excessive stress.
An overload of the heart may occur if it is stimulated excessively by the sympathetic
nervous system over a long period. Therefore, beta-blockers are said to have a
cardioprotective effect by reducing the effects of adrenaline and norepinephrine on the
heart (21). Thus, if blood pressure remains substantially elevated chronically, the heart
muscle can be damaged, thereby impairing its pumping capacity (22). In this case, the
injuries are manifested as an enlarged heart, where some of the muscle is replaced by
connective tissue.
A surgical procedure in which the aorta is constricted so that the heart must increase its
pumping power to allow the same amount of blood to pass can be used as an animal
model for the long-term impact of elevated blood pressure. Such an experiment set-up
with rats demonstrated that stimulating their hypothalamus to release more oxytocin
reduced the deleterious effects of the procedure on the heart muscle and its pumping
capacity (23). As there was no increase in the hormonal levels of oxytocin, the researchers
proposed that this beneficial effect must have been mediated by nerves. Again, it is most
likely that increased activity in the oxytocin-carrying nerve pathways had led to
increased parasympathetic stimulation of the heart.
133
The heart can enlarge but the musculature may degenerate with chronic overload. This
condition is named cardiomyopathy.
The deteriorated pumping capacity of the heart associated with high blood pressure is
frequently seen in people with type 2 diabetes (24). The so-called dB/dB mouse is often
used as a model for type-2 diabetes in humans. It has a genetic defect that causes it to
develop severe obesity and diabetes as well as high blood pressure and poor heart
function. Treating such mice with oxytocin can retard their disease progression and not
least the damage to the heart. In such an experiment, the structure of their heart muscle
remained intact without scarring and cell death, as well as the pumping function of the
heart was preserved (25). As the effect of the oxytocin on insulin and blood sugar was
relatively modest in this case, other effects on the heart of the peptide may have
prevailed. Along with these clinical observations, significantly lower levels of oxidative
stress markers and inflammatory cytokine activity in the heart muscle were seen. These
observations emphasize that oxytocin can not only counteract tissue damages during
acute stress exposure but also more chronic inflammatory conditions.
What is very exciting in a cardiac context is a possible regenerative effect by oxytocin via
a growth-stimulating effect on the heart muscle. Thus, oxytocin appears to be a very
important growth factor in the development of cardiac muscle. This has been
demonstrated on various types of isolated primitive stem cells that can differentiate into
heart muscle cells by adding oxytocin to the growth medium (26). Such observations
point to oxytocin as an important factor for the entire development of the heart,
particularly in the latter part of pregnancy where the level of the peptide is high in the
fetus (27).
But oxytocin as a growth factor can also be important for the hearts of adult individuals.
Thus, even in adult mice, stem cells have been found in the cardiac muscle and have been
removed and isolated. Subsequently, they could be prompted to express genes and
produce proteins specific to heart muscle cells by treating them with oxytocin (28). Also,
134
they formed fibres and began to contract rhythmically. Also, the influence of oxytocin led
to an upregulation of the oxytocin receptors in these cells. Thus, if the heart can replace
damaged muscle fibres with new ones, it can be of great importance for its regeneration
also following a coronary thrombosis. Such a restoring effect of oxytocin on heart muscle
fibres may, therefore, be part of the explanation, that a better regeneration can be
observed in animal reperfusion models for thrombosis if the peptide is given.
Oxytocin may not only stimulate the growth of muscle cells but also the formation of new
blood vessels (29). When tissues are or have been exposed to oxygen deficiency, the cells
release cytokines which cause stem cells to develop into blood vessels and, by so, restore
the blood- and thus oxygen supply (30). This is not at least important for the
reconstruction of a damaged heart muscle. Several animal studies have shown that the
regeneration of the cardiac muscle after occlusion of the blood supply can be improved
by the administration of mesenchymal stem cells. Part of this effect has been attributed
to an increased renewal of blood vessels. But these intriguing results have unfortunately
been less successful to replicate in clinical trials with patients who have had a coronary
thrombosis. One reason for this may be that the stem cells taken from the bone marrow
of the patients may have had little capacity to differentiate and form new tissue (31). This
could be due to the advanced age of the patients and not at least that they have or have
had diabetes in many cases. As mentioned, coronary thrombosis is a frequent
complication of diabetes, and, at the same time, diabetes may damage the stem cells in
the body. But on the other hand, the use of the patients' stem cells is to prefer to exclude
the risk of rejection.
There might be a solution to this situation. Recent animal studies indicate that stem cells
can be revitalized if treated with oxytocin before being returned to the patient. As
previously mentioned, a diabetic state can be induced in experimental animals by giving
them streptozotocin. In an experiment testing the capacity of rat marrow mesenchymal
stem cells to divide and form blood vessels, this ability was impaired in cells collected
from streptozotocin-treated diabetic animals. However, their capacity could be restored
if they had been cultured with oxytocin in advance (32). Stem cells from diabetic rats
were also tested for their capacity to restore the function of a whole damaged heart with
or without prior treatment with oxytocin. Here, it was found that the pumping function
of the injured hearts was improved by using oxytocin treated stem. This was not the case
if untreated stem cells were used. These observations gave the researchers reason to
argue that stem cells pre-treated with oxytocin might be an approach for post-thrombotic
treatment. The potential of oxytocin to enhance the ability of stem cells to restore
damaged cardiac muscle has also been shown in other studies (33). Perhaps these results
may inspire studies on the use of oxytocin for the enhancement of stem cells in other
contexts. Indeed, these results may reflect a general capacity of oxytocin to strengthen
and protect stem cells not only residing in the heart, skeletal muscles, bones, and the
immune system but in most tissue and organs of the body. This may, in fact, further
contribute to the potential of oxytocin to retard aging processes.
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Oxytocin and thrombosis in the brain
The counteracting effect of oxytocin on inflammatory reactions and oxidative stress
may be beneficial in the brain as it is in the heart. For the brain, it might be fortunate
that oxytocin is produced here and possibly can reach most of the remote corners of
the brain. Also, it has been suggested that oxytocin, could have a protective effect
against nerve damage by being able to counteract an "overheated" nerve activity if a
thrombotic event should occur in the brain.
Coronary thromboses are not the only critical situations where oxytocin may have the
capacity to mitigate the impact. This also applies to thrombosis in the brain. The
consequences of such blood clots vary greatly from paralysis in different parts of the body
over sensory disturbances to mental symptoms, depending on which location in the brain
that has been affected by the lack of blood supply. Studies on groups of people have
shown that if you first have had one thrombosis in your brain, the prognosis of not dying
of another one is better if you have a good social network (34). In line with this, mice that
are allowed interact with other mice demonstrate less tissue damage after a disruption
of the blood supply to a particular site of the brain compared to mice that live in isolation
(35). However, if the non-isolated mice received a substance that blocked oxytocin, the
tissue damages were comparable to those of the isolated mice. Conversely, the tissue
damage of the isolated mice could be alleviated by giving them oxytocin.
As the brain cannot be reached by immune cells from the blood, it has developed its
immune cells, which also have the potential to induce an inflammatory state when the
tissue is stressed. Oxytocin can also attenuate inflammatory reactions in the brain, but it
may also have other options to protect nerve tissue by increasing the responsiveness of
the gamma-aminobutyric acid (GABA) receptors in the nerve cells (36). GABA is the most
important inhibiting signalling substance of the brain. In this context, many sedatives
drugs are targeting the GABA system (37) and a short-term upregulation of this system
may contribute to the tranquilizing effects of sex and breastfeeding.
If brain cells are exposed to oxygen deficiency the same thing happens as for the muscle
cells of the heart, they become electrically unstable. This can amplify the damaging effects
because the instability causes the cells to start firing at a high intensity which, in turn,
increases their need for oxygen, a need that cannot be fulfilled. This would potentiate the
electric activity even more establishing a vicious spiral that also involves an impaired
breakdown of the excitatory substance glutamate due to lack of energy. Targeting the
GABA system has been proposed to reduce the risk of these so-called excitotoxicity crises.
In an experiment with isolated nerve cells collected from rat brains, an increased ability
to survive oxygen deficiency with less damage to their mitochondria was observed if
oxytocin was added to in their medium (36). Concomitantly, the number of chloride ions
(Cl-) which passes into the cells during stimulation with GABA was greater if oxytocin was
given. Opening for inward passage of Cl- across the cell membrane is an important
mechanism for nerve cells to increase the voltage difference across their membranes and,
by so, reduce their propensity to fire. In this regard, the high levels of oxytocin in the
infant during childbirth have been suggested to protect against brain damage that could
136
arise if a deficiency of oxygen might occur. This oxytocin is most likely originating from
the infant's own brain as the oxytocin produced by the mother does probably not cross
the blood-brain barrier to a significant extent. However, whether such a GABA dependent
protective effect of oxytocin on brain cells exists during oxygen deprivation remains
highly hypothetic and GABA receptor stimulating drugs do not appear to have any
obvious therapeutic effect when administered to patients suffering from brain
thrombosis (38).
Another possible protective effect of oxytocin against brain damage due to defective
blood vessels may be to inhibit the development of atherosclerosis itself. In this regard,
oxytocin seems to have a reducing impact on the ability of the monocytes to adhere to the
vessel wall, thereby attenuating the deposits of fats. By so, the age-related impairment of
blood supply to the brain tissue, and the risk for thrombus formation in the brain could
be postponed. Thrombotic obstruction of the blood flow in the very small arteries of the
brain is causing the so-called vascular dementia which, second Alzheimer's, is the most
frequent cause of dementia. An inhibition by oxytocin on the propensities of the
endothelial cells to adhere to monocytes is supported by an experiment where such cells
were isolated from the wall of small blood vessels in a human brain and exposed to
oxytocin (39). Oxytocin may have a similar effect on blood vessels elsewhere in the body.
Oxytocin is important for brain development
Some substances used by the brain for signalling are also important for brain
development both in the foetal state and after birth, but perhaps also later in life.
Among these, oxytocin appears to be indispensable for the huge nervous network to
develop normally. A defective oxytocin system may, therefore, mean abnormal wiring
of the nerves resulting in aberrant behaviour such as traits within the autism spectrum.
In the adult brain, oxytocin may also be important for certain learning processes.
The structure of the brain is constructed throughout the foetal state but also during the
time after birth where stem cells are differentiating into nerve cells as well as cells that
support the function of the nerve cells. It is still controversial to which extent stem cells
also can maintain and repair nerve tissue in adult humans. However, the kind of studies
that can be conducted to elucidate this topic indicate that this may be the case to some
extent – at least in certain areas of the brain (40).
An important element in the development of a nerve cell is the formation of filamentous
outgrowth which carries the electrical signals. These nerve fibres are developed during
differentiation when the cell begins to produce long protein filaments that force the cell
membrane out from the cell body (41). Most of the fibres become relatively short and
constitute the dendrites, through which the nerve cell receives signals. But most often
only one of these fibres develops into a long fibre (axon) through which the nerve cell
passes the signal further on. Axons can become several meters long (e.g. in the spinal cord
of giraffes) and are also quite long in large brains if they connect nuclei located far from
each other. Indeed, the brain is a very complicated system of nerve fibres that must grow
and mutually connect enabling them to manage behaviour and body functions
appropriately. Relatively minor disruptions in this huge network both concerning its
137
structure and functioning may result in behavioural deviations and/or impaired mental
capacity. It is, therefore, no wonder that some genetic anomalies have been detected
which causes the affected individuals to have difficulties conducting a proper life in the
narrow framework of this world (42). Such genetic defects can translate into metabolic
disturbances in the nerve cells, aberrant signal transmission, and incomplete
development of the nerve network.
Many of the small peptides that the brain uses for signalling also play an important role
in its development. Among these, oxytocin appears to be very important for stem cell
division and differentiation towards nerve cells. This peptide appears to be particularly
crucial for the stimulation of the build-up of filaments that constitutes the skeleton of
nerve fibres and thus the very structure of the nerve network (43). The importance of
oxytocin for the formation of nerves has been demonstrated in an experiment with rats
treated with oxytocin in the days following birth (44). In this case, there was increased
production of nerve-specific enolase in the hippocampus of the oxytocin-treated rats
after 3 weeks and 2 months. This protein is an enzyme that only forms in nerve cells and
can, therefore, be used as a marker for nerve cell differentiation. This result, therefore,
indicates that the effects of oxytocin very early in life may play a significant role in the
further development of the brain and consequently the behavioural habitus of the
individual (45). It may even be so that the high oxytocin level in the child around the time
of birth is important for its development.
Nerve fibers are formed by the construction of a skeleton of filaments inside the nerve cells
The necessity of oxytocin for the proper development of the nervous network has been
demonstrated in mice having a defect in the Magel2 gene (46). This gene is one of the
genes that are defective in Prader-Willi syndrome in humans. The Prader-Willi syndrome
is characterized by a deficient development of certain areas of the brain, not least the
138
hypothalamus. The phenotype of the Prader-Willi syndrome includes an impaired mental
capacity and excessive obesity. The defect in the Magel2 gene results in similar traits in
mice. If oxytocin was given to these mice every day only during the first week after birth,
they evolved into mice that had normal intelligence and social behaviour as adults.
Moreover, the significance of oxytocin during the period after birth for the development
of normal social and sexual behaviour as an adult has been demonstrated in voles (47).
Furthermore, studies in mice have shown that oxytocin has an impact on the
development of the sensory cerebral cortex by enhancing its responsiveness to sensory
stimuli during the postnatal period (48). A sensory stimulus of a certain quality – this
could be touch – potentiates the processing in the infant of sensory stimuli of other
qualities e.g. visual. Oxytocin was therefore proposed to be involved in these so-called
cross-modal mechanisms.
Defective oxytocin-dependent mechanisms have also recently been proposed to cause
disorders within the autism spectrum (49). In this regard, oxytocin may be pivotal for the
brain, early in life, to acquire the ability to relate signals from the body with several
different sensory inputs from the environment. By so, the child should be able to associate
– and therefore learn – that the quenching of hunger also relates to the face and mimicry
of the mother – not exclusively to her nipples. If this ability is diminished, it should cause
the boundary between the self and the outside world to remain diffuse, thereby
preventing the development of a normal consciousness of the self. Such disturbed selfperception
can cause a diminished capacity to suppress the perception of the self during
the processing of signals from the outside world, including identifying with other people.
This can then lead to a high degree of introversion, to defend the consciousness against
overload.
The role of oxytocin in the development and maintenance of the brain does not seem to
stop after childhood. In the article referred to above where the nerve-specific enolase
production was measured in the brain of rats after treatment with oxytocin, the
researchers reported that also adult rats exhibited an increased production activity of the
enolase in the brain when injected with oxytocin into its brain cavities (44). This indicates
that oxytocin also in the adult brain has the potential to stimulate the formation of nerve
cells from stem cells. In another study, also on adult rats, treatment with oxytocin caused
the dendrites of the nerve cells to develop in a more complex way, accompanied by an
improvement of the social skills of animals (50). Also, the oxytocin could counteract the
detrimental effect of cortisol on dendrite development along with an attenuation of the
anxiety-provoking effect of the hormone. If oxytocin could be demonstrated to exert a
similar effect on the adult human brain, this would give rise to even more considerations
concerning the links between behaviour and mental capacity.
Oxytocin as a signalling substance appears, in some cases, to be part of the learning
process itself. Learning is generally believed to be accomplished through modulation of
synapses between particular nerve cells resulting in an increased signalling activity.
Increased activity in a "learning" synapse is a result of stimulation with the
neurotransmitter glutamate. This causes structural changes in the synapse so that the
signal transmission capacity remains amplified. Oxytocin has been shown to potentiate
this mechanism in nerve pathways in the brain that are involved in social cognitive
139
functions (51). But besides social learning, observations are indicating that oxytocin is
also involved in learning associated with pain and possibly other sensory perception
qualities. Thus, it has recently been demonstrated that a nerve receptor denoted the
transient receptor potential vanilloid 1 channel (TRPV1) may be an alternative receptor
for oxytocin (52). The TRPV1 channel can be activated by chemical signals that trigger
activity in pain-transmitting nerves. The reason that capsaicin triggers pain is that the
substance act on this receptor, but conversely, it is conceivable that the analgesic effect
of oxytocin may involve a synaptic modulation of the pain pathways by an action on the
same receptor. However, in addition to being part of the pain mediation, the TRPV1
channel is involved in the regulation of nerve activity in the brain that relates to learning
processes associated with pain. Thus, it has been found that genetically engineered mice
lacking the TRPV1 channel have an impaired ability to develop a learned fear behaviour
conditioned by pain stimulation (53). Therefore, it plausible that oxytocin has the
potential to modulate learning processes that are conditioned by pain by acting on the
TRPV1 channels in the brain.
1. Schwarz EB, Ray RM, Stuebe AM, Allison MA, Ness RB, Freiberg MS, Cauley JA.
Duration of lactation and risk factors for maternal cardiovascular disease.
Obstetrics & Gynecology 2009; 113(5): 974-982.
2. Ram KT, Bobby P, Hailpern SM, Lo JC, Schocken M, Skurnick J, Santoro N. Duration
of lactation is associated with lower prevalence of the metabolic syndrome in
midlife–SWAN, the study of women's health across the nation. American Journal
of Obstetrics & Gynecology 2008; 198(3): 268.
3. Schwarz EB, McClure CK, Tepper PG, Thurston R, Janssen I, Matthews KA, SuttonTyrrell
K. Lactation and maternal measures of subclinical cardiovascular disease.
Obstetrics & Gynecology 2010; 115(1): 41-48.
4. Zhang H, Wu C, Chen Q, Chen X, Xu Z, Wu J, Cai D. Treatment of obesity and diabetes
using oxytocin or analogs in patients and mouse models. PLoS One 2013; 8(5):
e61477.
5. Burt RL, Leake NH, Dannenburg WN. Effect of synthetic oxytocin on plasma
nonesterified fatty acids, triglycerides, and blood glucose. Obstetrics and
Gynecology 1963; 21: 708-712.
6. Saito Y. Roles of atrial natriuretic peptide and its therapeutic use. Journal of
Cardiology 2010; 56(3): 262-270.
7. Dietz JR. Mechanisms of atrial natriuretic peptide secretion from the atrium.
Cardiovascular Research 20051; 68(1): 8-17.
8. Haanwinckel MA, Elias LK, Favaretto AL, Gutkowska J, McCann SM, AntunesRodrigues.
Oxytocin mediates atrial natriuretic peptide release and natriuresis
after volume expansion in the rat. Proceedings of the National Academy of
Sciences of the United States 1995; 92(17): 7902-7906.
9. de Boldab AJ, Borensteinab HB, Veressab AT, Sonnenbergab H. A rapid and potent
natriuretic response to intravenous injection of atrial myocardial extract in rats.
Life Sciences 1981; 28(1): 89-94.
10. Hassi J, Rintamäki H, Ruskoaho H, Leppäluoto J, Vuolteenaho O. Plasma levels of
endothelin-1 and atrial natriuretic peptide in men during a 2-hour stay in a cold
room. Acta Physiologica Scandinavica 1991; 142(4): 481-485.
11. Salama S, Boitrelle F, Gauquelin A, Malagrida L, Thiounn N, Desvaux P. Nature and
origin of "squirting" in female sexuality. The Journal of Sexual Medicine 2015;
12(3):661-666.
140
12. Blackburn RE, Samson WK, Fulton RJ, Stricker EM, Verbalis JG. Central oxytocin
and ANP receptors mediate osmotic inhibition of salt appetite in rats. American
Journal of Physiology 1995; 269(2 Pt 2): R245-251.
13. Li C, Wang W, Summer SN, Westfall TD, Brooks DP, Falk S, Schrier RW. Molecular
mechanisms of antidiuretic effect of oxytocin. Journal of the American Society of
Nephrology 2008; 19(2): 225-232.
14. Mukaddam-Daher S, Yin YL, Roy J, Gutkowska J, Cardinal R. Negative inotropic and
chronotropic effects of oxytocin. Hypertension 2001; 38(2): 292-296.
15. Gardiner SM, Compton AM, Bennett T, Palmer M, Moncada S. Control of regional
blood flow by endothelium-derived nitric oxide. Hypertension 1990; 15: 486-492.
16. Conti V, Russomanno G, Corbi G, Izzo V, Vecchione C, Filippelli A. Adrenoreceptors
and nitric oxide in the cardiovascular system. Frontiers in Physiology 2013; 4: 321.
17. Thibonnier M, Conarty DM, Preston JA, Plesnicher CL, Dweik RA, Erzurum SC.
Human vascular endothelial cells express oxytocin receptors. Endocrinology.
1999; 140(3): 1301-1309.
18. Oyama H, Suzuki Y, Satoh S, Kajita Y, Takayasu M, Shibuya M, Sugita K. Role of nitric
oxide in the cerebral vasodilatory responses to vasopressin and oxytocin in dogs.
Journal of Cerebral Blood Flow and Metabolism 1993; 13(2): 285-290.
19. Okamoto LE, Gamboa A, Shibao CA, Arnold AC, Choi L, Black BK, Raj SR, Robertson
D, Biaggioni I. Nebivolol, but not metoprolol, lowers blood pressure in nitric oxidesensitive
human hypertension. Hypertension 2014; 64(6): 1241-1247.
20. Kus K, Wisniewska A, Toton-Zuranska J, Olszanecki R, Jawien J, Korbut R.
Significant deterioration of anti-atherogenic efficacy of nebivolol in a double
(apolipoprotein E and endothelial nitric oxide synthase) knockout mouse model
of atherosclerosis in comparison to single (apolipoprotein E) knockout model
Journal of Physiology and Pharmacology 2014; 65(6): 877-881.
21. Stanley WC. In search of cardioprotection: a review of potential agents. Advanced
Studies in Medicine 2004; 4(6B): S472-S478.
22. Aslam F, Haque A, Foody J, Shirani J. The frequency and functional impact of
overlapping hypertension on hypertrophic cardiomyopathy: a single-center
experience. The Journal of Clinical Hypertension 2010; 12(4): 240-245.
23. Garrott K, Dyavanapalli J, Cauley E, Dwyer MK, Kuzmiak-Glancy S, Wang X,
Mendelowitz D, Kay MW. Chronic activation of hypothalamic oxytocin neurons
improves cardiac function during left ventricular hypertrophy-induced heart
failure. Cardiovascular Research 2017; 113(11): 1318-1328.
24. Bell DSH. Diabetic Cardiomyopathy. Diabetes Care 2003; 26(10): 2949-2951.
25. Plante E, Menaouar A, Danalache BA, Yip D, Broderick TL, Chiasson JL, Jankowski
M, Gutkowska. Oxytocin treatment prevents the cardiomyopathy observed in
obese diabetic male db/db mice. Journal of Endocrinology 2015; 156(4): 1416-
1428.
26. Paquin J, Danalache BA, Jankowski M, McCann SM, Gutkowska J. Oxytocin induces
differentiation of P19 embryonic stem cells to cardiomyocytes. Proceedings of the
National Academy of Sciences of the United States 2002; 99(14): 9550-9555.
27. Gutkowska J, Jankowski M, Antunes-Rodrigues J. The role of oxytocin in
cardiovascular regulation. Brazilian Journal of Medical and Biological Research
2014; 47(3): 206-214.
28. Matsuura K1, Nagai T, Nishigaki N, Oyama T, Nishi J, Wada H, Sano M, Toko H,
Akazawa H, Sato T, Nakaya H, Kasanuki H, Komuro I. Adult cardiac Sca-1-positive
cells differentiate into beating cardiomyocytes. The Journal of Biological
Chemistry 2004; 279(12): 11384-11391.
141
29. Kobayashi H, Yasuda S, Bao N, Iwasa M, Kawamura I, Yamada Y, Yamaki T, Sumi S,
Ushikoshi H, Nishigaki K, Takemura G, Fujiwara T, Fujiwara H, Minatoguchi S.
Postinfarct treatment with oxytocin improves cardiac function and remodeling via
activating cell-survival signals and angiogenesis. Journal of Cardiovascular
Pharmacology 2009; 54(6): 510-519.
30. Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology,
translational findings, and therapeutic implications for cardiac disease.
Circulation Research 2011; 109(8): 923-940.
31. Yan J, Tie G, Xu TY, Cecchini K, Messina LM. Mesenchymal stem cells as a treatment
for peripheral arterial disease: current status and potential impact of type II
diabetes on their therapeutic efficacy. Stem Cell Reviews and Reports 2013; 9(3):
360-372.
32. Kim YS, Kwon JS, Hong MH, Kang WS, Jeong HY, Kang HJ, Jeong Mh, Ahn Y.
Restoration of angiogenic capacity of diabetes-insulted mesenchymal stem cells
by oxytocin. BMC Cell Biology 2013; 14: 38.
33. Kim YS, Ahn Y, Kwon JS, Cho YK, Jeong MH, Cho JG, Park JC, Kang JC. Priming of
mesenchymal stem cells with oxytocin enhances the cardiac repair in
ischemia/reperfusion injury. Cells Tissues Organs 2012; 195(5): 428-442.
34. Ikeda A, Iso H, Kawachi I, Yamagishi K, Inoue M, Tsugane S. Social support and
stroke and coronary heart disease: the JPHC study cohorts II. Stroke 2008; 39(3):
768-775.
35. Karelina K, Stuller KA, Jarrett B, Zhang N, Wells J, Norman GJ, DeVries AC. Oxytocin
mediates social neuroprotection after cerebral ischemia. Stroke 2011; 42(12):
3606-3611.
36. Kaneko Y, Pappas C, Tajiri N, Borlongan CV. Oxytocin modulates GABAAR subunits
to confer neuroprotection in stroke in vitro. Scientific Reports 2016; 6: 35659.
37. Walters RJ, Hadley SH, Morris KD, Amin J. Benzodiazepines act on GABAA
receptors via two distinct and separable mechanisms. Nature Neuroscience 2000;
3(12): 1274-1281.
38. Liu J, Wang LN, Ma X, Ji X. Gamma aminobutyric acid (GABA) receptor agonists for
acute stroke. The Cochrane Database of Systematic Reviews 2016; 10: CD009622.
39. Liu S, Pan S, Tan J, Zhao W, Liu F. Oxytocin inhibits ox-LDL-induced adhesion of
monocytic THP-1 cells to human brain microvascular endothelial cells. Toxicology
and Applied Pharmacology 2017; 337: 104-110.
40. Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, Possnert G, Druid H,
Frisén. Neurogenesis in the striatum of the adult human brain. Cell. 2014; 156(5):
1072-1083.
41. Dent EW, Gertler FB. Cytoskeletal dynamics and transport in growth cone motility
and axon guidance. Neuron 2003; 40(2): 209-227.
42. Raymond FL, Tarpey P. The genetics of mental retardation. Human Molecular
Genetics 2006; 15(suppl 2): R110–R116.
43. Lestanova Z, Bacova Z, Bakos J. Mechanisms involved in the regulation of
neuropeptide-mediated neurite outgrowth: a minireview. Endocrine Regulations
2016; 50(2): 72-82.
44. Havránek T, Lešťanová Z, Mravec B, Štrbák V, Bakoš J, Bačová Z. Oxytocin
modulates expression of neuron and glial markers in the rat hippocampus. Folia
Biologica 2017; 63(3): 91-97.
45. Hammock EA. Developmental perspectives on oxytocin and vasopressin.
Neuropsychopharmacology 2015; 40(1): 24-42.
142
46. Schaller F, Watrin F, Sturny R, Massacrier A, Szepetowski P, Muscatelli F. A single
postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse
newborns deficient for the imprinted Magel2 gene. Human Molecular Genetics
2010; 19(24): 4895-4905.
47. Barrett CE, ArambulaSE, Young LJ. The oxytocin system promotes resilience to the
effects of neonatal isolation on adult social attachment in female prairie voles.
Translational Psychiatry 2015; 5: e606.
48. Zheng JJ, Li SJ, Zhang XD, Miao WY, Zhang D, Yao H, Yu X. Oxytocin mediates early
experience-dependent cross-modal plasticity in the sensory cortices. Nature
Neuroscience 2014; 17(3): 391-399.
49. Quattrocki E, Friston K. Autism, oxytocin and interoception. Neuroscience &
Biobehavioral Reviews 2014; 47: 410-430.
50. Sánchez-Vidaña DI, Chan NM, Chan AH, Hui KK, Lee S, Chan HY, Law YS, Sze MY,
Tsui WC, Fung TK, Lau BW, Lai CY. Repeated treatment with oxytocin promotes
hippocampal cell proliferation, dendritic maturation and affects socio-emotional
behavior. Neuroscience 2016; 333: 65-77.
51. Ninan I. Oxytocin suppresses basal glutamatergic transmission but facilitates
activity-dependent synaptic potentiation in the medial prefrontal cortex. Journal
of Neurochemistry 2011; 119(2): 324-331.
52. Nersesyan Y, Demirkhanyan L, Dawson Y, Asuthkar S, Cabezas-Bratesco D, Brauchi
S, Zakharian E. Crosstalk of pain and pleasure: TRPV1 is a novel oxytocin receptor.
Biophysical Journal 2017; 112(3) 407a-408a.
53. Marsch R, Foeller E, Rammes G, Bunck M, Kössl M, Holsboer F, Zieglgänsberger W,
Landgraf R, Lutz B, Wotjak CT. Reduced anxiety, conditioned fear, and
hippocampal long-term potentiation in transient receptor potential vanilloid type
1 receptor-deficient mice. Journal of Neuroscience 2007; 27(4): 832-839.
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Chapter X
Now we are coming to the hard-core
biology
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A lot of different things can happen when oxytocin docks into its receptor
Signals from hormones or neurotransmitters often trigger a cascade inside the cells,
where a variety of enzymes activate each other, thereby transmitting the signal and
affecting the functions of the cell. Several different cascades can be initiated
simultaneously by the same signal substance in a very complex system. A signal
substance can therefore simultaneously induce several different reactions. The effect
that a signal substance has on the cell depends on the cell concerned, its condition, and
the adjacent environment of the receptor in the membrane. Activation of the signal
enzyme AMPK appears to be important for the mitochondrial and antioxidant
properties of oxytocin. AMPK is otherwise most frequently activated directly if the
energy level is low in the cell, which is why this enzyme is perceived to be important in
securing the persistent energy supply of the cell. The fact that oxytocin also activates
AMPK makes sense as a kind of feed-forward mechanism since reproduction often
imposes high demands on energy efficiency. However, the growth-promoting
properties of oxytocin and its effects on metabolism involve some other signalling
cascades.
If you have reached this point in the text, you probably understand that communication
between cells is not a simple matter. The effect that a signal substance can have on a cell
is determined by the type of cell that the signal substance is targeting, but also the state
of the cell and how it is concurrently affected by all the other signal substances to which
it can respond. When a signal substance settles on its receptor its shape would change
slightly. As for peptide hormones such as oxytocin, their receptors are embedded in the
outer cell membrane where they stretch from the outside to the inside of the cells. They
can only be reached from the outside by such hormones where the attachment changes
the shape of the receptor. This, in the term, causes other proteins attached to the inside
part of the receptor to transmit the signal further into the cell via the so-called second
messengers. This can trigger one or more different signal cascades. One of the
mechanisms of action for second messengers may be to open or close ion channels and
thereby control the electrical impulse systems of the cell. Most important, this pertains to
nerve and muscle cells. Another type of mechanism is to activate various protein kinases,
which are enzymes that, in turn, activate other enzymes, etc. Such a cascade can, for
instance, end up in the activation of enzymes involved in different metabolic functions.
I have already mentioned one of these second messengers, namely calcium ions, which
play a major role when muscle contractions are caused by signalling substances. This also
applies to oxytocin. However, calcium ions as a second messenger are also involved in
some other mechanisms in the cells, including those in which activation AMP-activated
protein kinase (AMPK) occurs. I will return to that. Another second messenger that is also
very important for oxytocin signalling is diacylglycerol (DAG). DAG stimulates protein
kinase C, which can promote the growth of certain cell types and play an important role
in the protective effect of oxytocin on heart, in conjunction with NO (1). The individual
second messenger is usually just a single link in an extensive network of signal cascades
that interact with each other in an often very complicated way. Here, the various protein
kinases can activate or deactivate each other in a defined sequence, which can eventually
lead to a particular result – this could be that a muscle fibre contracts, a certain fuel is
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released, or that certain genes are read. The latter is the case, for example, when the
mentioned PPAR-α and PPAR-γ are activated. It may also happen that actions that would
otherwise take place will be blocked. To make the world even more complicated, when a
cell receives a signal, e.g. from a hormone, it may trigger activation of several different
signal cascades. This allows the cell to respond in several different ways at the same time.
This may well be the case when oxytocin pokes around (2). I am now going to present
some of the signalling pathways that oxytocin can activate, particularly those that seem
most interesting in a health promoting context.
Examples of oxytocin signalling pathways inside the cells
AMPK is part of one of the signal cascades that oxytocin can activate at least in the muscles
(3). This signalling pathway plays a significant role in the administration of fuel in the
cells including an enhancement in the use of fat. At the same time, activated AMPK
suppresses synthesis of fat and cholesterol in the liver by inhibiting the activity of the
sterol regulatory element binding proteins (SREBPs). These proteins are transcription
factors that promotes the production of enzymes responsible for the formation fat and
cholesterol. Thus, giving an AMPK-stimulating substance has been found to improve the
blood lipid profile in insulin resistant mice being genetically engineered to have a
deteriorated lipid metabolism (4). Provided that oxytocin also promotes AMPK activity
in the lipid synthesizing liver cells this may contribute to the beneficial effect of oxytocin
on blood lipids. In general, endogenous factors including the level of numerous hormones
are just as important for the blood lipid profile as are dietary habits.
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AMPK is otherwise stimulated when the energy level of cells for some reason is low, for
instance when energy is called for by the working muscles, or when the fuel supply to the
cells is low because the organism is starving. That oxytocin also activates this signalling
system makes sense because it can act by a feed-forward mechanism in this way.
Breastfeeding means that fuel resources are given to the offspring and by so, may lead
the mother into an energy deficit. It is of no wonder, that oxytocin shares this essential
signalling mechanism with a host of other signalling substances (5).
Since the mitochondria account for most of the power production of the cells, it is
conceivable that the AMPK signalling cascade also has an optimizing effect on the
performance of these organelles. Thus, it has been shown that increased AMPK activity
stimulates the production of UCP2 (6). As previously mentioned, UCP2 can decrease ROS
production in the mitochondria and can thereby acutely attenuate oxidative stress and
inflammatory reactions. Therefore, it is likely the beneficial effect of oxytocin on the
mitochondria also involves UCP2. The up-regulation of UCP2 by AMPK appears to involve
the transcription factor PPAR-α (6) which may play a role in the potential of oxytocin to
promote the production of enzymes that are responsible for the breakdown and burning
of fat as mentioned previously.
Moreover, the AMPK signalling pathway can promote the destruction of defective
mitochondria while new and more functional ones can emerge (7), similarly to what can
be observed by physical training (8). One of the renewal mechanisms of AMPK is that it
increases the reading of genes that are important for the demolition of worn-out
mitochondria, but also generally damaged proteins in cells (9). The tuning of
mitochondrial performance reduces their ROS production and attenuates inflammatory
responses in a longer perspective (10). Many resilient mitochondria in the muscle fibres
also ensure the high respiratory capacity of muscles thus enable them to perform highintensity
work. Oxytocin therefore may have the potential to counteract the age-related
loss of physical ability by mechanisms being similar to those of physical activity.
Furthermore, AMPK influences metabolism in such a way that substances that activate
this signal cascade, including metformin, can be used for the treatment of type-2 diabetes.
In addition to lowering blood glucose, this drug also reduces the oxidative stress and
inflammatory reactions caused by the high blood glucose level (11). In this way,
metformin can protect against damage to organs caused by the diabetic condition – this
is especially true for the pancreas. Particularly interesting is that the metformin, given in
the right doses, seems to be able slightly to extend the life in mice – even those, who are
healthy and normal weight (12). At the same time, an improvement in their antioxidant
defences can be observed. A human study has confirmed the beneficial effects of
metformin. In this case, a group of elderly diabetic patients treated with metformin was
compared with a group of people with the same gender and age distribution who did not
have diabetes. Despite their diabetes, the mortality was found to be slightly lower over
5½ years in the patients compared to the non-diabetic group not treated with metformin
(13). Maintenance processes particularly in the mitochondria may explain these
observations. Elimination of debris in the cells occurs by digestion, and so the process is
called autophagy. Autophagy generally plays a major role in the defence against cell
malfunctions. Unfortunately, approaches to stimulate AMPK signalling including physical
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exercise becomes harder and harder with age (14). Is it possible that maintaining a high
oxytocin level in older people could counteract this tendency?
But one may need to delve into an even deeper layer of the essence of aging to get the full
story of the possible potentials of oxytocin. Damage (mutations) in the DNA strand can
by itself be responsible for malfunctions in the cells and ultimately lead to cancerous
diseases. However, these changes are hardly responsible for the general aging-related
deteriorations in cell appearance and behaviour, such as the inability to divide and
participate appropriately in tissue functions. The behaviour of a cell is largely determined
by which genes on the DNA strands that are read because it determines which proteins
are produced. Thus, I have previously mentioned that, in this way, it is controlled into
which type of cell a stem cell develops. Which genes are being read is regulated by a
variety of systems. As already mentioned, the reading of a gene can be blocked by its DNA
being methylated. But the reading of the genes is also guided by the spatial organization
of the DNA strand. This structure is maintained by the attachment of the DNA strands to
DNA-binding proteins (histones)that they twist around. The structure is passed on to the
daughter cells in a dividing cell line, so that skin cells turn into new skin cells and muscle
cells turn into new muscle cells etc.
A progressive loss over the years of this structure in the entirely and partially
differentiated cells is believed to be one of the main causes of the deterioration of the
function of the cells in the aging organism (15). This could be attributable to an
attachment of the DNA to the histones that do not occur in a completely correct manner
when the DNA is copied in conjunction with the cell divisions. If such a loss of structure
is the essence of biological aging, it could explain how organisms can "immortalize"
themselves through reproduction. It is so, that when the germ cells are formed, the
packaging of the DNA breaks down and rebuilds, thereby resetting the biological clock.
The same applies when cloning of animals or plant proceeds satisfactorily. Thus, such
remodelling of the DNA in the cell nucleus taken from the donor organism must take place
following its introduction into the cytoplasm of the egg cell, since it is a nucleus which
derives from a differentiated cell. If successful, the procedure creates a hybrid cell with
the ability to constitute the origin of all cell types (totipotent) of the organism. At the same
time, the biological clock should also be reset, similar to what occurs during the formation
of a normal egg cell. Thus, there must be factors in the cytoplasm of the egg cell that
degrades the DNA packaging of the introduced cell nucleus and are responsible for its
regeneration to take place. In this way, the cell acquires the potential to form a foetus
(16). Such remodelling of the DNA structure of a differentiated cell, returning it to a nondifferentiated
state, seems to rely on a relatively simple system that can be initiated by
the activation of only 4 different genes (17)- a fact that may be intriguing for the research
on developing stem cells to be used for treatment purposes.
In its utmost consequence, this contention would be that aging can be eliminated by
activating a relatively simple system so that the structure of the DNA folding is broken
down and rebuilt in a way that returns the cells to an early foetal state. But at the same
time, the differentiation of cells and thus the whole organism would dissolve. Such an
approach does, therefore, make no sense to the individual but only makes allusions to the
short film "Shrinking Lover", where the lover, became sufficiently small to crawl back into
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the lap of his girlfriend, in this case, like an egg. What to bring home from this idea may,
however, be that the activation of mechanisms that counteract the age-related decay of
the DNA organization might delay aging processes. This would re-establish the ability of
differentiated cells to repair themselves and keep the potential of stem cells to replace
worn-out cell lines at a youthful level.
The decay of DNA organization and thus aging is probably an actively controlled process,
which is specific to the actual animal species – why should the average life span be
otherwise so different for instance between humans and pigs with roughly the same size
and metabolic activity? But lifetime is also affected by the circumstances in the
environment where the organism is located. Restricted access to food has long been
known to increase the lifetime of a variety of organisms, spanning from the protists to the
mammals (18). This indicates that very basic signalling mechanisms are decisive for how
long you live and also how long you can maintain a good health.
Naturally, there have been countless research studies and debate on this topic, but the
so-called "Silent Mating Type Information Regulators" or SIRTs are now believed to play
an essential role. SIRTs are a family of enzymes that are found down to the
archaebacteria, and these enzymes appear to be mandatory for the maintenance of a
stable DNA organization. Moreover, they increase their activity when the organism is
exposed to various forms of metabolic stress including hunger (19). AMPK is activated by
food shortages and, as mentioned, also directly by oxytocin, works in close interaction
with the SIRTs (20). However, another important player in the same signal cascade
system is NF-κB. NF-κB regulates the reading of various genes involved in inflammatory
responses but also appears to accelerate aging processes directly. Indeed, it has been
demonstrated that a blockade of NF-κB exclusively in the skin cells of aged mice results
in their skin acquiring characteristics and a gene-expressing profile similar to that of the
younger mice (21). The anti-inflammatory effect of oxytocin has been shown to involve
the attenuation of NF-κB activity as demonstrated in connection with the antiatherosclerotic
effect of oxytocin (22).
Another intracellular signalling substance both being susceptible to hunger and oxytocin
and at the same time acts on aging processes, is mTOR. mTOR stands for "Mammalian
Target of Rapamycin". Rapamycin is secreted by a particular bacterium and mTOR was
discovered as a substance that binds to rapamycin in the cells. When this occurs, it can
acutely attenuate the activity of the immune cells by inhibiting mTOR, why rapamycin is
sometimes used to prevent rejection of transplanted organs. However, deactivation of
mTOR can also have a rejuvenating effect on the stem cells that constitute the basis of
blood cells including immune cells (23). Oxytocin can reduce mTOR activity in intestinal
cells (24), and if something similar occurs with immune stem cells, it may help explain
the positive effects of oxytocin on immune competence.
The celebration of oxytocin's action on cell signalling that can strengthen the body does
not end here. Oxytocin also appears to activate a signalling cascade that stimulates
enzyme systems responsible for repairing damage to the DNA strands themselves. Brainderived
neurotrophic factor (BDNF) is a signal substance that is important for both the
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growth and preservation of nerve cells. This impact may be exerted by activating a signal
cascade that stimulates DNA repair enzymes. Increased activity of BDNF has been
suggested to contribute to the beneficial effects of physical activity on brain functions,
and concordantly, impaired BDNF function may promote nerve degenerative brain
disorders such as Alzheimer's (25). Cyclic AMP response element-binding protein (CREB)
is a protein that, when activated, enhances the reading of the apurinic endonuclease 1
(APE1) gene (26). APE1 is a key enzyme in the repair of oxidative DNA damage. CREB is
essential in the signal cascade through which BDNF exerts its nerve-sustaining effect.
However, BDNF is not alone in being able to activate CREB. Oxytocin seems to be among
the signalling substances which are capable of initiating a similar signal cascade. Studies
in mice have shown that sildenafil – also known as Viagra – may have an antidepressant
potential exactly by increasing the activity of the CREB signalling cascade. However, the
observed antidepressant effect in the mice could be abrogated by simultaneously
blocking the oxytocin receptors, and, also, the activating effect of sildenafil on CREB in
the hippocampus was inhibited (27). This might indicate that the antidepressant effect of
sildenafil could be mediated by an enhancement of an oxytocin-activated signal cascade.
Such a relationship is also supported in another study (28). Furthermore, the potential of
sildenafil to amplify the effect of oxytocin in the brain may lead to speculations that the
supportive effect of Viagra on erection may not only be related to direct effects on blood
vessels of the penis. The ability of oxytocin to increase activity in signalling systems that
promote CREB activity and thereby the ability of cells to repair DNA damage may not be
confined to nerve cells.
Thus, the various beneficial effects of oxytocin on body functions appear, in part, to be
mediated through several different signalling systems that are engaged in the regulation
of repair- and aging processes of cells. The same signal systems are also responsible for
the increase in metabolic efficiency when food is scarce. Conjunction between systems
that increase the ability of organisms to withstand hunger and those that extend their
lives appears to have emerged at an early stage of the biological evolutionary history. A
hypothesis, therefore, adopts the contention that it may have been of great importance
for the survival of the species that its individuals have been able to stay alive during long
periods of food shortage so that they subsequently would have been able to put offspring
into the world. Reproduction-associated signalling substances similar to oxytocin may
have been present in primitive organisms and have naturally been linked to signalling
systems inside the cells that upgrade their metabolic efficiency, as reproduction costs a
lot of fuel and may, therefore, challenge the energy balance of the organisms. That this
coupling at the same time had endorsed the physical strength and thereby the capacity of
birds and mammals to take care of their offspring would only have been an additional
evolutionary advantage.
The ability to activate signalling cascades that promote the regenerative functions of cells
is a property that oxytocin shares with several other signalling substances, but perhaps
oxytocin is the one that most easily can be recruited by thought and behaviour. Oxytocin
may also be the most prosperous endogenous agent to be activated for brain protection
considering anatomical and physiological circumstances. If this peptide holds what it
promises concerning its enhancing impact on the immune system, protection against
oxidative damage, and preserving effects on the DNA systems, we may face a very
interesting opportunity to prevent not only type-2 diabetes but also some other age-
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associated disorders. But until we have developed adequate drugs that target the
oxytocin system, we have to rely on measures that stimulates our own oxytocin
production – read behavioural modifications.
Oxytocin and cancer
The growth stimulating properties of oxytocin – also on some malign cells – could cause
some concern that it may promote the development of cancer. Such concern is one of
the reasons why growth hormone has not become an established remedy against ageassociated
frailty. However, unlike growth hormone, oxytocin also acts on some
systems which both may counteract the emergence of cancer cells and promote their
destruction if they should emerge. As the prostate is very sensitive to oxytocin, the
main worry of oxytocin and cancer has been focused on this gland – but even in this
case, men who frequently have an orgasm are less likely to develop prostate cancer. In
women, breastfeeding has a clear protective effect against breast cancer.
Growth hormone has been in the spotlight as a remedy to prolong the vitality of aged
people. Blood growth hormone has typically dropped to very lows levels by the age of 60,
which has led to a lot of research where seniors have been treated with this hormone as
a replacement for their declining production. However, while some protective effects
against loss of lean body mass can be observed by such treatment, it may also affect
insulin function in a detrimental direction (29). But what causes even more concern is
that there is quite solid evidence for a weak positive relationship between growth
hormone levels and the risk of cancer appearance (30). This may be explained by its
general stimulation of cell growth that also promotes the growth of cells that have the
potential to transform into cancer cells. More specifically, the growth-stimulating effect
of growth hormone is associated with stimulation of mTOR system (31) which appears
to play a significant role in the transformation of cells into cancer cells (32). Also, many
studies with mice, in particular, suggest that various defects in the growth hormone
system result in a longer rather than shorter life span, with delayed development of
cancer being one of the causes (33).
It could, therefore, be very interesting to look for substances that counteract the loss of
vitality of older people without at the same time being suspected of cancer promotion or
otherwise shorten the lifespan. What is being sought for is therefore a drug that
stimulates tissue regeneration including the necessary support of cell growth without
stimulating the formation and growth of cancer cells. Is oxytocin such a drug? The
sustaining mechanisms of oxytocin appear to differ from growth hormone in this regard.
As earlier mentioned, oxytocin appears to reduce rather than promote the activity of
mTOR. Also, in contrast to growth hormone, oxytocin enhances insulin sensitivity. We are
now back to the fact that oxytocin stimulates the same signalling systems that are
activated in connection with food scarcity. Activation of these signalling systems also
seems to have a generally negative effect on cancer development (34). Thus, food
restriction has been reported to reduce the incidence of various forms of cancer in
different animals, including monkeys. Naturally, signalling mechanisms that increase the
activity of DNA repair systems and decrease inflammatory responses are in the game
again and the AMPK signalling cascade may also be involved in this context. Indeed, in
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some cases, metformin can inhibit the development of cancer, and exactly the stimulation
of AMPK by metformin may be essential for the anticancer effect of the drug (35).
However, the world is awfully complicated and cells in many different types of tissue are
equipped with oxytocin receptors. This also applies to cells that have been transformed
into cancer cells. Therefore, whether oxytocin inhibits or promotes cancer may depend
on the types of cells involved. The knowledge we have today about which influence
oxytocin has on various cancers is predominantly based on experiments where isolated
cancer cells have been exposed to the peptide. There is a great dispute on whether
oxytocin stimulates or inhibits the growth of cancer cells because it is dependent on the
type of cancer being studied. Even if the cancer cells are collected from the same affected
organ, this could be the breast, oxytocin has been reported both the increase (36) and
decrease (37) cell division activity. This can be explained by oxytocin having the capacity
to stimulate several different signalling systems in the cells. The outcome of oxytocin
targeting a cell may, therefore, depend on which signal cascade is being predominantly
activated when oxytocin settles in its receptor. This applies, not at least, regarding
whether activation or inhibition of cell divisions occurs. The environment in the cell
membrane where the oxytocin receptor is located – especially the neighbouring proteins
– may determine which signal cascade is further activated within the cell – and these
environments may vary according to the type of cancer cell (38).
One should always address the question to what extent results from experiments with
isolated cells can be extrapolated to whole organisms. This applies not least in the context
of oxytocin and cancer. For instance, what would the implications of a possible
reinforcement by oxytocin of the immune system be in this regard? Another approach is
to study populations where factors known to influence oxytocin activity are tested for
association with the occurrence of various cancers (39). The most robust statistical
correlation seen in such studies is a negative relationship between the rate of
breastfeeding and breast cancer development. However, these results do not prove that
the elevated oxytocin level exerts a protective effect, as some other factors including sex
hormones are also affected by breastfeeding. The same applies to findings of negative
statistical relationships between breastfeeding on one hand and the development of
ovarian and uterine cancer on the other. However, the fact that some studies also have
detected a negative association between breastfeeding and gastrointestinal cancer may
indicate that factors additional to sex hormones may be at play. Oxytocin has also been
suggested to be involved in the negative relationship between physical activity level and
the development of different cancers – including cancer in the gut – as the level of the
peptide also may increase during physical exercise, but this is even more speculative.
However, that an inhibitory effect of physical activity on cancer may involve oxytocin is
supported by a trial on mice. In this case, the exercise intervention increased oxytocin
levels, while the growth of cancerous tumours in their teats was reduced. Furthermore,
this was accompanied by a decreased production of proteins involved in the division of
cancer cells in the tissue. However, the beneficial effects of the exercise could be
abrogated by giving a substance that blocks the action of oxytocin. Conversely, the effect
of exercise could be mimicked by giving oxytocin to the mice (40).
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Breastfeeding seems to have a protective effect against breast cancer
Today, the main concern about a possible cancer-causing effect of oxytocin appears to
address prostate cancer. Oxytocin has been reported to stimulate the growth of cancer
cells collected from this gland (41). The prostate gland produces most of the seminal fluid
and the cells forming their tubules are equipped with oxytocin receptors, whereby
oxytocin can boost sperm discharge. But oxytocin also boosts the growth of these cells
both the benign and unfortunately also the malignant ones. At the same time, the prostate
gland can produce oxytocin itself. The basis for an evil spiral is therefore present. High
blood levels of hypothalamic-produced oxytocin could increase the number of oxytocin
receptors in the prostate and thereby the responsiveness of the prostate gland to
oxytocin. This could trigger the prostate cells to produce more oxytocin themselves,
which, in turn, could further increase the number of oxytocin receptors. This might
further promote the division of any emerging cancer cell. Frighteningly, elevated oxytocin
concentrations have been reported in men with prostate cancer but, again, it is difficult
to deduce the causal relationship from such data.
Tranquilizing in this regard may be that oxidative stress appears to be a major factor for
prostate cells to transform into the cancer cell (42) and the protective effect of oxytocin
against oxidative and inflammatory stress might exceed its growth-stimulating effect. It
has been reported from an investigation on men that those who had frequent sperm
discharges showed a slightly lower risk of developing prostate cancer (43). The
implication of these results has been disputed and an accumulation of harmful substances
in the sperm being released by the ejaculation has been proposed as an explanation. I
would suggest hormonal mechanism as a more plausible interpretation where the
stimulation of the prostate gland as a result of sex overall may diminishes rather than
increases the risk of cancer development. But again, one must be aware that conclusions
about causal relationships based on population studies always are speculative.
To make things even more thwarting, the cancer-protective effects of antioxidants can
surprisingly also be disputed. Naturally, reducing oxidative stress should reduce the
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likelihood of damages to cell systems that otherwise may initiate a carcinogenic
transformation – particularly mutations in the DNA. However, the production of ROS is an
important element in fighting cancer cells and cells which may be in progress towards
cancer cells. Therefore, the impact of antioxidants on cancer risk may depend on how
they act as antioxidants (44). In this regard, it must be important to distinguish between
the risk of cells developing into cancerous cells and the risk of cancerous cells not being
destroyed. The potent antioxidant effect of oxytocin being exerted by mobilization of the
enzymatic defence in the cells must be extremely interesting to address. Such an effect
diverges from the shielding mechanisms of the dietary antioxidants. A lot of research
remains to be conducted on oxytocin and cancer, encompassing both tests with isolated
cells and long-term preclinical studies with both male and female animals.
Why does the level of preserving substances decrease with age?
To understand why the organisms do not fully exploit the potential for cell repair and
maintenance, one must comprehend the over-all prerequisites of biological evolution
where death is a necessity.
Both the mass and the strength of our muscles diminish as we age, as is the case for the
bones as well. Through sustained physical training, we can to some extent postpone this
decay. However, it will inevitably have manifested itself in a life-hampering way as we
approach the age of 90. A decisive factor for this is the decline in the production of
restorative hormones. This applies to both growth hormone (45) and sex hormones (46).
It is also likely that oxytocin levels decrease with age at least after menopause, as oxytocin
production is stimulated by oestrogens. However, it is difficult to estimate the general
activity of oxytocin by measuring it in blood samples, as it is very dependent on adequate
stimuli. Due to its fast degradation it can therefore vary greatly over a short time. So, it
makes more sense to measure oxytocin reactions in the brain to various stimuli, but this
is not possible in humans. In rats and monkeys, such experiments do not provide any
clear answer to whether the oxytocin activity declines with age (47). If the release of
oxytocin does not decline with age the sensitivity to the peptide may, as the expression
of its receptor probably subside in elderly people due to DNA methylation of its gene as
found in skin cells (48).
But why does the production of growth hormone, sex hormones, and probably also
oxytocin decline as we grow old when they otherwise can counteract the decay of the
body? Why is it not so, that preserving hormones such as oxytocin rather increase with
age to battle the progressing global inflammation which ultimately is responsible for our
exit from this world? That we pose such questions at all, is due to the fact, that we
understand life from a distorted perspective. To be able to comprehend the phenomenon
of aging, one must dig into the dynamics of natural selection – even down to the molecular
level. One has to realize that we exist only by a myriad of different molecules having built
up an unimaginably intertwined structure of collaborations. Our life and longevity have
therefore been dictated by how this molecular collaboration has evolved.
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But how, for example, has the interaction emerged, between chains of nucleic acids
(DNA/RNA) and chains of amino acids (proteins) being one of the prerequisites for the
life that we know today? This must be a result of these complex molecules, having
acquired an effective way to reproduce themselves by different ways of collaboration. By
so, they have become many of their own kind. It can also be said the other way around –
the molecules that are numerous today are the ones that have been the most smart to
cooperate with other molecules in achieving a great capacity to multiply.
A body is a complex system of cooperating molecules that have attained a great ability to
protect themselves and to multiply. Some of these molecules are relatively simple such
as different sugar molecules of which there is a huge amount. Usually, such compounds
are perceived just as something that the more complicated molecules of the body are
using as a source of energy for instance. But would there have been many sugars in the
world if no complicated molecules such as enzymes have produced them? Nah. Indeed,
there is a lot of sugars on earth, because sugars have had a great "success" in
"cooperating" with proteins that form them.
The citric acid cycle is an example of a solid piece of molecular cooperation.
What about signal substances such as oxytocin? – based on their quantity, it appears like
pure misery. There are probably only a few tons of oxytocin on the entire planet, so why
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has this compound been able to hang on for at least 75 million years since the mammals
appeared on the scene. The reason for this is that other molecules have "collaborated"
with oxytocin, and hereby, made them more efficient to reproduce. Exactly concerning
oxytocin – this molecule has exhibited extremely good "competencies" in the art of
molecular collaboration. Accompanied by its receptor, it has "managed" to interact with
– and influence – a variety of signalling systems within a large number of different cell
types. And most important, it does so in a way that supports the multiplication of the
organisms that host oxytocin.
So, the success of oxytocin is indisputable. But what would happen in a fantasy world
where this peptide suddenly stops "supporting" other molecules? For protein signalling
substances such as oxytocin, the trial will be brief, because their existence depends on
their genes being read. Since the reading of the signalling substances closely matches the
need for actual signalling effect in the animal, their production may, in some cases,
initially flare up due to the absence of a negative feedback. However, if the signal cannot
be replaced by another signalling system the organism would eventually die – or for
oxytocin in mammals, the species would die by being unable to provide milk to their
offspring. A few species including homo sapiens might be smart enough to get along with
a miserable life without the generosity of oxytocin. However, the formation of oxytocin
may cease after some generations as it is disadvantageous to put resources into the
production of compounds that do not take part in the household of the organism. The
oxytocin gene would presumably remain intact and readable for many generations, as the
elimination of inactive genes most often has no particular survival value. Therefore,
oxytocin (together with its receptor) would still exist for a long time as a kind of idea
imprinted in our DNA ready to be woken up to flourish again should the right
circumstances appear. But over a very long time, random structural changes in the DNA
and associated proteins around the oxytocin gene makes restoration of its reading less
and less likely. In an even more remote future, spontaneous mutations in the oxytocin
gene itself would have killed even the "idea" of oxytocin since the gene is no longer
protected by natural selection. At that time, it is definitively over and out with this
amazing substance. But do not worry – these fantasies only serve to illustrate how
oxytocin exists entirely by the virtue of its "collaboration". Molecules have no
consciousness and therefore do not go on strike.
The number of a given biological molecule must be determined by its ability to multiply
and, not at least, how fast it does it. For molecules being hosted by organisms, this means
how fast the organism can reproduce. Furthermore, a short generation time enables the
organism to dissipate its offspring to other areas at a fast rate. This would mean more to
the total number of organisms than how long time each individual stay alive. Longevity
can even, in some cases, reduce the number of the actual organism as the old organisms
may use resources that otherwise might have been available for new and perhaps more
adaptive individuals. From this perspective, a limited life span of the single individuals is
comprehensible and factors that prolong the life of organisms may, therefore, in some
cases, be detrimental rather than beneficial in a biological context.
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Sexual activity for longer health span – can it be argued for by evolutionary biology?
Organisms that fail to multiply by reproduction do not propagate their particularities
of molecules and do therefore usually not have any biological justification. Conversely,
natural selection may favour individuals with a high reproductive potential. In this way,
a high functionality of signalling systems that promote reproduction may be coupled to
strength and longevity. Such a connection is straightforward in simple organisms, but
it may have remained in humans to some extent.
It is obvious to ask why the literature on health science is so rich in reports of the healthpromoting
effects of oxytocin. After all, the oxytocin system and its predecessors evolved
in ancient times presumably just as promotors of muscle contractions related to
reproductive tasks. Religious people might be inclined to claim that oxytocin is a divine
substance created for the benefit of animals and humans. People being more down-toearth
may argue that oxytocin has become a hype in health science, not least because it
has a lot of connotations to sex. Therefore, positive results could have been published to
a greater extent than negative ones. Such an explanation cannot be completely excluded.
But a linkage between oxytocin and a lot of functions that have no direct relationship with
reproduction is nevertheless very plausible in an evolutionary framework. Imagine that
an molecular incident happens by chance that couples one of the signal cascades inside
the cells being triggered by oxytocin to a function that does not directly relate to
reproduction in the first place. This could be that the high level of calcium ions inside the
cells that initiate muscle contraction acquire an additional function as an enhancer of
metabolic efficiency. If such new coupling is particularly advantageous in situations that
relate to reproduction – for instance breastfeeding – the individuals which have been
gifted with this coupling will be particularly effective in bringing offspring into the world
and thereby achieving greater dissemination.
A coupling between sexual and/or nursing activities on one side and the maintenance of
a "young" immune and nervous system on the other may have developed in this way. This
may have taken place hundreds of millions of years ago. That proteins in the oxytocin
family could have taken part in this game can certainly not be ruled out, as these
substances have probably been on the field for a period of about 600 million years. As
mentioned, oxytocin-like proteins are found in primitive animals including nematodes.
Primitive animals can achieve high adaptability to environmental changes by a large
diversity accompanied by short generation time. In this way, a population of such species
can quickly change its characteristics through breeding. In such animals, a death shortly
after their loss of ability to breed may be very appropriate in order not to compete with
individuals that still are participating in the progress of the population. In this case, it
would be a good idea to have an immune system that is able swiftly to erode and kill you.
A sudden death, after having executed one's reproductive duties, is a widespread
phenomenon in the animal kingdom particularly being known among fish after they have
spawned their eggs. On the other hand, it is crucial to have an immune system that can be
strictly controlled while you are still engaged in the conservation of the population. Could
it be, that even humans still hold such characteristic just in a more subtle form?
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Seen in this light, it may make sense if the activity of oxytocin and other preserving
substances decreases in older individuals especially after they have lost the ability to put
offspring into the world. This obviously applies to nematodes but may possibly also exist
in humans to some extent. Keeping these hormones at a youthful level would help to
sustain the lives of individuals who no longer participate in the reproduction but continue
to consume the food that otherwise could have been available to the fertile individuals.
Now, many will probably object that man must have passed the stage for such primitive
selection mechanisms a long time ago. We have our highly developed society, where there
is a need for grandparents to help the upbringing of their grandchildren. However,
selection mechanisms work very slowly when the selection pressure is limited. This is
evident when one looks at the frequency of severe overweight attributable to systems
regulating our food intake that still are tuned in for potential food shortages.
These contentions may lead to the argumentation that a maintained activation of
reproductive mechanisms may delay degenerative phenomena in the body. This may hold
true not at least for a stimulation of the oxytocin system by letting the satisfying sexual
activities go on also as a senior. But is there, in fact, any pieces of evidence for this
hypothesis? Only a few – but this may be attributable to the fact that it is a delicate and
difficult topic to investigate. Thus, it is hardly possible to address the issue by long-term
controlled intervention studies. However, there are some questionnaire surveys on
specific groups of people that may give us a clue. A statistical correlation between
longevity and previously experienced pleasure with sex has been reported among 75-
year-old women which were independent of variations in social status, smoking, and
general self-perception of health (49). For the men, a similar correlation was seen with
the frequency of sex. In another study, middle-aged men demonstrated a negative
correlation between the frequency of orgasms and mortality after 10 years, which was
also independent of social status and health parameters (50).
1. Faghihi M, Alizadeh AM, Khori V, Latifpour M, Khodayari S. The role of nitric oxide,
reactive oxygen species, and protein kinase C in oxytocin-induced
cardioprotection in ischemic rat heart. Peptides 2012; 37(2): 314-319.
2. Viero C, Shibuya I, Kitamura N, Verkhratsky A, Fujihara H, Katoh A, Ueta Y, Zingg
HH, Chvatal A, Sykova E, Dayanithi G. REVIEW: Oxytocin: Crossing the bridge
between basic science and pharmacotherapy. CNS Neuroscience and Therapeutics
2010; 16(5): e138-56.
3. Lee ES, Uhm KO, Lee YM, Kwon J, Park SH, Soo KH. Oxytocin stimulates glucose
uptake in skeletal muscle cells through the calcium-CaMKK-AMPK pathway.
Regulatory Peptides 2008; 151(1-3): 71-74.
4. Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JYJ,
Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M. AMPK
phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and
atherosclerosis in diet-induced insulin-resistant mice. Cell Metabolism 2011;
13(4): 376-388.
5. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient
energy gauge provides clues to modern understanding of metabolism. Cell
Metabolism 2005; 1(1): 15-25.
158
6. Tian XY, Ma S, Tse G, Wong WT, Huang Y. Uncoupling Protein 2 in Cardiovascular
Health and Disease. Frontiers in Physiology. 2018; 9: 1060.
7. Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis.
Nature Reviews Molecular Cell Biology 2018; 19(2): 121-135.
8. Reznick RM, Shulma GI. The role of AMP-activated protein kinase in mitochondrial
biogenesis. The Journal of Physiology 2006; 574(1): 33–39.
9. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the
aging process via an integrated signaling network. Ageing Research Reviews 2012;
11(2): 230-241.
10. Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase inhibits NF-
κB signaling and inflammation: impact on healthspan and lifespan. Journal of
Molecular Medicine 2011; 89(7): 667-676.
11. Chakraborty A, Chowdhury S, Bhattacharyya M. Effect of metformin on oxidative
stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients.
Diabetes Research and Clinical Practice 2011; 93(1): 56-62.
12. Martin-Montalvo A1, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, ScheibyeKnudsen
M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang
Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier
M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nature
Communications 2013; 4: 2192.
13. Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G,
Mukherjee J, Currie CJ. Can people with type 2 diabetes live longer than those
without? A comparison of mortality in people initiated with metformin or
sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes,
Obesity and Metabolism 2014; 16(11): 1165-1173.
14. Reznick RM, Zong H, Li J, Morino K, Moore IK, Yu HJ, Liu ZX, Dong J, Mustard KJ,
Hawley SA, Befroy D, Pypaert M, Hardie DG, Young LH, Shulman GI. Agingassociated
reductions in AMP-activated protein kinase activity and mitochondrial
biogenesis. Cell Metabolism 2007; 5(2): 151-156.
15. Sun L, Yu R, Dang W. Chromatin architectural changes during cellular senescence
and aging. Genes 2018; 9(4): 211.
16. Niemann H, Tian XC, King WA, Lee RS. Epigenetic reprogramming in embryonic
and foetal development upon somatic cell nuclear transfer cloning. Reproduction
2008; 135(2): 151-163.
17. Stadtfeld M, Hochedlinger K. Induced pluripotency: history, mechanisms, and
applications. Genes & Development 2010; 24(20): 2239-263.
18. Fontana L, Partridge L. Promoting health and longevity through diet: from model
organisms to humans. Cell 2015; 161(1): 106-118.
19. Wang Y, Liang Y, Vanhoutte PM. SIRT1 and AMPK in regulating mammalian
senescence: a critical review and a working model. FEBS Letters 2011; 585(7):
986-994.
20. Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, Ido Y. AMPK and
SIRT1: A Long-Standing Partnership? American Journal of Physiology.
Endocrinology and Metabolism 2010; 298(4): E751-E760.
21. Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY. Motif module map
reveals enforcement of aging by continual NF-kappaB activity. Genes &
Development 2007; 21(24): 3244-3257.
22. Ahmed MA, Elosaily GM. Role of Oxytocin in deceleration of early atherosclerotic
inflammatory processes in adult male rats. International Journal of Clinical and
Experimental Medicine 2011; 4(3): 169-78.
159
23. Rando TA, Chang HY. Aging, rejuvenation, and epigenetic reprogramming:
resetting the aging clock. Cell. 2012; 148(1-2):46-57.
24. Klein BY, Tamir H, Hirschberg DL, Glickstein SB, Welch MG. Oxytocin modulates
mTORC1 pathway in the gut. Biochemical and Biophysical Research
Communications 2013; 432(3): 466-471.
25. Yang JL, Lin YT, Chuang PC, Bohr VA, Mattson MP. BDNF and exercise enhance
neuronal DNA repair by stimulating CREB-mediated production of
apurinic/apyrimidinic endonuclease 1. Neuromolecular Medicine 2014; 16(1):
161-174.
26. Yang JL, Tadokoro T, Keijzers G, Mattson MP, Bohr VA. Neurons efficiently repair
glutamate-induced oxidative DNA damage by a process involving CREB-mediated
up-regulation of apurinic endonuclease 1. The Journal of Biological Chemistry
2010; 285(36): 28191-28199.
27. Matsushita H, Matsuzaki M, Han XJ, Nishiki TI, Ohmori I, Michiue H, Matsui H,
Tomizawa K. Antidepressant-like effect of sildenafil through oxytocin-dependent
cyclic AMP response element-binding protein phosphorylation. Neuroscience
2012; 200: 13-18.
28. Khoshneviszadeh M, Rahimian R, Fakhfouri G, Payandemehr B, Khodagholi F,
Ejtemaei Mehr S, Dehpour AR. Oxytocin is involved in the proconvulsant effects of
Sildenafil: Possible role of CREB. Toxicology Letters 2016; 256: 44-52.
29. Blackman MR, Sorkin JD, Münzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE,
Jayme J, O'Connor KG, Christmas C, Tobin JD, Stewart KJ, Cottrell E, St Clair C, Pabst
KM, Harman SM. Growth hormone and sex steroid administration in healthy aged
women and men: a randomized controlled trial. JAMA. 2002; 288(18): 2282-2292.
30. Jenkins PJ, Mukherjee A, Shalet SM. Does growth hormone cause cancer? Clinical
Endocrinology 2006; 64(2): 115–121.
31. Hayashi AA, Proud CG. The rapid activation of protein synthesis by growth
hormone requires signaling through mTOR. American Journal of Physiology.
Endocrinology and Metabolism 2007; 292(6): E1647-E1655.
32. Xie J, Wang X, Proud CG. mTOR inhibitors in cancer therapy. F1000 Research 2016;
5: 12688.
33. Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ. The GH/IGF-1 axis in
ageing and longevity. Nature Reviews Endocrinology 2013; 9(6): 366-376.
34. Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and
molecular mechanisms. Trends in Pharmacological Sciences 2010; 31(2): 89-98.
35. Morales DR, Morris AD. Metformin in cancer treatment and prevention. Annual
Review of Medicine 2015; 66: 17–29.
36. Taylor AH, Ang VT, Jenkins JS, Silverlight JJ, Coombes RC, Luqmani YA. Interaction
of vasopressin and oxytocin with human breast carcinoma cells. Cancer Research
1990; 50(24): 7882-7886.
37. Cassoni P, Sapino A, Negro F, Bussolati G. Oxytocin inhibits proliferation of human
breast cancer cell lines. Virchows Archiv 1994; 425(5): 467-472.
38. Strunecká A, Hynie S, Klenerová V. Role of oxytocin/oxytocin receptor system in
regulation of cell growth and neoplastic processes. Folia Biologica 2009; 55(5):
159-165.
39. Imanieh MH, Bagheri F, Alizadeh AM, Ashkani-Esfahani S. Oxytocin has
therapeutic effects on cancer, a hypothesis. European Journal of Pharmacology
2014; 741: 112-123.
160
40. Alizadeh AM, Heydari Z, Rahimi M, Bazgir B, Shirvani H, Alipour S, Heidarian Y,
Khalighfard S, Isanejad A. Oxytocin mediates the beneficial effects of the exercise
training on breast cancer. Experimental Physiology 2018; 103(2): 222-235.
41. Xu H, Fu S, Chen Q, Gu M, Zhou J, Liu C, Chen Y, Wang Z. The function of oxytocin: a
potential biomarker for prostate cancer diagnosis and promoter of prostate
cancer. Oncotarget 2017; 8(19): 31215-31226.
42. Khandrika L, Kumar B, Koul S, Maroni P, Koul HK. Role of Oxidative Stress in
Prostate Cancer. Cancer Letters 2009; 282(2): 125–136.
43. Leitzmann MF, Platz EA, Stampfer MJ, Willett WC, Giovannucci E. Ejaculation
frequency and subsequent risk of prostate cancer. JAMA 2004; 291(13): 1578-
1586.
44. Saeidnia S, Abdollahi M. Antioxidants: friends or foe in prevention or treatment of
cancer: the debate of the century. Toxicology and Applied Pharmacology 2013;
271(1): 49-63.
45. Martin FC, Yeo AL, Sonksen PH. Growth hormone secretion in the elderly: ageing
and the somatopause. Baillière's Clinical Endocrinology and Metabolism 1997;
11(2): 223-250.
46. Ferrini RL, Barrett-Conno E. Sex hormones and age: A cross-sectional study of
testosterone and estradiol and their bioavailable fractions in community-dwelling
men. American Journal of Epidemiology 1998; 147(8): 750-754.
47. Ebner NC, Maura GM, Macdonald K, Westberg L, Fischer H. Oxytocin and
socioemotional aging: Current knowledge and future trends. Frontiers in Human
Neuroscience 2013; 7: 487.
48. Cho SY, Kim AY, Kim J, Choi DH, Son ED, Shin DW. Oxytocin alleviates cellular
senescence through oxytocin receptor-mediated ERK/Nrf2 signalling. British
Journal of Dermatology 2019; 10: 1111
49. Palmore EB. Predictors of the longevity difference: a 25-year follow-up.
Gerontologist. 1982; 22(6): 513-518.
50. Davey Smith G, Frankel S, Yarnell J. Sex and death: are they related? Findings from
the Caerphilly Cohort Study. BMJ. 1997; 315(7123): 1641-1644.
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Chapter XI
Approaching the end
162
Climax
Love and friendship are good for the oxytocin function but can sometimes be
complicated to establish and maintain. Sex may be less complicated particularly if you
enjoy your body without involving others and you should not feel bad about granting
yourself an orgasm to have a burst of oxytocin. A short little duty nookie once a week
may have some effect, but there may be far greater potential in sex to get the oxytocin
going. By persistent practice, the sexual sensory perception may, over time, be
amplified manifold by primitive learning. This may lead to a much stronger oxytocin
response as it appears to be dependent on the strength of the sensory experience.
Moreover, the increased pleasure of sex would encourage you to embark upon it more
frequently.
With our approach to life in modern society, we would never grasp the biological premise
that our existence is only justified as long as we can contribute to the maintenance of a
population. We rather strive to live an active life far beyond the time where we have lost
the ability to put children into the world and need to care for them. Therefore, we seek
any option available to extend our life- and health span and the pharmaceutical industry
is spending huge resources in this business. Furthermore, the concept of biohacking has
emerged during recent years. This is about controlling different biological systems by
one's own initiative – not at least our body. In this case, it could include intermittent
fasting, intake of different functional foods, a particular way of performing physical
activity, and mindfulness. Some of these approaches may involve the oxytocin system to
some extent but much more may be achieved by using hacking methods that target this
system more directly and effectively.
Providing oxytocin-like substances as drugs to healthy people to take advantages of their
putative anti-inflammatory and restoring capacities is hardly just around the corner for
several reasons, which have already been described, but also may include ethical aspects.
But how else can we increase our oxytocin function? – If I fail to answer this, the reader
will probably ask what this book can be used for. Some may get the idea to purchase
oxytocin inhalers by the internet – but don't – you can never know if the product has been
"enhanced" with other active substances to provide the product with an immediate and
more significant psychological effect. The effect of oxytocin delivered through the nose
may also be quite limited and could have unwanted psychological side effects.
Furthermore, it is also necessary to use the spray several times a day to have any
substantial effect. Therefore, for now, the only appropriate way to increase the oxytocin
activity is through thoughts and behaviour. Moreover, the oxytocin produced by one's
hypothalamus is pure and can not only be delivered to the blood in large quantities but
also inside the brain via nerves precisely at places where it is most pertinent.
Now I can then encourage people to grant each other more passion in appropriate
situations. This is hereby done. But should such recommendation not always be given
independently of what has been presented in this book? Furthermore, this
recommendation will also ring hollow to people who have no one to care about one's
embraces. Unloved people may acquire a dog to receive its unconditional love, but
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perhaps, it may not be allowed to keep pets in your housing community – or you may not
like dogs at all. It may even be that your nature is not affectionate at all and you therefore
rather find any caresses or hugs repulsive. Oxytocin may well enhance the ability to be
passionate in most people, but if you have a personality without any substrate for
oxytocin to exert such an effect at all, meeting you with love would be of no health benefit
to you. Finally, physical exertions may increase oxytocin levels which are also associated
with health benefits not conditioned by oxytocin. However, most people lack enough
time, strength, and willpower to exercise so hard that oxytocin becomes a major factor.
Having said all that – and you are not a breastfeeding woman – only the pleasure of sex
and sensuality may remain as an unassailable remedy for anybody to boost the activity
of the oxytocin system. Here the parole may be "caressing each other (- or oneself) is
something teenagers do – and we do no longer find it appropriate to waste time on that
kind of trivialities". But I hope that such an attitude can be killed by reading this book. It
is OK with a natural scepticism directed against the scientific claims about the beneficial
effects that oxytocin should have on the body and mind. However, if you find just one of
them plausible it may be enough for you to take sex and tactile pleasures more seriously
as a health initiative. I this regard, I would rush to take the precaution that it is naïve to
think that just by having an orgasm every day will make your mitochondria and stem cells
magnificent and you therefore never have to care about other elements of your lifestyle.
Frequent intense sexual pleasure sensations throughout the entire life should rather be
regarded as an important health-promoting measure in parallel to approaches such as
maintaining a high physical activity level.
Sex should not even be considered the only avenue for oxytocin release if conditions are
present for the use of other sources to stimulate the oxytocin system. Good sex alone or
with a partner probably always gives rise to solid discharges of oxytocin to the brain and
body, but it must be kept in mind that most of what is released has been broken down
after few minutes. We do not know how important such short-term bursts oxytocin is
compared to a smaller but sustained elevation. However, it may be argued that short
discharges of oxytocin would enhance both the sensitivity and the sustained production
of the peptide. This is indicated by the fact that the biological effects of a single daily
injection of oxytocin have been seen. But such reinforcement might always act in synergy
with other factors that increase the overall oxytocin level – including a friendly and
accommodating way to interact with one's companion.
But returning to the sex issue, how can a sex life that leads to frequent and powerful
oxytocin responses be established? As mentioned, a positive correlation has been
demonstrated between the strength of the orgasm and the increase in the concentration
of oxytocin in the blood, concordantly with reports of a failed oxytocin reaction if no
orgasm could be achieved. An experiment with humans further indicates that the sensory
pleasure itself is a prerequisite for a robust oxytocin release to take place (1). Therefore,
the greater intensity of the pleasant sensation is during sex the higher the oxytocin
response may be. But how can it increase then? In this context, I will refrain from advising
on candlelight dinners and whispers of tender words but instead refer to the wealth of
literature on the web and glossy magazines. Furthermore, about intercourse techniques,
the reader may be inspired by the millions of videos being freely available. I prefer instead
164
to confine myself to a few instructions of a very instrumental nature, which are based on
knowledge of learning and the nervous system.
The nerve processes that take place in the brain in connection with sex are probably far
more complicated than those required to solve a difficult differential equation. It is
therefore of no wonder that sex is also about such "boring" things as focusing, learning,
and training. Mobile phones have therefore hardly been good for our sex lives not only
because they can be a disruptive element during the activity itself, but also because they
can affect our brain in a way that compromises our ability to sustain the focus on things
that we currently are about to do. Exactly the focus itself is crucial for an intense sexual
experience. Psychologists define the concept of absorption as a state of consciousness
where it is so much directed at a particular thing that other stimuli from the world are
experienced in an aberrant way or not perceived at all. Our consciousness can handle
very little contemporarily and may, therefore, be absorbed by deep thoughts or intense
sensory stimuli. If such sensory stimulus is of longer duration it can bring the brain into
a mode of trance where the activity in the forehead is reduced and higher functions of
consciousness such as the perception of time and place but also one's existence vanishes.
Such a trance is referred to as an altered state of consciousness, because it still relates to
the outside world to some degree but does so in a distorted way (2). An altered state of
consciousness can be introduced by the rhythmic stimulation associated with music and
dance. It can also occur during hard physical activity, where it can be experienced as a
kind of euphoria during running (runners high). In this case, the condition is probably
evoked through a combination of the rhythmic sensory stimuli from the movements and
the physical challenge. Physical stressors such as hunger, cold, and oxygen deficiency can
also by themselves lead to reduced activity in the frontal lobes and thus to an altered
consciousness (3). Impaired activity of the forehead is often associated with euphoria
because the consciousness no longer deals with the realities. This can be very dangerous
in critical situations because you no longer attend to yourself and your survival.
Absorption
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Intense sensations associated with sex can also induce an altered state of consciousness
(4), which is in line with the decreased activity in the frontal lobes, that can be observed
during orgasm using fMRI(5). The fact that sex can make consciousness of one's existence
dissolve is the reason why the orgasm is called "the little death". Small deaths may not
necessarily postpone the great one but may improve the quality of life beforehand. But
how can we induce more of these small deaths? In other words, how can the sensory
perception during sex be amplified and thereby potentiate the oxytocin response? In this
regard, learning could be an effective remedy. I am not talking about what is usually
associated with learning such as learning the reaction equation for photosynthesis. It is
more about a primitive kind of learning not involving consciousness. Learning of this
nature can be stored in deep layers of the brain or even in the spinal cord, and may
translate into acquired reflexes, as demonstrated in a dog by Russian physiologist Ivan
Pavlov in the late 1800s. He made dogs drool alone in response to the sound of a bell
because they were taught to associate the bell with a meal as they heard it every time
they were fed. Pavlov explained it as a learning, and thus behaviour, being conditioned by
the association between the bell and the food being served.
Associating one thing with something else probably forms the basis for all learning, both
the kinds that involve consciousness and the most primitive. The reason why we capable
of learning is that we must be able to respond appropriately to sensory input from our
surroundings. Therefore, learning may result in alterations in the way we perceive
certain sensory stimuli. If you just once have experienced getting sick by eating too many
plums, you may risk feeling nauseous only by the smell or taste of plums. Thus, the
perception associated with eating plums has been altered by a learning process
conditioned by previous experience of sickness. This kind of primitive learning can be
very hard to deal with because it can be stored in places where it is difficult for
consciousness to access and thus process.
Learning is based on a modulation of signal transfers between the nerves. In this context,
chronic pain without an organic cause may be due to inappropriate signalling between
pain-transmitting nerves. This condition may have been initiated by an adequate pain
sensation caused by tissue damage in the first place. However, the pain may have been
precipitated as a persistent perception as a result of primitive learning mechanisms (6).
Such an unfavourable form of learning can occur in the pain-transmitting synapses
located in the spinal cord but also in the sensory cerebral cortex where the pain signals
are processed (7,8). Such learning may be triggered by repetitive high-intensity pain
stimuli and result in a substantially amplified perception of pain signals that normally
only would result in mild pain perception or no pain perception at all.
What does the modulation of pain perception established by primitive learning have to
do with sex? First, it must be emphasized that it is in the brain rather than in the genital
area that sex is joyful. The areas of the brain where sexual pleasure is generated are
probably susceptibility to primitive learning in the same way as areas responsible for
pain perception. If so, sexual pleasure may be amplified by primitive learning similar to
pain. The fact that perception of sexual pleasure can be triggered by tactile stimulation of
other parts of the body than the genitals is probably not news to most people. However,
many consider the erotic exploration beyond the genitals just as a part of the foreplay to
the veritable act – the intercourse – where the genitals are solely stimulated. This is a
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natural response pattern because the pleasure by stimulating the genitals is preprogrammed
also to be perceived in this area. This is convenient because it encourages
us to keep going with the stimulation of the genitals. However, that such perception is a
matter of nerve wiring is illustrated by the fact, that stimulation of the nipples may also
result in pleasure sensations in the genitals rather than in the chest/breast region.
Interestingly, NMR-scans have confirmed that apart from being processed in the part of
the sensory cortex dealing with sensory input from the chest – nipple stimulation is also
dealt with in an area normally procession input from the genitals (9).
The brain can be re-programmed to elicit aversive responses to stimuli not previously
being perceived as aversive. This may also be the case for pleasure where stimuli not
being particularly pleasurable in the beginning may become so by learning processes.
Indeed, that may also apply to tactile stimulation. If the pleasure of a certain tactile input
can be strongly potentiated by learning it may change from being disturbing to take part
in the overall experience of enjoyment and by so, render the sexual gratification from
being located in the pelvis to dissipate all over the body. But it must be taken into account
that the potential for conditioned learning may be dependent on the intensity of the
experience that conditions it. Therefore, it may be profitable to go all the way with the
concomitantly "exploration" of the alternative body parts. In this regard, some persons
are very fortunate to be able to achieve orgasm solely by nipple stimulation. Reports of
an increased orgasmic intensity from women using a novel agent that causes the erection
of the small muscles in the nipples (10) argue for a greater general awareness for this
body part during the sexual act. Furthermore, the high wiring of the nipples to the limbic
system including the oxytocin system should not be disregarded where breast
stimulation has been shown to result in elevated levels of oxytocin in women also not
having breastfeeding children (11).
Provided that such learning process is successful you will have developed an alternative
gateway to intense sexual pleasure sensations which may be at least just as efficient as
that of your genitals. Alternating the stimulation of the two gateways separately or in
combination may trigger powerful pleasure waves before the regular orgasm sets in.
Such sensation would probably elicit considerable discharges of oxytocin. The
reinforcement of the joy of sex also during the foreplay can enhance the desire for
frequent sex which further may improve the capacity of the oxytocin system. This may
also apply to sexual activities not having intercourse as a goal including those practiced
alone. Moreover, the enhanced pleasure sensations outside the orgasms might also make
you feel gratified without achieving one. Most interestingly, one may hypothesize that an
alternative route to intense sexual pleasure may access the pleasure functions in a way
that is less dependent on sexual arousal. This could for instance be true if oxytocincarrying
nerves acting on the limbic system are triggered via nipples stimulation. A sexual
pleasure unconditioned by sexual arousal would be possibly less dependent on
testosterone. Therefore, seniors with low testosterone may have a less hard job to
maintain a gratifying sex life and still enjoy the health benefits of oxytocin in this way.
Possessing a more direct gateway to the oxytocin system may likewise enable men to
defend their virility based on the importance of oxytocin-carrying nerves for the
induction of erection.
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Sensory perceptions can reinforce each other so that they are experienced with greater
intensity than the sum of each of them. This applies not least to the sexual sensations.
The phenomenon of 2 + 2 = 5 is called synergy.
Resolution
Although the health aspects of frequent gratifying sex may be comparable – if not more
pronounced – than exercise and healthy food habits, it may be dubious from a political
point of view to make recommendations in this regard. However, factual information
may promote awareness among people for the importance of maintaining a high
activity of their oxytocin system and that this can be obtained by sex.
Numerous human population studies and experiments with animals point to the fact that
oxytocin is pivotal to ensure our mental and physical health and that its different
functions in ourselves and our fellow humans can be influenced by our behaviour.
However, before the decision-makers of a community can come up with
recommendations and actions concerning oxytocin (and anything else) documentation is
needed that a particular intervention would have the desired effect. But in this case, it is
neither practically feasible nor ethically justifiable to conduct placebo-controlled blinded
intervention studies on people for several years that address the effects of such things as
sexual habits and parenthood. And should it nevertheless be possible to prove some
beneficial health effects of behavioural changes concerning these topics, it would be
difficult to evaluate the role of oxytocin. This is because other factors such as the
autonomic nervous system always will be important co-players.
Even if it one day should be possible with some credibility, for example, to claim that half
an hour sex every day prevents women from getting osteoporosis as 90s, it would be
problematic to include this in the health recommendations in line with half an hour daily
exercise, smoking cessation and consuming a lot of vegetables. The same is even more
true for recommendations to live in a passionate marriage and to have many good friends.
Such recommendations would be even harder to comply with than for smokers to quit
the tobacco or for obese people to run 5 kilometres every day. If one tries to encourage
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people to do something impossible to live up to, they may feel inadequate or stressed.
Appeals towards lonely people to find more friends would just make them feel even more
lonely and advising men and women with a low sexual drive to be more sexually active
may cause frustrations. The latter are no-goes as sex with no pleasure is, at best, a waste
of time as it hardly produces any appropriate oxytocin reaction.
So, what should be done at a community level to increase oxytocin activity among people?
More time must be allowed for sensuality and reflection on the signals from our body and
mind rather than of suppressing them in the chase for the biggest flat-screen TV – in other
words – there is a need to revoke a bit of the mindset of 1960s. How this should be
encouraged is up the politicians. In some cases, it appears that more focus has been put
on the economic consequences of the Covid-19 pandemic than on the atrocities caused
by its destruction of life and health. This reflects our fear for not being able to defend a
system which only can be sustained by an extreme level of consumption. But to maintain
the civilization, mankind must find other dominating avenues to stimulate the pleasure
systems. In other words, consumption of T-bone steaks and shopping weekends to
remote cities must be shown a back seat. Less resource demanding and polluting
entertainments should be put in the front where more sensuality may be one of them.
This might appear tedious to somebody but in some cases, it could be a matter of attitude
and lack of fantasy.
Fortunately, the object for sin and shame has already changed from sex to a CO2-careless
behaviour. This means that today in many societies, even the most reputable media
discuss eroticism with innocence and evaluates a newly developed orgasm gaming app
without blushing. This could, over time, allow the massage profession (not least the
intimate) to achieve the same prestige as the restaurant business so that the best massage
therapists might acquire the same star status as some kitchen kings. Getting a good
tantric massage could become something that is encouraged by your partner to
strengthen your oxytocin system and enabling you to accept what is being offered in bed
at home. On the other hand, the popularity of sex robots' underlines, to my opinion, a very
regretful trend of extreme artificiality, consumerism, and cognitive indolence. Even if
they are developed with very delicate artificial skin and intelligence that has access to the
internet, it will take a long time – if ever – before it is possible to mimic an oxytocin system
in such a thing – not to mention enable it to have a real orgasm. In the lack of a sex partner,
why not take a wonderful masturbation session where you let your own fantasies unfold
instead. Think about sexual pleasure sensations as the expression by the consciousness
that maintaining and restoring processes are going on in your brain and body.
I hope that after reading this book, you have become aware of our hormone queen in a
way that can affect your mindset and actions just a little bit. Even the most self-centred
and selfish person should thus be led to a more rewarding approach to life on both the
sexual and social level, if nothing else, based on considerations of his or her health. I will
end with the advice "Keep your hypothalamus fit".
1. Murphy MR, Checkley SA, Seckl JR, Lightman SL. Naloxone inhibits oxytocin release at orgasm
in man. Journal of Clinical Endocrinology and Metabolism 1990; 71(4): 1056-1058.
2. Dietrich A. Functional neuroanatomy of altered states of consciousness: the transient
hypofrontality hypothesis. Consciousness and Cognition 2003; 12(2): 231-256.
SLUT P{ BOGEN

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