The Neurobiology of Social Distance
Authors: Danilo Bzdok, Robin I.M. Dunbar
Journal: Trends in Cognitive Sciences (2020)

From babies to the elderly, psychosocial embedding in interpersonal relationships is crucial for survival.Insufficient social stimulation affects reasoning and memory performance, hormone homeostasis, brain grey/white matter connectivity and function, as well as resilience to physical and mental disease.Feelings of loneliness can spread through a social network, causing negatively skewed social perception, escalating morbidity and mortality, and, in older people, precipitating the onset of dementia (e.g., Alzheimer's disease). Never before have we experienced social isolation on such a massive scale as we have in response to coronavirus disease 2019 (COVID-19). However, we know that the social environment has a dramatic impact on our sense of life satisfaction and well-being. In times of distress, crisis, or disaster, human resilience depends on the richness and strength of social connections, as well as on active engagement in groups and communities. Over recent years, evidence emerging from various disciplines has made it abundantly clear: perceived social isolation (i.e., loneliness) may be the most potent threat to survival and longevity. We highlight the benefits of social bonds, the choreographies of bond creation and maintenance, as well as the neurocognitive basis of social isolation and its deep consequences for mental and physical health. Never before have we experienced social isolation on such a massive scale as we have in response to coronavirus disease 2019 (COVID-19). However, we know that the social environment has a dramatic impact on our sense of life satisfaction and well-being. In times of distress, crisis, or disaster, human resilience depends on the richness and strength of social connections, as well as on active engagement in groups and communities. Over recent years, evidence emerging from various disciplines has made it abundantly clear: perceived social isolation (i.e., loneliness) may be the most potent threat to survival and longevity. We highlight the benefits of social bonds, the choreographies of bond creation and maintenance, as well as the neurocognitive basis of social isolation and its deep consequences for mental and physical health. Humans, like all monkeys and apes, are intensely social. As an unsurprising consequence, most of us find social deprivation stressful. Social isolation, or a lack of social opportunity, gives rise to a sense of loneliness. Directly or indirectly, this feeling has many wide-ranging consequences for our psychological well-being as well as for our physical health, even our longevity. In short, loneliness kills people. The neuroscientist John Cacioppo argued that the sense of loneliness has evolved as an alarm signal to ensure that we remain firmly embedded within our social cocoon [1.Cacioppo J.T. Cacioppo S. The phenotype of loneliness.Eur. J. Dev. Psychol. 2012; 9: 446-452Crossref PubMed Scopus (22) Google Scholar, 2.Cacioppo J.T. et al.Evolutionary mechanisms for loneliness.Cogn. Emot. 2014; 28: 3-21Crossref PubMed Scopus (0) Google Scholar, 3.Cacioppo J.T. Hawkley L.C. Perceived social isolation and cognition.Trends Cogn. Sci. 2009; 13: 447-454Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar]. In 2019, the World Health Organization declared that loneliness is a major health concern worldwide [4.Cacioppo J.T. Cacioppo S. The growing problem of loneliness.Lancet. 2018; 391: 426Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. In many metropolitan cities around the globe, >50% of people already live in single-person households. The UK recently appointed its first Minister of Loneliness. The feeling of loneliness has been found to spread from person to person through social networks [3.Cacioppo J.T. Hawkley L.C. Perceived social isolation and cognition.Trends Cogn. Sci. 2009; 13: 447-454Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar]. Once lonely, humans can become trapped in a psychological downward cycle that can be difficult to escape from. This is in part reinforced by a skewed perception of negative cues and social threat from others, or the expectation of being socially excluded by others. The biased world-view leads to escalated suicide rates [5.Bangee M. et al.Loneliness and attention to social threat in young adults: findings from an eye tracker study.Pers. Individ. Dif. 2014; 63: 16-23Crossref Scopus (43) Google Scholar,6.Cacioppo J.T. et al.The cultural context of loneliness: risk factors in active duty soldiers.J. Soc. Clin. Psychol. 2016; 35: 865-882Crossref Scopus (12) Google Scholar], among other consequences. This 'learned social helplessness' can be dangerous because, among all existing species, we depend longest on other individuals. We explore here the neurobiology of social isolation and the consequences it has for our health and psychological well-being. First, we outline the evidence for the many benefits of social interaction. We then consider why one cannot have an unlimited number of friends, even though they are highly beneficial. Next, we briefly survey the behavioral patterns that play a central role in creating and maintaining strong social bonds. Finally, we examine key neurobiological mechanisms underlying social interplay, and the impact that social deprivation has on them. There is now accumulating evidence that friendships are a conditio sine qua non for health quality [7.Domínguez S. Arford T. It is all about who you know: social capital and health in low-income communities.Health Sociol. Rev. 2010; 19: 114-129Crossref Scopus (0) Google Scholar, 8.Kana'iaupuni S.M. et al.Counting on kin: social networks, social support, and child health status.Social Forces. 2005; 83: 1137-1164Crossref Google Scholar, 9.Liu L. Newschaffer C.J. Impact of social connections on risk of heart disease, cancer, and all-cause mortality among elderly Americans: findings from the Second Longitudinal Study of Aging (LSOA II).Arch. Gerontol. Geriatr. 2011; 53: 168-173Crossref PubMed Scopus (0) Google Scholar, 10.Pinquart M. Duberstein P.R. Associations of social networks with cancer mortality: a meta-analysis.Crit. Rev. Oncol. Hematol. 2010; 75: 122-137Crossref PubMed Scopus (200) Google Scholar, 11.Reblin M. Uchino B.N. Social and emotional support and its implication for health.Curr. Opin. Psychiatry. 2008; 21: 201-205Crossref PubMed Scopus (323) Google Scholar, 12.Rodriguez-Laso A. et al.The effect of social relationships on survival in elderly residents of a Southern European community: a cohort study.BMC Geriatr. 2007; 719Crossref PubMed Scopus (0) Google Scholar, 13.Smith K.P. Christakis N.A. Social networks and health.Annu. Rev. Sociol. 2008; 34: 405-429Crossref Scopus (731) Google Scholar, 14.Tilvis R.S. et al.Social isolation, social activity and loneliness as survival indicators in old age; a nationwide survey with a 7-year follow-up.Eur. Geriatr. Med. 2012; 3: 18-22Crossref Scopus (0) Google Scholar]. The tighter someone is embedded in a network of friends, the less likely they are to become ill. The higher your social capital, the faster you get better if you fall ill, the quicker you recover from surgery, and the longer you will live. Previous research [15.Holt-Lunstad J. et al.Social relationships and mortality risk: a meta-analytic review.PLoS Med. 2010; 7e1000316Crossref PubMed Scopus (2365) Google Scholar] collated 148 epidemiological studies (~300 000 people in total) to identify common factors that influence mortality. In the specific case of death due to cardiovascular disease, the three factors with by far the biggest effect were (i) the frequency of social support from others, (ii) how well integrated the person was into their social network, and (iii) whether the patient gave up smoking – two, arguably even three, social reasons. By contrast, the factors that doctors are conventionally most concerned about all had much less impact on survival rates. Key factors included obesity, diet, alcohol consumption, how much exercise was taken, drug treatments prescribed, and local air pollution. These authors conducted a follow-up analysis of 70 studies of longevity in older people, which followed ~3.5 million people over an average of ~7 years [16.Holt-Lunstad J. et al.Loneliness and social isolation as risk factors for mortality: a meta-analytic review.Perspect. Psychol. Sci. 2015; 10: 227-237Crossref PubMed Scopus (918) Google Scholar]: social isolation, living alone, and feeling lonely increased the chances of dying by ~30%, even after accounting for age, sex, and health status. Many other studies have shown that social isolation (though not self-reported feelings of loneliness) was a significant predictor of the risk of death. For example, a longitudinal analysis of ~6500 British men and women aged 50–59 years [17.Steptoe A. et al.Social isolation, loneliness, and all-cause mortality in older men and women.Proc. Natl. Acad. Sci. 2013; 110: 5797-5801Crossref PubMed Scopus (646) Google Scholar] found that being socially isolated increases the risk of dying in the next decade by ~25%. Quantitative analysis of nearly ~400 000 married couples in the American Medicare database revealed that, for men, the death of their spouse increased their own chances of dying in the immediate future by 18%. The death of the husband in turn increased the wife's risk of dying by 16% [18.Elwert F. Christakis N.A. The effect of widowhood on mortality by the causes of death of both spouses.Am. J. Public Health. 2008; 98: 2092-2098Crossref PubMed Scopus (133) Google Scholar]. Similar effects on morbidity rates have been found with respect to social support. A series of elegant prospective studies using data from the Framingham Heart Study [19.Fowler J.H. Christakis N.A. Dynamic spread of happiness in a large social network: longitudinal analysis over 20 years in the Framingham Heart Study.BMJ. 2008; 337a2338-a2338Crossref Scopus (790) Google Scholar,20.Christakis N.A. Fowler J.H. Connected: The Surprising Power of Our Social Networks and How They Shape Our Lives. Harper Press, 2009Google Scholar] found that the chances of becoming happy, depressed, or obese were all strongly mirrored by similar changes in the closest friend. There was a smaller significant effect due to the behavior of the friend's friend. A detectable effect was even present due to the friend of a friend's friend, but nothing beyond. This contagion phenomenon was especially strong if the friendship was reciprocal (i.e., both individuals recognized each other as a friend). If the friendship was not mutual, the social contagion effect was negligible. The investigators also documented a strong effect of 'geographical contagion'. If you have a happy friend who lives within a radius of 1 mile, you are 25% more likely to be happy. In addition, you are 34% more likely to be happy if your next-door neighbor is happy. People who belong to more groups are less likely to experience bouts of depression. Such findings emerged from the UK Longitudinal Study of Ageing (ELSA) that repeatedly profiled around ~5000 people from the age of 50 years onwards. Previous research showed [21.Cruwys T. et al.Social group memberships protect against future depression, alleviate depression symptoms and prevent depression relapse.Soc. Sci. Med. 2013; 98: 179-186Crossref PubMed Scopus (104) Google Scholar] that depressed people reduce their risk of depression at a later time-point by almost a quarter if they join a social group such as a sports club, church, political party, hobby group, or charity. Indeed, joining three groups reduced the risk of depression by almost two-thirds. On a more general note, surveys on social visits to pubs, social evening dinners, or regular attendance at religious services converged on one core conclusion: people who engaged in any of these activities typically had more friends, were happier, and felt more satisfied with their life. Such individuals were more immersed in their local community and trusted their neighbors more [22.Dunbar R.I.M. Breaking bread: the functions of social eating.Adapt. Hum. Behav. Physiol. 2017; 3: 198-211Crossref PubMed Scopus (25) Google Scholar, 23.Dunbar R.I.M. Social structure as a strategy to mitigate the costs of group living: a comparison of gelada and guereza monkeys.Anim. Behav. 2018; 136: 53-64Crossref PubMed Scopus (7) Google Scholar, 24.Dunbar R.I.M. Religiosity and religious attendance as factors in wellbeing and social engagement.Relig. Brain Behav. 2020; (Published online January 22, 2020. https://doi.org/10.1080/2153599X.2020.1712618)Crossref Scopus (0) Google Scholar]. The causal directionality was difficult to pin down in these cases because of the cross-sectional nature of the data. Nevertheless, path analysis provided some indication that intensity of social exchange was the candidate driver. The impetus to access social capital in the wider community [7.Domínguez S. Arford T. It is all about who you know: social capital and health in low-income communities.Health Sociol. Rev. 2010; 19: 114-129Crossref Scopus (0) Google Scholar] extends beyond humans. There is now a wealth of evidence from long-term field studies of wild baboons that socially well-connected females experience less harassment by other monkeys [7.Domínguez S. Arford T. It is all about who you know: social capital and health in low-income communities.Health Sociol. Rev. 2010; 19: 114-129Crossref Scopus (0) Google Scholar,23.Dunbar R.I.M. Social structure as a strategy to mitigate the costs of group living: a comparison of gelada and guereza monkeys.Anim. Behav. 2018; 136: 53-64Crossref PubMed Scopus (7) Google Scholar], have lower levels of cortisol stress hormones [25.Wittig R.M. et al.Focused grooming networks and stress alleviation in wild female baboons.Horm. Behav. 2008; 54: 170-177Crossref PubMed Scopus (157) Google Scholar,26.Crockford C. et al.Social stressors and coping mechanisms in wild female baboons (Papio hamadryas ursinus).Horm. Behav. 2008; 53: 254-265Crossref PubMed Scopus (0) Google Scholar], faster wound healing [27.Archie E.A. et al.Social affiliation matters: both same-sex and opposite-sex relationships predict survival in wild female baboons.Proc. R. Soc. B Biol. Sci. 2014; 28120141261Crossref PubMed Scopus (83) Google Scholar], produce more offspring, and live longer [28.Silk J.B. Social bonds of female baboons enhance infant survival.Science. 2003; 302: 1231-1234Crossref PubMed Scopus (594) Google Scholar, 29.Silk J.B. et al.Strong and consistent social bonds enhance the longevity of female baboons.Curr. Biol. 2010; 20: 1359-1361Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 30.Silk J.B. et al.The benefits of social capital: close social bonds among female baboons enhance offspring survival.Proc. R. Soc. B Biol. Sci. 2009; 276: 3099-3104Crossref PubMed Scopus (279) Google Scholar, 31.Cheney D.L. et al.Network connections, dyadic bonds and fitness in wild female baboons.R. Soc. Open Sci. 2016; 3160255Crossref PubMed Scopus (30) Google Scholar]. Such ramifications of social capital appear to hold up across a diversity of species, including chimpanzees [32.Wittig R.M. et al.Social support reduces stress hormone levels in wild chimpanzees across stressful events and everyday affiliations.Nat. Commun. 2016; 713361Crossref PubMed Scopus (50) Google Scholar], macaques [33.Brent L.J.N. et al.Family network size and survival across the lifespan of female macaques.Proc. R. Soc. B Biol. Sci. 2017; 28420170515Crossref PubMed Scopus (0) Google Scholar, 34.Vandeleest J.J. et al.Decoupling social status and status certainty effects on health in macaques: a network approach.PeerJ. 2016; 4e2394Crossref PubMed Scopus (16) Google Scholar, 35.Young C. et al.Responses to social and environmental stress are attenuated by strong male bonds in wild macaques.Proc. Natl. Acad. Sci. 2014; 111: 18195-18200Crossref PubMed Scopus (0) Google Scholar], feral horses [36.Nunez C.M.V. et al.Sociality increases juvenile survival after a catastrophic event in the feral horse (Equus caballus).Behav. Ecol. 2015; 26: 138-147Crossref Scopus (0) Google Scholar,37.Cameron E.Z. et al.Social bonds between unrelated females increase reproductive success in feral horses.Proc. Natl. Acad. Sci. 2009; 106: 13850-13853Crossref PubMed Scopus (0) Google Scholar], and dolphins [38.Frere C.H. et al.Social and genetic interactions drive fitness variation in a free-living dolphin population.Proc. Natl. Acad. Sci. 2010; 107: 19949-19954Crossref PubMed Scopus (0) Google Scholar]. A key underlying reason for these effects, at least in humans, is likely that loneliness impairs the immune system and reduces resistance to diseases and infections. Research has found [39.Pressman S.D. et al.Loneliness, social network size, and immune response to influenza vaccination in college freshmen.Health Psychol. 2005; 24: 297-306Crossref PubMed Scopus (225) Google Scholar] that freshmen students who reported feeling lonely had a reduced immune system response when they were given a flu vaccine compared to students who felt socially well engaged. Moreover, those students with only four to 12 close friends had significantly poorer responses than those with 13–20 friends. These two effects seemed to interact with each other: having many friends (a large social group of 19 or 20 friends) seems to buffer against a weakened immune response. Nevertheless, feeling lonely and having few friends results in a particularly poor immune defense. Other investigators [40.Kim D.A. et al.Social connectedness is associated with fibrinogen level in a human social network.Proc. R. Soc. B Biol. Sci. 2016; 28320160958Crossref PubMed Scopus (18) Google Scholar] used data from the Framingham Heart Study to show that people with fewer contacts in their social network had elevated serum fibrinogen concentrations. By contrast, people enjoying many social contacts had low fibrinogen levels. Fibrinogen plays an important role in blood clotting when a blood vessel has been ruptured, and also facilitates wound healing and tissue repair more generally: high concentrations thus signal poor health. Endorphins constitute a core component of the psychoendocrine mechanisms underpinning friendship (Box 1). Other research has found [41.Sarkar D.K. et al.Opiate antagonist prevents μ- and δ-opiate receptor dimerization to facilitate ability of agonist to control ethanol-altered natural killer cell functions and mammary tumor growth.J. Biol. Chem. 2012; 287: 16734-16747Crossref PubMed Scopus (0) Google Scholar] that social bonds stimulate the release of the body's natural killer cells, one of the white blood cells of the innate immune system whose core function is to destroy harmful bacteria and viruses.Box 1How Endorphins Create FriendshipsPrimates service their relationships through social grooming. Grooming triggers the endorphin system in the brain through a very specific neural system: the afferent CT fibers [163.Olausson H. et al.The neurophysiology of unmyelinated tactile afferents.Neurosci. Biobehav. Rev. 2010; 34: 185-191Crossref PubMed Scopus (210) Google Scholar]. These axon bundles have receptors at the base of most hair follicles, have the unusual properties of being unmyelinated (and hence are very slow, especially compared to the pain receptors in the skin), have no return motor loop (unlike pain and other proprioceptive neurons), respond to a very specific stimulus (light slow stroking at ~2.5 cm per s), and directly trigger the endorphin reward system [164.Nummenmaa L. et al.Social touch modulates endogenous μ-opioid system activity in humans.NeuroImage. 2016; 138: 242-247Crossref PubMed Scopus (48) Google Scholar]. Although humans no longer have the full fur covering that encourages social grooming, we still have the receptors and instead use physical contact in the form of touching, stroking, caressing, and hugging as a means for strengthening social ties in our closer relationships [165.Suvilehto J.T. et al.Topography of social touching depends on emotional bonds between humans.Proc. Natl. Acad. Sci. 2015; 112: 13811-13816Crossref PubMed Google Scholar,166.Suvilehto J.T. et al.Cross-cultural similarity in relationship-specific social touching.Proc. R. Soc. B. 2019; 28620190467Crossref PubMed Scopus (3) Google Scholar].Physical touch is intimate, and hence limited mainly to close family and friends (see Figure 2 in main text). To bond our wider range of relationships as well as our more intimate ones, humans exploit several behaviors that also trigger the endorphin system. These joint activities include laughing [167.Dezecache G. Dunbar R.I.M. Sharing the joke: the size of natural laughter groups.Evol. Hum. Behav. 2012; 33: 775-779Crossref Scopus (0) Google Scholar,168.Manninen S. et al.Social laughter triggers endogenous opioid release in humans.J. Neurosci. 2017; 37: 6125-6131Crossref PubMed Scopus (47) Google Scholar], singing [169.Pearce E. et al.The ice-breaker effect: singing mediates fast social bonding.R. Soc. Open Sci. 2015; 2150221Crossref PubMed Scopus (45) Google Scholar,170.Weinstein D. et al.Singing and social bonding: changes in connectivity and pain threshold as a function of group size.Evol. Hum. Behav. 2016; 37: 152-158Crossref PubMed Scopus (56) Google Scholar], dancing [171.Tarr B. et al.Naltrexone blocks endorphins released when dancing in synchrony.Adapt. Hum. Behav. Physiol. 2017; 3: 241-254Crossref Scopus (8) Google Scholar,172.Tarr B. et al.Synchrony and exertion during dance independently raise pain threshold and encourage social bonding.Biol. Lett. 2015; 1120150767Crossref PubMed Scopus (82) Google Scholar], feasting [22.Dunbar R.I.M. Breaking bread: the functions of social eating.Adapt. Hum. Behav. Physiol. 2017; 3: 198-211Crossref PubMed Scopus (25) Google Scholar], and emotional storytelling [53.Dunbar R.I.M. et al.Emotional arousal when watching drama increases pain threshold and social bonding.R. Soc. Open Sci. 2016; 3160288Crossref PubMed Scopus (16) Google Scholar]. An important feature of all these behaviors is that behavioral synchrony seems to ramp up the level of endorphin release [172.Tarr B. et al.Synchrony and exertion during dance independently raise pain threshold and encourage social bonding.Biol. Lett. 2015; 1120150767Crossref PubMed Scopus (82) Google Scholar,173.Cohen E.E.A. et al.Rowers' high: behavioural synchrony is correlated with elevated pain thresholds.Biol. Lett. 2010; 6: 106-108Crossref PubMed Scopus (0) Google Scholar]. Primates service their relationships through social grooming. Grooming triggers the endorphin system in the brain through a very specific neural system: the afferent CT fibers [163.Olausson H. et al.The neurophysiology of unmyelinated tactile afferents.Neurosci. Biobehav. Rev. 2010; 34: 185-191Crossref PubMed Scopus (210) Google Scholar]. These axon bundles have receptors at the base of most hair follicles, have the unusual properties of being unmyelinated (and hence are very slow, especially compared to the pain receptors in the skin), have no return motor loop (unlike pain and other proprioceptive neurons), respond to a very specific stimulus (light slow stroking at ~2.5 cm per s), and directly trigger the endorphin reward system [164.Nummenmaa L. et al.Social touch modulates endogenous μ-opioid system activity in humans.NeuroImage. 2016; 138: 242-247Crossref PubMed Scopus (48) Google Scholar]. Although humans no longer have the full fur covering that encourages social grooming, we still have the receptors and instead use physical contact in the form of touching, stroking, caressing, and hugging as a means for strengthening social ties in our closer relationships [165.Suvilehto J.T. et al.Topography of social touching depends on emotional bonds between humans.Proc. Natl. Acad. Sci. 2015; 112: 13811-13816Crossref PubMed Google Scholar,166.Suvilehto J.T. et al.Cross-cultural similarity in relationship-specific social touching.Proc. R. Soc. B. 2019; 28620190467Crossref PubMed Scopus (3) Google Scholar]. Physical touch is intimate, and hence limited mainly to close family and friends (see Figure 2 in main text). To bond our wider range of relationships as well as our more intimate ones, humans exploit several behaviors that also trigger the endorphin system. These joint activities include laughing [167.Dezecache G. Dunbar R.I.M. Sharing the joke: the size of natural laughter groups.Evol. Hum. Behav. 2012; 33: 775-779Crossref Scopus (0) Google Scholar,168.Manninen S. et al.Social laughter triggers endogenous opioid release in humans.J. Neurosci. 2017; 37: 6125-6131Crossref PubMed Scopus (47) Google Scholar], singing [169.Pearce E. et al.The ice-breaker effect: singing mediates fast social bonding.R. Soc. Open Sci. 2015; 2150221Crossref PubMed Scopus (45) Google Scholar,170.Weinstein D. et al.Singing and social bonding: changes in connectivity and pain threshold as a function of group size.Evol. Hum. Behav. 2016; 37: 152-158Crossref PubMed Scopus (56) Google Scholar], dancing [171.Tarr B. et al.Naltrexone blocks endorphins released when dancing in synchrony.Adapt. Hum. Behav. Physiol. 2017; 3: 241-254Crossref Scopus (8) Google Scholar,172.Tarr B. et al.Synchrony and exertion during dance independently raise pain threshold and encourage social bonding.Biol. Lett. 2015; 1120150767Crossref PubMed Scopus (82) Google Scholar], feasting [22.Dunbar R.I.M. Breaking bread: the functions of social eating.Adapt. Hum. Behav. Physiol. 2017; 3: 198-211Crossref PubMed Scopus (25) Google Scholar], and emotional storytelling [53.Dunbar R.I.M. et al.Emotional arousal when watching drama increases pain threshold and social bonding.R. Soc. Open Sci. 2016; 3160288Crossref PubMed Scopus (16) Google Scholar]. An important feature of all these behaviors is that behavioral synchrony seems to ramp up the level of endorphin release [172.Tarr B. et al.Synchrony and exertion during dance independently raise pain threshold and encourage social bonding.Biol. Lett. 2015; 1120150767Crossref PubMed Scopus (82) Google Scholar,173.Cohen E.E.A. et al.Rowers' high: behavioural synchrony is correlated with elevated pain thresholds.Biol. Lett. 2010; 6: 106-108Crossref PubMed Scopus (0) Google Scholar]. People who are more socially integrated have better-adjusted biomarkers for physiological function, as indexed by lower systolic blood pressure, lower body mass index, and lower levels of C-reactive protein – the latter being another molecular response to inflammation. This insight was evident in each of four age groups (adolescents, young adults, middle age, and old age) based on data from four large longitudinal American health databases [42.Yang Y.C. et al.Social relationships and physiological determinants of longevity across the human life span.Proc. Natl. Acad. Sci. 2016; 113: 578-583Crossref PubMed Scopus (161) Google Scholar]. The investigators found that, in adolescence, lack of social engagement had as big an effect on risk of inflammation as lack of physical activity. In old age, lack of friends had a bigger effect on risk of hypertension than the usually cited clinical causes such as diabetes. Even more worrying, the effects of social relationships on these physiological measures of good health during adolescence and young adulthood can persist into old age. In a longitudinal study of 267 males, for example, research found [43.Cundiff J.M. Matthews K.A. Friends with health benefits: the long-term benefits of early peer social integration for blood pressure and obesity in midlife.Psychol. Sci. 2018; 29: 814-823Crossref PubMed Scopus (3) Google Scholar] that the more socially integrated a child was at 6 years of age, the lower their blood pressure and body mass index (a measure of fatness) two decades later. This result held up when they controlled for race, body mass index in childhood, parental socioeconomic status, childhood health, and extraversion. Social isolation may well have pervasive effects on brain connectivity. If rats are socially isolated when young (a condition that can give rise to feelings of loneliness in humans), neural function and plasticity are altered [44.Alquicer G. et al.Postweaning social isolation enhances morphological changes in the neonatal ventral hippocampal lesion rat model of psychosis.J. Chem. Neuroanat. 2008; 35: 179-187Crossref PubMed Scopus (0) Google Scholar, 45.Barr A.M. et al.Abnormalities of presynaptic protein CDCrel-1 in striatum of rats reared in social isolation: relevance to neural connectivity in schizophrenia.Eur. J. Neurosci. 2004; 20: 303-307Crossref PubMed Scopus (0) Google Scholar, 46.Ueno H. et al.Region-specific impairments in parvalbumin interneurons in social isolation-reared mice.Neuroscience. 2017; 359: 196-208Crossref PubMed Scopus (19) Google Scholar, 47.Makinodan M. et al.A critical period for social experience-dependent oligodendrocyte maturation and myelination.Science. 2012; 337: 1357-1360Crossref PubMed Scopus (387) Google Scholar]. In particular, episodes of social isolation can irretrievably alter the function of the prefrontal cortex (the part of the brain that is central to managing our social relationships; see below), as well as its axon myelination (the laying down of the fatty sheaths around neurons that enable them to transmit signals faster and more efficiently) [44.Alquicer G. et al.Postweaning social isolation enhances morphological changes in the neonatal ventral hippocampal lesion rat model of psychosis.J. Chem. Neuroanat. 2008; 35: 179-187Crossref PubMed Scopus (0) Google Scholar]. Although short periods of loneliness in humans rarely have any long-term adverse outcomes, persistent loneliness escalates the risk of Alzheimer's disease and depression [48.Holwerda T.J. et al.Feelings of loneliness, but not social isolation, predict dementia onset: results from the Amsterdam Study of the Elderly (AMSTEL).J. Neurol. Neurosurg. Psychiatry. 2014; 85: 1