ABSTRACT. We need general, useful theory for how human mental adaptations relate to mental disorders. I have tried to develop such theory, focusing on human social and non-social adaptations, exemplified by a diametric, opposite nature to the psychotic-affective spectrum in relation to the autism spectrum. The theory is consilient with Marco Del Guidice's life history approach, with Simon Baron-Cohen's theories for autism, and with the bulk of genetic, neurological, and psychological evidence, barring mistakes and misinterpretations. I show how. The theory is based in evolutionary principles, and has direct implications for diagnosis, psychological therapies, and pharmacological treatments.

ABSTRACT. BACKGROUND Appendectomy is a relatively common pediatric procedure with little short-term negative impact. However, not much is known about long-term consequences beyond the perioperative risks. It is important to assess those consequences because this organ appears to have significant roles in maintaining appropriate gut biofilms for healthy digestive functioning and its lymphoid tissue might also play a role in the immune system. METHODS We tested the long-term health consequences of appendectomy by examining risk for 28 diseases within ~1 million Danish residents followed from birth to 30 years of age depending on whether appendectomy occurred in the first 12 years of life. Robust results were obtained by using stratified Cox regressions with sufficiently statistically-powered samples of cases (surgery) and controls. Our estimates of risk are adjusted for diseases occurring before surgery and for 18 covariates including parental history of the same diseases, birth metrics, and sex. RESULTS We found significantly elevated relative risks for many diseases, with the risks of various digestive (RR between 1.47-1.64) and genitourinary (RR between 1.30-1.72) diseases being particularly increased after appendectomy. The only decreased risk was found for inflammatory bowel disease (RR=0.58). Moreover, absolute risk differences suggest that effects on digestive tract (AR up to 2.81% increased) and genitourinary (AR up to 0.88% increased) diseases should be noticeable at the population level. CONCLUSIONS Our results provide evidence for longer-term health risks associated with appendectomy. This suggests that the appendix is important for the establishment of normal digestive and immunological function and that its removal may also be associated with other disease risks. These findings are consistent with the appendix having retained at least some of its ancestral functionality in modern humans. The decreased risk of IBD following appendectomy, previously found in other large epidemiological studies, remains puzzling.

ABSTRACT. The Developmental Origins of Health and Disease (DOHAD) hypothesis suggests that negative exposures during prenatal and early life development can produce long-term health effects. One such exposure is fetal malnutrition which can lead to restricted growth and low birthweight. Food aid has been used since World War II to buffer pregnant mothers and other vulnerable populations from the effects of malnutrition. This project examines the efficacy of food aid in two respects. First, it estimates the effect of past maternal food aid receipt on food security among Iraqi mothers who were pregnant both before and after implementation of the United Nation’s Oil-for-Food program in 1996. Second, the study assesses the degree to which receiving food aid during pregnancy affects young adult health outcomes. Methods. The population-based survey includes a random sample of 40 families living in the Slemani governorate of northeastern Iraq. This retrospective survey collected data on mother’s food insecurity and food aid receipt during her pregnancies in the 1990s. Data were also collected on young adult chronic physical and mental health outcomes for the two children in the household born before (1994-1995) or after (1997-1998) the introduction of food aid. Health outcomes include depression, anxiety, stress, height, weight, waist and hip circumference, and blood pressure. Results. Analyses will compare the health measures of current young adults age 20-24 born before and after the UN Oil for Food program’s introduction conditional on the status of maternal food aid receipt. Each model will measure the average effect of maternal food aid receipt during prenatal development on young adult health outcomes. Discussion. The findings of this project further our understanding of food aid’s role in disrupting or perpetuating the pathway linking fetal malnutrition to poor adult physical and mental health outcomes.

ABSTRACT. Evidence suggests that postnatal growth patterns of preterm and small for gestational age infants are predictive of multiple pathologies during adulthood, including metabolic syndrome, diabetes, hypertension, and malignancy. Early life growth courses are influenced by a complex interplay of genetics, epigenetic programming, infant nutrition, and perinatal morbidity. Variations in perinatal growth are both reflective and predictive of adverse health outcomes, and it is unclear to what extent manipulating growth trajectories may modify associated long-term consequences.

African Americans living in the USA exhibit higher rates of both premature birth and specific adult pathologies when compared to white counterparts. Research has documented multiple social factors contributing to this pattern of health disparity, and has pointed to the role of psychosocial stress and racial discrimination in the pathogenesis of preterm birth and the development of poor neonatal and adult health outcomes. It is likely that both evolutionary history and lived experience are influential in programming fetal and postnatal growth.

While recently developed growth charts describe global trends in expected growth velocity of preterm infants, there is no documented data on the observed variation of postnatal growth between sub-populations of preterm infants in the USA. It would be surprising if there were not postnatal growth differences based on distinctive fetal growth and body composition patterns. The specific factors that may be associated with these differences remain to be clarified. My ongoing research seeks to characterize observed differences in postnatal growth patterns among preterm infants based on both ethnicity and maternal exposure to adversity.

Ultimately, knowledge of optimal growth rates for distinct populations of neonates will help guide clinical practice so that we may encourage healthy growth among all infants while remaining aware of population-specific growth goals.

ABSTRACT. Mismatch between ancestral and current environments has figured prominently in the field of evolutionary medicine, with changes in diet and physical activity leading the charge. Here, I argue that mismatch in the arena of social organization also has significant effects on our health and overall wellbeing, and I argue specifically that changes that distance young children from emotionally committed caregivers can be detrimental to both groups.

My hypothesis has three components: (1) throughout nearly the entirety of our evolution, children grew up in proximity to various categories of related older individuals; (2) Hamilton’s Rule predicts that these children would have been ‘worthy’ recipients of care (i.e., worthy in the sense of increasing a donor’s inclusive fitness); (3) there must have been coevolution of mechanisms that motivate and guide nepotistic transactions in adaptive directions. Most of these, I suspect, were emotional, and are still with us, implying that we’ll feel happy and fulfilled when we behave in ways that help our young dependents, and feel the opposite when we don’t. Thus, a major source of our discontent (e.g., 6.5 million of 35 million Americans aged 65 or older are depressed) could be a shortage of nearby investment-grade kin, combined with a plethora of seemingly desirable distractions that too often turn out not to comport well with our emotional design.

But there may be hope for us after all, if our helping-leads-to-happiness neural mechanisms are not overly specific. While it’s unlikely that watering the houseplants triggers a burst of happy feelings, helping puppies probably does, and so does helping children—all of them.

So, my advice is to be nice. You’ll be happier for it.

ABSTRACT. Earlier studies of migrant Bangladeshis showed that women who developed in Bangladesh have a different reproductive phenotype from Bangladeshi and European women who mature in the UK. Specifically, developing in Bangladesh (where infectious disease loads are higher and quality of health care is lower than the UK) lowers levels of reproductive hormones and shortens the length of the reproductive lifespan. However, child migrants to the UK have a modified adult phenotype that more closely matches that of women who grew up in the UK. In order to assess epigenetic modifications of the reproductive phenotype, we established a mouse model to replicate effects of infectious disease exposure in early life. Mice treated with Dextran sodium sulfate had a phenotype mirroring women who grew up in Bangladesh, including a later puberty, lower levels of progesterone and anti-Müllerian hormone, and lower numbers of primordial and primary ovarian follicles. Transcriptome analysis of ovaries from the treatment group revealed up-regulated genes that induce follicle growth, and down-regulation of genes promoting apoptosis. Repressed genes include Srd5a1 (encoding the enzyme 5α-reductase), down-regulation of which (through increased methylation) matched findings from Bangladeshi migrants obtained using cheek swabs. In mice, expression of Srd5a1 was also significantly reduced in the hypothalamus where neurosteroids direct central activation of both the HPG and HPA axes through binding and activating specific neuronal (GABA) receptors. Our studies link central changes in activation and functioning of the adrenal axis with possible epigenetic regulation of Srd5a1 expression during a crucial developmental window. Changes in activation of hypothalamic control centres (via reduced 5α-reductase activity) could provide a mechanism for changes in ages of puberty and adrenarche, as well as modified adult functioning of these axes. We reveal that epigenetic modifications comprise flexible, regulatory mechanisms mediating phenotypic changes through altered gene expression. Funding: ESRC/BBSRC, UK.

ABSTRACT. While rises in cortisol are likely adaptive response to normative stressors, chronic and/or severe stress during development may result in endocrine depletion and a subsequently ‘blunted’ phenotype that cannot mount appropriate responses to challenges. This blunting is thought to be a risk factor for post-traumatic stress disorder (PTSD). Perinatal PTSD is of particular concern, not only for maternal health but also because perinatal cortisol levels are thought to mediate life history tradeoffs via fetal programming of HPA axis. We explored the relationship between PTSD, early life adversity, current stressors, and hair cortisol in a cohort of 101 low-income pregnant women oversampled for current mood disorder drawn from a longitudinal study of perinatal mental health at an urban safety-net hospital. We found that lower levels of hair cortisol predicted greater PTSD symptoms in response to current stressors. We also found that lower hair cortisol moderated the effect between early life stress and PTSD, but that this effect was attenuated by the presence of higher levels of current stress. This research provides support for the HPA axis blunting hypothesis of susceptibility to anxiety disorders during pregnancy. We consider how HPA blunting could result in maladaptive fetal programming if highly stressed women express a mismatched endocrine milieu.

ABSTRACT. Invasive placentation with extended pregnancy is a shared derived characteristic unique to eutherian mammals which possess a highly effective system of hemostasis, platelets. These are found in all mammals but no other group of animals. We propose that platelets and megakaryocytes (which give rise to platelets) evolved from an ancestral 2N thrombocyte which became polyploid and then fragmented cytoplasm in the pulmonary circulation producing platelets. Possession of platelets enabled the evolution of invasive placentation, and allowed safe separation, without hemorrhage, of the placenta from the uterus at birth. This explains why invasive placentation is limited to mammals.

ABSTRACT. A primary objective of medical genetics is to provide insights about disease etiology, including the complex interactions of both genes and environments. To this end, anthropological genetics offers a particular set of insights and tools with which to study signatures of environmental adaptation made by human populations experiencing novel or extreme environmental stimuli. Adaptations made during a period of extreme environmental circumstances may facilitate subsequent gene-environment mismatch when environmental pressures subside. The Beringian environment first encountered by the founding population of Native Americans in their migration from East Asia into the New World is a prime example. Previous research from our lab has identified a unique genetic architecture private to the Americas that dates to the period of Beringian occupation. Our dataset consists of high frequency SNP alleles (p > 0.30) identified from whole genome scans in the Thousand Genomes Project. Here we identify signatures of natural selection embedded within this American architecture, lending novel insights to the understanding of complex diseases and personalized medical trajectories. We generated novel software to annotate more than twenty thousand unique American SNPs with respect to four lines of evidence that are indicators of functional change related to adaptation: (1) genic or non-genic, (2) synonymous or non-synonymous, (3) ontological class, and (4) clinical significance. We compare the distributions for each category between the American SNPs and a set of matched randomly distributed SNPs in an American sample, which serve as a control. We identify multiple unique genic signatures related to human health outcomes within the American architecture that arose during the Beringian context and are now shared broadly by all extant Native Americans. Our work provides a novel set of candidate loci for investigating gene-environment mismatch in New World populations.

ABSTRACT. Since 2006 there has been an influx into Sydney of 30,000 students and migrants from Nepal. We have documented high rates of activation of latent TB in this group, despite the absence of active TB being a condition for their emigration. This natural experiment parallels that of the 100,000 Tibetans who fled to Dharamshala in India following the 1959 Chinese occupation. These refugees and their children have some of the highest rates of TB in the world. Nepal and Tibet both have a moderate to high TB incidence rate of 120-150/100,000 per annum, with lower rates at higher altitudes. The prevalence of latent TB, however, in Tibetan refugees in the US is 90-98%. In the case of the Nepalese, causes of reactivation such as diabetes, poor immigration screening or recent contact with active cases in Australia are thought to be unlikely. Three environmental and evolutionary explanations are currently being considered. The first is that a return to normoxia, or in the case of Tibetans descending to Dharamshala, an increase of 25 mm Hg in ambient paO2, favours the growth of M tuberculosis, a largely aerobic organism. The second is that descent from altitude reverses the hypoxia related increase in cellular and innate immunity which accompanies activation of the Hypoxia Inducible Factor (HIF) pathway. HIF is the master regulator of the immunological and metabolic tissue and organismal responses to hypoxia. The third is that the proven adaptations to altitude of populations in Tibet and Nepal, which involve a lowered threshold for activation of the HIF pathway, permanently impair immunity and that this impairment, in concert with the first two explanations, amplifies the risk of tuberculosis upon descent. These observations are likely to have important implications for the prevention and treatment of tuberculosis and other infections in populations living at altitude.

ABSTRACT. Protective responses such as pain, vomiting and anxiety are regulated by evolved mechanisms that express the response when a threshold is exceeded for the intensity or duration of a cue correlated with the situation in which the response is useful. Such thresholds are heritable so natural selection shapes them to levels that tend to be optimal in general, but that may vary widely between individuals, presumably because environments vary substantially. Repeated expression of a protective response indicates that an individual’s response is inadequate for what is likely a very harsh environment and that a stronger, longer response to a lower threshold would increase fitness. Facultative adaptations that shift the threshold to greater sensitivity and the response to greater intensity and duration have been documented for pain and anxiety and may be common for other responses. Such systems are inherently vulnerable to slipping into a runaway positive feedback cycle. Such positive feedback is a recognized cause of chronic pain, although applications of this knowledge are still in development. Panic disorder can also result from positive feedback that lowers the response threshold. This presentation reviews evidence for the pathogenic process and describes other clinical conditions that may be explained by the same mechanism including pathological cough and vomiting. The results may be useful for strategies to prevent and treat syndromes of excess response in defensive systems.

ABSTRACT. Introduction: How the long chain fatty acids DHA and EPA in the diet permitted human brain evolution, and how much our brains need today to function optimally is still a hot topic for debate. DHA and EPA are considered as semi-essential because only insufficient amounts can be produced from other nutrients, such that they must be ingested with the diet. The Dietary Reference Intake (DRI) of DHA and EPA, or of food containing these fatty acids, has not yet been established, but consumption of fish is routinely recommended. Here we analyze data from a large cohort study to assess the association between fish consumption and scholastic performance in children and adolescents. Methods: We analyzed data from the German cohort of children and adolescent health KiGGS, which was conducted 2003-2006 and included more than 17,000 children. We applied ordered logistic regressions to test for associations between fish intake and school performance. We also included potential confounders in our models. Results: We found a statistically significant association between an intake of 8 g of fish per day and last grades in both German and mathematics. For the outcome German, higher levels of fish intake also had a positive effect. These relationships were not linear but tended to decrease again with higher intakes of fish. Discussion: Our result confirms previous reports of a positive association between fish intake and scholastic performance. Interestingly, this relationship was not linear but tended to decrease again in the highest categories of fish intake. We hypothesize that mercury or other pollutants in the fish could be detrimental at high levels. We recommend a minimal intake of 8 g fish per day for all children. Upper limits have yet to be established.

ABSTRACT. Successful life history strategies depend in part upon an organism's ability to appropriately adjust reproductive investment in response to signals of current and/or future environmental conditions. In women, evidence suggests that reproductive investment is modulated by physiological mechanisms that vary ovarian hormone concentrations in concert with temporal changes in energy availability.

Some cross-populational studies have observed that lower average ovarian steroid concentrations are associated with lower average energy intake (but not with variation in populational or individual fertility). Moreover, because dietary fat and energy intake are typically highly correlated across populations, it has hitherto been difficult to determine the independent association of either macronutrient with cross-populational variation in ovarian steroids.

To break this degeneracy we measured and compared ovarian steroid concentrations from Central Asian pastoralists (high-fat despite low-energy diet), U.S. and German women (high-fat/high-energy diets), and Bolivian agropastoralists (low-fat/low-energy diet).

We found that ovarian steroid concentrations are greater in Central Asians than in US and German women (hitherto the populations with the highest known ovarian steroid concentrations). Bolivians had the lowest steroid concentrations.

We also compared ovarian steroid concentrations of women who grew up in East vs. West Germany during 1961-1989, when these genetically similar populations had different economic systems and resources (consequently East Germans were shorter). Nonetheless, our East German sample had significantly higher ovarian steroid concentrations than our West German sample. We hypothesize that this pattern may be due to the East Germans' higher dietary fat intake.

The findings of these two studies argue against energy intake alone as the major dietary factor in cross-populational variation in ovarian steroids, and suggest a significant role for dietary fat. These findings also suggest the hypothesis that temporal variation in dietary fat intake, like that in energy, may be an important signal of environmental quality that modulates an individual’s reproductive investment.

ABSTRACT. In the last decade, accumulating evidence suggests that the microbiome – the community of microorganisms inhabiting our bodies – has an important influence on brain activity, cognition and behavior. The bulk of the human microbiome resides primarily in the intestine, but microbes and their products have been increasingly identified in tissues previously assumed to be sterile, including the blood and the brain. One mechanism for microbial influence on behavior is low grade inflammation, including neuroinflammation, that may result in anxiety and depression-like behaviors. Also, the microbiome has been shown to have bidirectional effects on the stress response, memory, and social behavior. These effects appear to be microbe specific in some instances and raise the possibility of using microbial therapies to treat behavioral diseases. I outline the evidence for microbial influence on brain development, brain activity, mood and behavior that lay the groundwork for the potential microbial interventions for brain disorders. This presentation will explore the hypothesis that neurocognitive effects of microbes can be predicted by their status as mutualist, pathobiont or pathogen. Risk and reward from the microbiome may provide an explanation of why our brains are exquisitely sensitive to our resident microbes.

ABSTRACT. People have been consuming variants of kombucha, a sugared tea fermented with symbiotic bacteria and yeast, for thousands of years. Although kombucha is often consumed for its purported health benefits, there is currently a paucity of research examining a) whether kombucha does indeed improve health and b) the mechanisms through which this might take place. A growing body of research finds that the gut microbiota is an important regulator of immune function in the body. Moreover, administering probiotics that promote a healthy gut microbiome improves physical and psychological health by reducing excessive levels of inflammation. In the current talk, I will present the hypothesis that kombucha, through promoting a healthy microbiome and decreasing systemic inflammation, may yield a variety of benefits for physical and mental health. Further, I will present preliminary results of ongoing research conducted in our lab examining relationships between kombucha, immune function, and inflammation. I will close by discussing future directions for this research.

ABSTRACT. The capacity of the gut microbiome to recruit signalling along the gut-brain axis in order to influence many core aspects of brain function and behaviour is increasingly appreciated. This includes a broad range of behaviours relevant to depression, anxiety and pain as well as host stress physiology. Exposure to psychological stressors in turn may impact substantially on the microbiome-gut-brain axis. This includes an impact on the structure and function of the gut microbiome itself as well as key neurotransmitters at both levels of this bidirectional communication system including serotonin and the metabolism of its amino acid precursor, tryptophan. Importantly, many of the behaviours influenced by the gut microbiota rely on intact serotonergic neurotransmission while other neuroactive agents produced via host-microbe interactions are also of important in this regard. Research efforts continue to identify the precise mechanisms underpinning these effects and to interrogate the translational relevance of a promising body of preclinical data derived from a variety of experimental approaches. Microbiota-deficient animals in particular consistently show alterations in the availability of tryptophan as well as serotonergic alterations in the gastrointestinal tract and the CNS. In this respect the gut microbiome may be necessary not only to determine the set point but may also prime the gut-brain axis for appropriate stress responses. Prototypical stress-related clinical gut-brain axis disorders such as irritable bowel syndrome are associated with aberrations in the stress response and tryptophan metabolism. Neuropsychiatric disorders, including major depression, are also now linked to compositional alterations in the gut microbiome which are associated with prominent symptomatic and neurobiological features. These translational insights will be critical as we move promising preclinical research towards mechanisms and therapeutic targeting of the gut microbiome in the clinical setting and advance towards a psychobiotic approach to managing stress-related disorders in the future.

ABSTRACT. Microbiota of the human gut, oral cavity, nasal cavity, and brain may modulate Alzheimer’s Disease (AD) pathogenesis, and changes in the microbial composition of these body regions across human evolutionary history suggest escalation of age-matched AD risk. Dysbiosis in these body regions may promote immunoregulatory dysfunction, systemic inflammation, and epithelial barrier permeability. In turn, pro-inflammatory agents-- and occasionally microbes themselves-- may infiltrate the brain and promote AD pathogenic processes, modulated by APOE-genotype. Dysbiotic conditions throughout the body may influence AD susceptibility or pathogenesis by promoting peripheral inflammation and barrier permeability, which can facilitate neuroinflammation, reactive oxygen species translocation to the brain, and bacterial translocation to the brain. These processes, subsequently, promote beta-amyloid accumulation, microglial dysfunction, and neuronal damage. I will introduce these ideas and go into greater detail about the relationship between Alzheimer's and microbiota of the human nasal cavity. The subsequent two talks will discuss the oral cavity and gut symbiotic microbiota with relation to Alzheimer's.

ABSTRACT. The gut microbiome plays an essential role in host metabolism. Shifts in the gut microbiome both across evolution and within an individual’s lifetime may increase the energy available for brain maintenance and development. We see changes in the production of short-chain fatty acids (SCFAs) between nonhuman primates and humans. Specifically, we see a shift away from butyrate production in humans, a SCFA that is used by the gut epithelium for energy. Humans not only have fewer bacterial taxa associated with butyrate production, but also had significantly fewer butyrate-producing pathways present compared with other phylogenetic groups (humans=1.90±0.88 pathways, apes=3.00±1.41, Old World monkeys=3.03±0.76, New World monkeys=2.70±0.82, lemurs=2.27±0.59) (F=8.02, p<0.001). This decrease in butyrate production is likely associated with increases in the production of other SCFAs, acetate and propionate, which directly provide energy to the brain either directly or increase adiposity. We also see shifts in the gut microbiome related to energy production and lipid metabolism during pregnancy, lactation, and early development in both nonhuman primates and humans. In particular, we see increases in the relative abundance of Actinobacteria during pregnancy and the relative abundance of Proteobacteria during both pregnancy and lactation. Additionally, relative abundances of Proteobacteria are markedly higher during the first 8 months of human infant life. These changes in the metabolic functions of the gut microbiome both between and within species provide nutritional support for brain maintenance and may supply key nutrients for brain growth and development. However, these same gut microbial shifts are also associated with increased inflammation and risk of metabolic disorders, particularly in industrialized human populations. Thus, there may be a tradeoff between a metabolically-efficient gut microbiome that supports a large, energetically expensive brain and modern human health.

ABSTRACT. The need for responsible antibiotic stewardship can be difficult to reconcile with the clinician’s task of preventing septic patients from progressing to severe sepsis and septic shock. Empiric antibiotics are typically administered before culture results, yet antibiotics carry non-trivial risks. The diagnosis of sepsis is often based on SIRS criteria, however they are nonspecific and frequently met by patients presenting with conditions other than bacterial infections.

This retrospective chart review includes 200 patients who were administered antibiotics while in the Emergency Department (ED) and admitted. From clinical documentation we are able to determine whether these patients met SIRS criteria and/or were deemed to have sepsis by the physician ordering antibiotics. Changes to, or discontinuation of, antibiotics by the admitting team are recorded as are final culture data, discharge diagnosis, and whether patients were prescribed antibiotics at discharge.

Our study finds that the majority of patients administered antibiotics in the ED of our academic community hospital do not meet SIRS or qSOFA criteria prior to administration of antibiotics and are formally documented as not having sepsis or septic shock. Most of patients in this study received vancomycin and piperacillin-tazobactam for a wide variety of suspected sources of infection. The overall mortality rate for this group during the admission was 4%, which was comparable to all-cause hospital mortality. Approximately 50% were found to not have an infection. Of note, about 40% had received antibiotics within 3 months of presentation.

These findings suggest that an opportunity exists for increased antibiotic stewardship in the emergency department in the management of patients who are being treated for possible sepsis and septic shock. Stable patients in whom infection cannot be definitively ruled out may benefit more from prompt, thorough evaluation by an admitting team prior to initiation of empiric antibiotics.

ABSTRACT. Shoulder evolutionary studies often focus on traits of the scapula alone. This approach makes an implicit assumption that the scapula evolves independently. However, the scapula shares both functional and developmental relationships with the basicranium and vertebral column. We hypothesize that these anatomical regions limit the ability of the scapula to evolve independently, and instead comprise a functional trait complex. In addition, the scapula also has analogous characteristics to the pelvis. Genetic covariances underlie all these relationships, and so accounting for the constraints imposed by these covariances is essential for accurate models of trait responses to selection.

To investigate this, we obtained linear dimensions in six primate taxa: humans, chimpanzees, macaques, tamarins, marmosets, and colobus monkeys. We examine if the functional and developmental relationships between the shoulder (scapula and clavicle) with the basicranium and vertebrae are reflected in genetic covariances among their morphological traits, that in turn would influence the ability of these elements to respond to selection. Pelvic dimensions are included as well, given developmental parallels between the limb girdles. Humeral dimensions not associated with the shoulder are also examined, as these traits do not have direct functional or developmental relationships with the other anatomical regions. All dimensions were standardized by measurement means within species. We calculated evolvability and residual covariances to assess our hypothesis.

Results show a consistent pattern among all six primate genera. The scapula is not evolutionarily independent from the basicranium or vertebrae with an equal magnitude as the scapula with the pelvis. The scapula is less evolvable with the basicranium, with vertebrae, and with the pelvis than with the humerus. We conclude that the scapula, vertebrae, and basicranium mutually limit each other in response to directional selection, forming a functional trait complex. This has important implications for models of shoulder evolution, function, and disorders.

ABSTRACT. Background/Aims: Breastfeeding is a highly evolved biological mechanism with proven positive effects on the health status of mothers and infants. But it has been rendered complex in societies with a strong influence of western medicine and heavy marketing of infant formula. While the factors affecting rates of breastfeeding vary widely, grandparents remain a source of influence across time and cultures.

Method: A qualitative study of 73 adults from 17 focus groups was conducted in Perth, Western Australia. Different family member types were present in each focus group. Transcribed data from the focus groups were coded in vivo and analysed using an interpretative phenomenological framework.

Results: Grandparents’ breastfeeding experiences, beliefs and attitudes influenced parents’ expectation to successfully breastfeed. In cases where grandmothers failed to breast feed, mothers found it easier to justify formula feeding their infants. Grandparents, while agreeing that breast feeding was best for infants said as parents they were curtailed by the inability to feed in public. The lack of commercially produced infant foods was a source of anxiety for grandmothers when efforts to breastfeed failed, which often led to early introduction of solid foods. Grandparents’ experience contrasts with the challenges faced by parents today as mothers are forced to return to work, and the abundance of commercial infant food means failure to initiate and sustain breastfeeding has a relatively easier solution.

Conclusions: The intergenerational influence on breastfeeding seen in this study sample underscores the importance of breastfeeding education and support for parents and grandparents to ensure future generations benefit from this unique mammalian trait.

ABSTRACT. Autoimmune diseases (ADs), in which the immune system attacks the body's own healthy tissues, affect almost one in twenty and are the fourth leading cause of disability in women. Over the past century ADs have rapidly increased in Western, affluent societies, suggesting that changes in our ecology and lifestyle are driving this development. According to the hygiene hypothesis decreased early microbial exposure in modern environments is causing disruption to immunoregulation bringing about a surge in ADs. However, this explanation does not account for the observations that (a) 80% of autoimmune patients are female, (b) ADs co-occur more often in women than in men, and (c) the incidence of some ADs is increasing more rapidly in women. As we show, the female preponderance in autoimmunity is most pronounced from menarche onwards and decreases again around menopause, suggesting that the divergence in sex hormone levels during the reproductive years plays an important role in AD aetiology. After exploring the effect of the menstrual cycle, pregnancy, and contraceptive use on AD incidence and symptoms, we discuss how ovarian steroids can influence mechanisms for central and peripheral tolerance induction as well as the balance between cellular and humoral responses of the adaptive immune system. Using an evolutionary perspective, we suggest that tolerance induction as well as cyclical immunity in females have been shaped by natural selection to optimise the implantation and gestation of an allogeneic foetus, and suggest ways that trade-offs between immunocompetence and reproduction in different ecologies can affect AD development. We suggest that these immune mechanisms are currently out of balance because of a mismatch between the conditions that they evolved in and our modern lifestyles. Finally, we propose the novel hypothesis that current changes in AD prevalence and patterns are caused by increases in ovarian hormone exposure throughout a woman’s lifetime, which we relate to reduced immune challenges, increases in reproductive lifespan, changes in reproductive patterns, and enhanced positive energy balance, complementing existing theories on the role of obesity and changes in microbial exposure in AD aetiology.

ABSTRACT. Palaeomicrobiology has experienced significant advances based on the development of new and more efficient ancient DNA techniques, allowing the identification of pathogens and other bacterial genomes present in the analysed material. Soft tissues are often used as a source of ancient DNA, in particular in the form of fixed tissue specimens, but the sampling is still destructive and problematic for irreplaceable samples. However, to our knowledge, no prior study tried to extract biomolecules from the embedding liquid. For the storage of organs and tissues in medical collections, ethanol-based fixatives are often used as an embedding liquid Ethanol is less damaging to DNA than other embedding chemicals such as formalin. To test the potential of this source for historical DNA, we compared the metagenomes from tissues and from their preserving solution for 16 ethanol-preserved samples dated to between 1760 and 1889, with known diagnoses of tuberculosis, leprosy, syphilis and virus-induced skin tumours. In addition, we performed a mitochondrial enrichment to assess the proportion of endogenous DNA present in the fixative. We found similar communities in the extracts obtained from the tissue and from the preserving solution, and we successfully retrieved ancient mitochondrial sequences from the liquid component. This approach offers strong potential to analyse high-valued historical samples without destructive sampling.

ABSTRACT. Fasting, the abstention from food or liquids for a prolonged period of time is a widespread practice that exists in cultures that vary in social complexity and access to resources. Evolutionary theories have primarily focused on explaining reactive fasting such that fasting evolved in response to fluctuations in resource availability. This theory, however, is unable to explain variation in deliberate fasting that exists across cultures.

Herein I propose and test three possible functions of deliberate fasting in humans: behavioral immunity, signaling, and performance enhancement. Regarding behavioral immunity, numerous human and non-human studies show that deliberate fasting increases longevity, delays the onset of chronic disease, and improves immune function. Some studies also show that fasters are less likely to consume toxic and pathogenic substances. Collectively, evidence suggests that fasting might function as a behavioral immune strategy, however systematic cross-cultural tests of this hypothesis are unavailable for confirmation.

Deliberate fasting could also function as a signal of in-group commitment through the display of fasting during public rituals that occur across the lifespan, particularly in the context of religious rituals. A third function of fasting is performance enhancement, whereby individuals use fasting to improve skills across a range of learned behaviors, such as hunting and shamanistic healing.

The current study tested these three functions of fasting in 129 cultures in the Human Relations Area Files (eHRAF). First, the term “fasting” was searched, and data were iteratively coded for type of fasting, function, and age category of abstainers. Although findings lend support for all three functions, signaling appears to best explain the function of deliberate fasting. This study concludes with a discussion of the evolutionary and public health implications of this research, and emphasizes the need for more biocultural research on fasting, particularly during vulnerable periods of human development.

ABSTRACT. The application of evolutionary biological principles to clinical medicine represents an immense enrichment of medicine with a further, necessary explanatory background. However, evolutionary medicine largely skips an essential part of medical knowledge and medical education: the pre-clinical phase. Thus, there is a fundamental lack of awareness of the evolution of man himself that has taken place and is taking place – even without a clinical (pathological) context. In short: The evolution of the healthy human being is missing. The current main topics of Evolutionary Medicine (microorganisms, diseases of civilization, psychiatry) deal with problems, for which human history lies at its center. However, in this short period of time (in comparison to the environment and microorganisms), man’s evolution has been too slow. It is precisely at this point that there is a lack of awareness among physicians. An awareness that man can be placed in the greater history of evolution and its relevance for disease. Most of the contents of human evolutionary history are much older than man – rather they begin with life itself. The use of oxygen, for example, is the starting point for benefits (e.g. multicellular organisms), but also for problems that still characterize ageing and diseases (including tumors) today. The evolution of human organ systems (anatomy and physiology), supplemented by the molecular level, and thus the evolution of normal biochemical and genetic processes (biochemistry and molecular biology), are an urgently needed framework of content. For the timeframe, the basic features of phylogeny are, of course, indispensable. Altogether, this can be integrated into existing pre-clinical subjects, which can be used to pave the way for questions of evolutionary backgrounds in the clinic as early as the first semesters.

ABSTRACT. Background: Hypertensive left ventricular hypertrophy (LVH) with reduced compliance due to myocardial fibrosis is a leading cause of human heart failure (Gradman & Alfayoumi, 2006; Talman & Ruskoaho, 2016). Adult Masai giraffe (Giraffa camelopardalis tippelskirchii) ventricles thicken in response to pressure but do not stiffen. This may be a natural animal model of resistance to diastolic dysfunction via fibrosis inhibition.

Purpose: To establish whether normal giraffe adult ventricles fibrose with hypertrophy and to identify pathways involved in pressure-responsive thickening without fibrosis.

Methods: Review of cardiac fibrosis peer-reviewed literature, veterinary databases, and privately-accessed data on 136 giraffe necropsies.

Findings: Minimal evidence of ventricular fibrosis was found in the necropsy reports, communications with DVMs, or veterinary literature. Within the developmental pathways related to cardiac fibrosis, three genes (TGF-β1, FGF23, and FGF2) with fibrosis-promoting and two (FGF21 and FGF16) with inhibiting effects were identified belonging to gene families with significant mutations unique to giraffes (Agaba et al., 2016; Itoh & Ohta, 2013).

Discussion: The hypertrophied giraffe myocardium lacks fibrosis seen in other mammals. Five candidate genes involved in cardiac remodeling (including one in the ACE pathway, which is uniquely adapted in giraffes) may play key roles in this adaptation (Wang et al., 2017). Hypertrophy without fibrosis likely evolved within the past 11.5 mya since divergence from a common ancestor with okapis (Agaba et al., 2016). Identification of these five genes and linked mechanisms has translational significance for models of human diastolic heart failure.

ABSTRACT. Atherosclerosis is the leading cause of death in our species (Mozaffarian et al.). The vast majority of research focuses on proximate and hyper-proximate causes for atherosclerosis. Non-proximate hypotheses to explain potential adaptive benefits of vulnerability to atherosclerosis are infrequently advanced. One under-leveraged approach is to develop phylogenetic models of atherosclerosis vulnerability which can be used to:

1) Identify natural animal models of differential vulnerability 2) Identify selective pressures underlying evolved vascular vulnerability 3) Develop novel, testable hypotheses explaining adaptive bases for vulnerability to atherosclerosis

Our study features the use of systematic review to identify the taxonomic range of atherosclerosis occurrence and from these findings generate novel non-proximate hypotheses. Consulted databases included the BIOSIS Citation Index and Zoological Record databases within Web of Knowledge. We identified cases of non-induced atherosclerosis in 134 chordate species ranging from bluefin tuna to ostriches.

The appearance of spontaneously (naturally) occurring atherosclerosis in all vertebrate orders suggests a conserved, adaptive component of this vascular vulnerability. Potential hypotheses arising from our findings explaining the persistence of this vulnerability center on the antipathogenic features of vascular endothelium. One hypothesis is that atherosclerosis arose 540-510 million years ago with the evolution of the vascular endothelium, a ubiquitous trait among vertebrates that plays a key role in the initiation and development of the condition (Folcik et al.; Monahan‐Earley et al.). The collection and analysis of more necropsy data would likely reveal spontaneously (naturally) occurring atherosclerosis in numerous more vertebrates and would facilitate the formation and thorough examination of this and more such hypotheses.

ABSTRACT. Primates developed a diagonal foot placement involving rotating the pelvis and shoulders in opposite directions during the stride which also provides power in an elastic stretch shortening cycle in sport. Evolution of a valgus knee and elbow enabled efficient balance and weight bearing in an arboreal environment but also allows transfer of rotary momentum that may be linked to bipedalism in evolving simultaneously with advantages over other species.

Relatively shorter lower limbs in first hominids required a greater angle of inclination of the femur. The moment arms of Gluteus maximus(GM), previously underestimated, are altered by pelvic and femoral adaptations in bipedalism that also enable rotation of the pelvis that is the beginning of the rotary kinetic chain, similarly illustrated in comparative anatomy from the big toe to the thumb. The stronger biarticular connection of GM with greater moment arms as the hip flexes stabilizes the more flexible knee in transfer of increased torque in the coronal and transverse planes from hip to the lower leg.

This has great significance in sport performance and injuries in change of direction,hitting and throwing.

Changes in GM provide a link from the lower leg via the thoracolumbar fascia to the thorax and upper arm providing power, elastic energy and stability not only in locomotion but also the rotary kinetic chain.Research in injuries such as anterior cruciate ligament rupture and prevention programs has major relevance and may gain insight and solutions with new knowledge gained from studying evolution.

ABSTRACT. Background: Osteosarcoma is the most common pediatric bone malignancy. It is linked to periods of peak skeletal growth, increased bone cell turnover, and activation of the GH/IGF-1 pathways. Most osteosarcoma research has focused on proximate causes while potential adaptive components of vulnerability to osteosarcoma have received minimal research attention. Purpose: To develop non-proximate hypotheses for vulnerability to osteosarcoma by creating comprehensive taxonomies of non-human species with confirmed cases of spontaneous osteosarcoma and integrating these with life history and developmental information. Methods: Formal systematic review using PRISMA standards conducted to comprehensively identify species with confirmed cases of osteosarcoma. Life history characteristics of identified species were then mapped on to taxonomic findings from the systematic review. Results: Osteosarcoma is widespread across vertebral taxa with dynamic, environmentally-sensitive skeletal growth properties. Disproportionate occurrence during early-life peak growth periods and adolescence points to accelerated skeletal growth as a risk factor. Discussion: All taxa with vulnerability to osteosarcoma share environmentally-sensitive skeletal growth. Accelerated skeletal growth during critical life phases—gestation, early-life, and adolescence—enhance fitness through ecologically-influenced optimization of size and competitive advantage over conspecifics. Adaptive non-pathological accelerated bone growth and malignant osteoblastic transformation share GH/IGF-1 pathways. Experimental interference with GH/IGF-1 pathways may modify vulnerability to malignant osteoblastic transformation but would be predicted to also limit a growing organism’s ability to optimize size to environmental conditions. This study demonstrates how the integration of systematic review-derived taxonomy and life history information can generate a novel, testable non-proximate hypothesis for a high impact human cancer.

ABSTRACT. Re-emerging infectious diseases are of worldwide significant importance, however survival mechanisms of many pathogens remain unclear. Studying historic pathogen genomes provides researchers with crucial information to identify and characterize past pathogens and also gives important information about the evolution and host interactions of these pathogens. Archival formalin fixed tissues could become valuable sources for retrospective molecular analysis. Museum collections provide researchers with well documented, and precisely dated sample data bases for genome wide analysis. However, the use of formalin fixed specimens is so far limited due to chemical modifications induced by formaldehyde. Thus, DNA recovery from these samples is challenging and new standards for processing and analysis need to be established. In this project we collected ten samples from the pathological collection in the Narrenturm at the Vienna Museum of Natural History. The samples are associated with diagnoses of tuberculosis, leprosy, and anthrax and originate from autopsy material collected between 1851 and 1936. To improve the DNA recovery, we tested three different extraction protocols with different digestion temperature and chemicals. To optimize the downstream work flow of DNA processing, we also compared double stranded and single stranded libraries for each sample. Our first results revealed that double stranded library preparation was not effective for our samples and most of the libraries were self-ligated adapters. Currently, we are testing our extraction protocols with the single stranded library method. DNA retrieval from formalin fixed tissues provides us with the opportunity to study the evolution of pathogens over the last few centuries and also helps us to analyse the progressing of diseases in natural conditions before the antibiotic-era.

ABSTRACT. For many decades, the retrieval of ancient DNA from Egyptian mummies was considered challenging, due to issues surrounding the preservation and contamination of the extracted DNA. However, recent advances in ancient DNA methods, combined with next-generation sequencing, have enabled reliable retrieval of human mitochondrial and nuclear genomic data as well as metagenomic data. This opens up the possibility to also study the general health status of individuals, including pathogens that they might harbor. Here we analyze soft tissue and skeletal samples of 119 Egyptian mummies from different time periods using a metagenomic approach. First, Red Complex bacteria correlating with periodontal disease were identified in the oral microbiome. By screening the soft tissue and skeletal remains, the genomes of two ancient pathogens, a 2,200-year-old Mycobacterium leprae strain and a 2,000-year-old human hepatitis B virus, were successfully reconstructed. Our results demonstrate the suitability of Egyptian mummies as a source for metagenomic studies and give the opportunity to evaluate the health status of ancient Egyptian populations over time. Furthermore, the genomics data collected for M. leprae and hepatitis B virus helps to refine the current phylogeographic models of their previous distribution and spread.

ABSTRACT. Do you have questions about how the NIH supports medical research?  Come get answers from an NIH staffer who has worked at the NIH for the past sixteen years. Attendees will learn how the NIH is organized, how it supports biomedical research, and how peer review works. There will be ample time to ask questions about funding opportunities, peer review, and career development awards.

ABSTRACT. Iron is an essential micronutrient for all living things, including bacteria. However, excess iron can be toxic impacting numerous physiological systems. We have utilized experimental evolution to produce iron resistant strains of Escherichia coli K-12 MG1655. However, the molecular mechanism of how these strains handle iron resistance needs to be fully understood. To examine these mechanisms, we grew these strains and their controls in excess ferrous (Fe2+) iron medium. The mRNA expression of iron-responsive and oxidative stress genes was examined by Real-time PCR. The results showed that the mRNA expression of the iron storage gene (ftn) and iron regulatory gene (fur) both significantly increased in the Fe2+-resistant population compared to their controls. Iron uptake gene (fec A) mRNA expression significantly decreased in iron resistant populations in comparison to controls to reduce iron uptake in the excess iron environment. The mRNA expressions of oxidative stress genes, such as sodA (superoxide dismutase A) and soxR (superoxide regulator), were significantly upregulated in the Fe2+-resistant population in comparison to the controls. These two genes also increased their mRNA expression significantly when control populations are placed in toxic Fe 2+ medium. In summary, this study shows that iron resistant E. coli grown in excess iron medium have improved storage of excess iron as well as increasing sensitivity to ameliorate superoxide free radical damage thereby reducing intracellular oxidative stress.

ABSTRACT. Most emerging pathogens causing infectious disease in humans originate from interspecies transmission. In addition to introducing new pathogens to humans, animal populations can also serve as reservoirs for human pathogens. Thus, they play an important role in re-emerging and newly emerging infectious diseases as the latter mainly originate from animal wildlife. Europe is predicted to be one of the major hotpots for newly emerging zoonotic diseases in the future. Therefore, regular screening of pathogen prevalence in potential animal reservoir populations is strongly recommended. Here, we focus on pathogen screening in Swiss wild animal populations, particularly in European hedgehogs (Erinaceus europaeus). This species is well adapted to life in urban habitats, harbors multiple disease vectors and the detection of some human pathogens, like Salmonella spp., herpes viruses and the FSME virus, was described in previous studies.

To investigate on bacterial and viral pathogen prevalence in our samples we applied a metagenomic approach to analyze the microbiome and virome in hedgehog lungs: We used the MEGAN Alignment Tool for general screening of bacterial pathogens in shotgun sequenced DNA libraries and 16S amplicons of hypervariable region V3 and V4. Furthermore, tissue extracts were enriched for viral particles and used for viral pathogen screening.

Our results will contribute to the knowledge of pathogen presence in Erinaceus europaeus populations and therefore further elucidate their function as pathogen reservoir. As awareness is a crucial point to combat re-emerging and newly emerging disease, the general public health will directly benefit from our results.

ABSTRACT. During the 20th century, biomedicine rapidly reduced the global burden of infectious disease, which led to dramatic increases in life expectancy worldwide. In the 21st century, non-infectious diseases, including mental disorders, are responsible for most of the disease burden. The causes of mental disorders, however, are still mysterious. Worse, many pharmacological treatments, such as antidepressants and antipsychotics, have only moderate to weak efficacy, lack precision in targeting biological systems that underlie symptoms, and/or induce debilitating side effects. Unlike most biomedicine that bases diagnoses on recognizable dysfunctions and objective tests, psychiatric diagnoses are based on the number and types of symptoms, because too little is known about the biological bases of mental disorders to classify them based on causation. This leaves psychiatric diagnoses vulnerable to the influence of sociocultural norms and attitudes as opposed to evidence of dysfunction. Case-control investigations using DSM or ICD diagnoses as phenotypic measures are common in biomedical research. However, if our diagnoses have poor validity as natural entities (Hyman, 2010), this generates noise in genetics, neuroimaging, and other studies.

Critics from within psychiatry are calling attention to the failure of psychiatric research to improve public health and to rampant conflicts of interest that bias the research. There is an urgent need for a broader, more integrative approach to the study and treatment of mental disorders that incorporates cross-cultural data from a diverse range of societies and evolutionary theory.

We propose that combined insights from biological anthropology, a biological and social science that studies humans and their primate relatives, and evolutionary theory can help: 1) disentangle true disease states from conditions that are merely socially undesirable; 2) identify discrete psychiatric conditions; 3) determine the extent to which conditions vary across socio-ecological contexts; and 4) ultimately, develop a psychiatric taxonomy that corresponds to evolutionarily meaningful, universal phenotypes.

ABSTRACT. Evolutionary medicine needs by definition pluridisciplinarity. We aim to describe our experience of an extra-curricular Evolutionary Medicine platform for research and diffusion in Central Spain. A pluridisciplinary core organization with a physician, a geneticist and an anthropologist, with endorsement of two Research Health Institutes and the National Museum of Natural Sciences made it possible to design and offer seminars and meetings over the last 10 years, inviting to all of them guest speakers from different disciplines. The annual meetings were held at University Hospitals and reached an audience between 69 and 162 participants. The seminars were intendedly held below 40 participants and were symbolically held both at the Hospital and at the National Museum of Natural Sciences. To each of the offered topics at least one physician and one biologist was invited. Over the years invited disciplines broadened to different specialties in Medicine, to Psychology, other Health Sciences, Philosophy and other. The interested audience was also composed of all the mentioned disciplines. A high interest in an evolutionary perspective of Health Sciences and the presence of several Universities and Hospitals in a 5 million inhabitants Madrid region was of advantage. In 9 annual meetings and 37 seminars, 112 different speakers gave 186 presentations. We have noticed a higher interest of Biologists in Health Sciences than Physicians in Evolutionary Theory. Within physicians, higher interest was perceived from specialties in the interface with Biology, such as Microbiology and Genetics. We were repeatedly motivated to offer written material, thus we began to publish and complete four volumes with 44 written contributions of selected topics. Summarizing, we notice a demand for an evolutionary perspective of health and disease, which converges in a necessary pluridisciplinarity as a necessary condition. Research interests and interesting diffusion topics emerge from putting together experts with different scientific background.

ABSTRACT. Atrial fibrillation (AF) is the most common arrhythmia in humans and is associated with significant morbidity and mortality. The massive body of AF investigation has been focused nearly exclusively on proximate causation. Non-proximate explanations for the vulnerability remain essentially unexamined. Our study uses formal methods of systematic review to generate testable non-proximate hypotheses to explain human vulnerability to AF. Using taxonomies derived from systematic reviews, we created phylogenies of vulnerability to AF for chordates, horses, and dogs. Correlating the findings from these phylogenies with life history information, we developed non-proximate testable hypotheses for vulnerability to AF. The equine phylogeny demonstrated increased vulnerability in breeds with higher vagal tone, leading to the hypothesis that variations in autonomic tone may shift AF vulnerability. The canine phylogeny demonstrated vulnerability in larger breed dogs without structural heart disease, leading to the hypothesis that atrial mass, volume, and architecture may increase vulnerability. The chordate phylogeny demonstrated documentable AF only in mammalian species, leading to two hypotheses. First, the atrialization of the sinus venosus in endotherms and not ectotherms points to it as an element of vulnerability related to functional adaptation. Second, the reduced number of pulmonary veins and their separation from the left atrium in birds explain the absence of AF in this taxa. Further, this finding points to adaptive pulmonary vein architecture as a substrate for vulnerability. We conclude that identifying taxa with and without vulnerability to AF offers a pathway for the generation of novel non-proximate hypotheses. Finally, we present a roadmap for researchers to identify natural animal models of AF resistance and enhanced vulnerability which can facilitate the development expanded and evolutionarily-informed research agendas.

ABSTRACT. Whether adaptive evolution or genetic drift shape life history trait evolution across species has been for long an open question. African killifishes (oviparous Cyprinodontiformes) offer a natural experiment in life history trait evolution as they independently evolved short lifespan and rapid aging (annual life cycles) at least three times. Using a comprehensive whole-genome sampling of 46 species of African killifishes, we found that short-lived species, which evolved in dry climates, underwent genome expansion. Proliferation of transposable elements drove genome expansion in annual species, which also display higher gene family turn-over rates and relaxed selection in genes in known ageing pathways. Whole-genome re-sequencing in wild Nothobranchius populations showed bottle-necks and a genome-wide signature of relaxation of selection in populations from dryer climates. We found that ecology drove the evolution of short lifespan, associated with the genome-wide accumulation of tens of thousands of slightly deleterious mutations. Hence, drift, more than adaptive evolution, was the dominant signal underlying the evolution of short lifespan and rapid aging in annual killifish. The second part of my presentation will present our recent findings on how the gut microbiota plays a causal role in modulating ageing and lifespan and how understanding the interaction between adaptive immune system and the microbiota gives us novel insights into the biology of ageing and offers new possibilities for future therapeutic interventions.

ABSTRACT. While short-lived animals have typically been selected as models in human aging research due to convenience, it has become increasingly clear that primates age differently than other taxa. Great apes are of particular significance due to their close phylogenetic relationship to humans and because they are long-lived. In order to better understand the evolution of the unusually long human lifespan, it is critically important to examine the forces that constrain lifespan in our closest extant relatives. Here, I synthesize research findings on aging among wild chimpanzees (Pan troglodytes schweinfurthii) from a 30+ year naturalistic study in the Kibale National Park, Uganda. This research used an unusually large sample of >25,000 biological specimens and a detailed daily record of activity and social behavior. While the maximum lifespan of chimpanzees exceeds 60 years, the average adult lives only about 30-35 years. We predicted that older chimpanzees would show senescent features commonly associated with degenerative aging in humans, and that rapid physiological aging would coincide with the ages of accelerated mortality. Indeed, chimpanzees exhibit age-associated increases in clinical signs of illness and in glucocorticoid levels, along with declines in muscle mass, respiratory rates, and certain aspects of activity. However, these changes were moderate and were associated with relatively little loss of function in what can only be described as a challenging physical and social environment. Rather than exhibiting frailty syndromes, individuals who survived to late ages exhibited unexpectedly robust physical condition and high levels of social participation and status. These data complement evidence from small-scale human societies that have pointed to a surprising rarity of the degenerative diseases that plague aging populations in the developed world. Early mortality selection, in combination with healthy lifestyle factors, in these populations reveal valuable samples of resilient individuals that could help expose the keys to successful aging.

ABSTRACT. The proposal by George Williams that natural selection can favour alleles that promote late-life disease due to antagonistic pleiotropy (AP)1 leaves open the question of how such alleles exert their pathological effects. One type of proximate mechanism was suggested by Misha Blagosklonny, particularly to explain major effects on ageing of growth-promoting pathways such as TOR (target of rapamycin): that AP affecting growth factors can in later life promote futile run-on of entire biological programmes. Because such programmes are senseless in fitness terms, yet promoted by wild-type gene function in a concerted fashion, Blagosklonny refers to them as quasi-programmes2.

Guided by our studies of generation of senescent pathologies by quasi-programmes in an animal model, the nematode Caenorhabditis elegans3,4, we have tentatively identified a quasi-programme-driven disease syndrome affecting post-menopausal women. In both invertebrates and vertebrates, reproductive females are capable of consuming their own biomass to increase production of yolk or milk to assure offspring survival, with resulting atrophy of source organs. For example, in many mammals during lactation bone is consumed to provide calcium for milk production, and this leads to transient osteoporosis. We postulate that in women the decline in oestrogen during menopause triggers a lactational quasi-programme, leading to irreversible osteoporosis and ectopic deposition of calcium. The latter manifests as vascular calcification, contributing to cardiovascular disease, chondrocalcinosis contributing to osteoarthritis, as well as other calcium deposition pathologies. The existence of this putative lactational reactivation syndrome is supported by a review of relevant literature examining correlations between osteoporosis and calcium deposition pathologies, sex specificity and timing of onset of pathologies and effects of hormone replacement therapy.

1. Williams,G. C. Evolution 11, 398 (1957). 2. Blagosklonny,M. V. Cell Cycle 5, 2087 (2006). 3. Ezcurra,M. et al. Curr Biol 28, 2544 (2018). 4. Wang,H. et al. NPJ Aging Mech. Disease 4, 6 (2018).

ABSTRACT. From an evolutionary perspective, age at menarche is considered as a life history trait that captures dimensions of an individual’s energetic experience during development. However, some elements of these relationships are rapidly being transformed as new global economic forces interact with nutritional shifts. The increasing number of reports in the literature on the association between high BMI and advanced age at menarche suggests that a trend towards earlier age at menarche may be a concomitant effect of the overweight/obesity epidemic. Mexico for its part, is in the midst of an obesity epidemic. A recent report highlights the worrying increase in the prevalence of overweight and obesity in young children alongside persisting under-nutrition, a scenario particularly marked in rural, poor and food-insecure groups. We use the findings of our secondary analysis on trends in age at menarche in 20th century Mexico and differences associated with area of residence, ethnicity and socioeconomic status, to advance some evolutionary hypotheses on the consequences of the double burden of malnutrition on age at menarche, the potential mechanisms and its implication for health.

ABSTRACT. Public health interventions aimed at improving infant birth weight, health and survival, often target mothers. Supplementation of pregnant and lactating women with additional energy and micronutrients has been a common practice, especially in populations with poor nutritional status. However, supplementation often has unexpected outcomes. Not only are improvements in infants health much smaller than expected but also the supplemented mothers experience faster resumption of ability to conceive again. Thus, supplementation of women leads to an undesirable increase in fertility. Reductions in women’s workloads brought about by labor-saving development initiatives have similar side effects on women’s reproductive physiology.

Using the framework of life history theory, I will discuss the impact of improvements in women’s energetic status via nutritional supplementation or reduction in physical activity. I will argue that in order to understand the effects of supplementations or labor reduction it is important to consider the long-term reproductive strategy, trade-offs in energy allocation to competing physiological functions and trade-offs between children’s quantity versus children’s quality. In addition, it is likely that supplementation will differently impact women depending on their prior developmental history (i.e. conditions experienced during their own fetal and childhood development). Therefore, evolutionary perspective suggests that public health interventions in the area of maternal and child health should be comprehensive and include not only short-term supplementations for women but also provide knowledge about family planning and access to contraception.

ABSTRACT. Intimate partner violence (IPV) is a global public health problem that shows marked variability in prevalence and endorsement, which is often explained in terms of material (wealth, education) and ‘cultural’ (attitudes and norms) factors. We expanded upon this work with insights from the evolutionary behavioral sciences. Specifically, we theorized that post-marital residence patterns influence IPV risk by altering the availability of kin support, and thereby a woman's bargaining power. We also assessed whether fertility conflict (i.e., a husband who wants more children than his wife) increased a woman’s risk for IPV. To test these ideas, we applied Bayesian multilevel modelling to the Demographic and Health Surveys data from 11 countries and 42,000 couples, representing 476 ethnic groups. We found that wealth was associated with reduced risk and endorsement with increased risk of IPV. The effects of postmarital residence and fertility conflict were mediated via endorsement (i.e., attitudes towards IPV) and supported our predictions that women who leave their natal group for marriage are at greater risk of IPV, and that men who desire more children than their wives are more likely to perpetrate IPV. IPV risk (via endorsement) also differed between ethnic groups and countries, suggesting unmeasured socio-ecological factors and/or an influence of cultural history. In sum, our models support some predictions from evolutionary ecology (albeit with modest effect sizes), and extend previous work on this global health issue.

ABSTRACT. Throughout human history it is likely grandparents supported the health of their families and communities. Evidence that grandparents have a positive impact on the health and well-being of grandchildren in contemporary industrialized societies, particularly in resource poor families, is growing. As some governments and communities can no longer support the needs of diversifying family types, grandparents are increasingly being recognized for the family and public health resources they contribute. There is little understanding, however, of the health consequences contributing resources to their families through childcare has for these grandparents. This paper will examine two extremes of the grandparent-childcare continuum by investigating the impact of non-custodial childcare (babysitting) by grandparents on their longevity and the health of grandparents who are raising their own grandchildren. This paper incorporates data from Europe and Australia to examine the potential costs and benefits of providing childcare for grandparents’ health. Using data from the longitudinal Berlin Ageing Study (n = 516), survival analyses show that help provided by grandparents, in the form of babysitting, is associated with increased longevity. Grandparents who provided childcare showed a mortality hazard that was 33% lower than among grandparents who did not provide help. Mediation analysis showed this association was only partially accounted for by health. At the other end of the care spectrum, data from a Western Australian study of grandparents who are raising their own grandchildren, shows negative health consequences of custodial grandcare. Survey data from 500 grandcarers illustrates the negative impact across eight domains of physical and mental health, compared to age matched community norms, as measured by the SF-36 Health Assessment. Understanding the diverse forms of grandparental help and the consequences they have for grandparental health will inform public health policy around healthy ageing and the targeted use of support services for grandparents and their families.

ABSTRACT. Evidence is recently accumulating that also innate immune systems can provide forms of immune memory, such as immune priming in invertebrates or trained immunity in vertebrates. Immune priming can even be specific. However, to date it is unknown whether and how the level of specificity in immune priming can adapt during evolution in response to natural selection. We tested the evolution of priming specificity in an invertebrate model, the beetle Tribolium castaneum. Using controlled evolution experiments, we selected beetles for either specific or unspecific immune priming towards pathogenic bacteria. After 14 host generations of selection, specificity of priming was not universally higher in the lines selected for specificity, but rather depended on the bacterium used for priming and challenge. The evolved differences in priming specificity were mirrored in the transcriptomic response, revealing an involvement of metabolic and transcription-modifying genes and pointing to similar mechanisms acting in vertebrate trained immunity. Our study shows that evolutionary studies in invertebrates could help to understand basic principles in immunity. Given the potential medical importance of trained immunity in humans, this bears large potential for the field of evolutionary medicine.

ABSTRACT. Parasites are considered to be drivers of primate evolution, but few studies have demonstrated fitness impacts of endemic helminth parasites on primates. While the simple life cycles of most parasites and pathogens may favor reduced virulence, parasites with other transmission modes may have higher virulence in some hosts. Parasites employing “predation-mediated transmission” have separate adult and larval stages infecting predator and prey species and depend on the transmission of the larval parasite from the prey host to the predator host for life cycle completion. Thus, parasites with trophic transmission that increase host mortality and predation risk in prey hosts should be favored over less virulent strains. We tested whether a parasite with this transmission mode influences mortality in wild gelada monkeys (Theropithecus gelada) in Ethiopia, where prevalence of infection with the larval tapeworm Taenia serialis reaches over 15%. Using survival analyses, we demonstrate strikingly higher mortality in both (1) geladas exhibiting the cysts characteristic of T. serialis infection and (2) the dependent offspring of female with cysts, relative to individuals that lack signs of disease. This research is among only a handful of studies to demonstrate explicit fitness costs of parasitism in primates and highlights the importance of using parasite evolution as a framework in which to evaluate infection dynamics in wildlife. Similar principles should apply to understanding parasites of humans, including related species in the genus Taenia.

ABSTRACT. Major histocompatibility complex (MHC) genes encode proteins that initiate adaptive immune responses through the presentation of foreign antigens to T cells. The high polymorphism found at these genes, thought to be promoted and maintained by pathogen-mediated selection, contrasts with the limited number of MHC loci found in most vertebrates. Although expressing many diverse MHC genes should broaden the range of detectable pathogens, it has been hypothesized to also cause deletion of larger fractions of self-reactive T cells, leading to a detrimental reduction of the T cell receptor (TCR) repertoire. However, a key prediction of this TCR depletion hypothesis, that the TCR repertoire should be inversely related to the individual MHC diversity, has never been tested. Here, using high- throughput sequencing and advanced sequencing error correction, we provide evidence of such an association in a rodent species with high inter-individual variation in the number of expressed MHC molecules, the bank vole (Myodes glareolus). Higher individual diversity of MHC class I, but not class II, was associated with smaller TCR repertoires. Moreover, sex significantly affected the TCR diversity – males had smaller TCR repertoires compared to females. Our results thus provide partial support for the TCR depletion model, while also highlighting the complex, potentially MHC class-specific mechanisms by which autoreactivity may trade off against evolutionary expansion of the MHC gene family.

Reference: Migalska M, Sebastian A, Radwan J (2019) Major histocompatibility complex class I diversity limits the repertoire of T cell receptors. Proc Natl Acad Sci 201807864. doi: 10.1073/PNAS.1807864116

ABSTRACT. Major histocompatibility complex (MHC) molecules mediate the adaptive immune response against pathogens. Certain MHC alleles are generalists: they present an exceptionally large variety of antigenic peptides. However, the functional implications of such elevated epitope binding promiscuity in the MHC molecules are largely unknown. According to what we term the pathogen-driven promiscuity hypothesis, exposure to a broad range of pathogens favors the evolution of highly promiscuous MHC variants. Consistent with this hypothesis, we found that in pathogen-rich geographical regions, humans are more likely to carry promiscuous MHC class II DRB1 alleles, and the switch between high and low promiscuity levels has occurred repeatedly and in a rapid manner during human evolution. We also show that selection for promiscuous peptide binding shapes MHC genetic diversity. In sum, our study offers a conceptually novel mechanism to explain the global distribution of allelic variants of a key human immune gene by demonstrating that pathogen pressure maintains promiscuous MHC class II alleles. More generally, our work highlights the hitherto neglected role of epitope binding promiscuity in immune defense, with implications for medical genetics and epidemiology.

ABSTRACT. Autoimmune diseases are a major source of morbidity. Few studies have examined the evolutionary factors affecting the incidence of autoimmune diseases, but some new evidence indicates that it can be a byproduct of highly sensitive immune screening mechanisms. We modeled the evolution of the immune precision under the following assumption: high sensitivity confers better protection against pathogens but increases the risk of autoimmune incidents. We took eco-evolutionary feedbacks into consideration to account for the mutual effect of the risk of encountering pathogens and the average immune sensitivity in the population. The population density and the parasite transmission rate led to an increased prevalence of autoimmune pathologies. The pathogen's virulence, the lifespan of the host and the costs of autoimmunity define the evolutionary stable immune sensitivity and specificity. The outcome of immune evolution also depends on whether or not the host becomes immune to the same pathogen after recovery. Our findings show that the immune tradeoffs, population structure and immune memory affect the evolution of immune precision and the incidence rate of autoimmune diseases.

ABSTRACT. Reduction of parasite diversity in modern human populations is suspected to be a primary cause for the increase of autoimmune disorders. However, the long-term evolutionary consequences of decreased parasite diversity on the host immune system are not well understood. We used the cavefish Astyanax mexicanus to understand how loss of biodiversity, a hallmark of cave adaptation, influences the evolutionary trajectory of the vertebrate host immune system by comparing river with cave morphotypes. We show that cavefish display a more sensitive proinflammatory immune response towards bacterial endotoxins, which is characteristic to other vertebrate species inhabiting environments with decreased biodiversity. Surprisingly, cellular immune responses, such as phagocytosis, are drastically decreased in cavefish. Using an image-based immune cell phenotyping approach and single-cell RNA sequencing, we identified a shift in the overall immune cell composition in cavefish as the underlying cellular mechanism associated with altered immune responses. The shift results in an overall decrease of immune cells mediating inflammation and cellular immune responses such as phagocytosis (i.e. neutrophils and monocytes). Moreover, we find that immunopathological phenotypes in visceral adipose tissue are drastically reduced in cavefish. Our data indicate that a more sensitive immune system in cavefish is compensated by a reduction of the immune cells that play a role in mediating the proinflammatory response. These findings reveal that cavefish are an effective model system to study the evolution of auto-inflammatory processes.

ABSTRACT. Many research scientists and educators in evolutionary medicine are seeking to develop resources that could be used by instructors at various levels of education to help students better understand the value and importance of evolutionary medicine or to use evolutionary medicine as a lens for learning evolutionary concepts more generally. Emerging research about how people learn can provide guidance about ways to make these resources more effective and ways to structure pedagogy to enhance learning experiences. This session will provide an overview of some of the research about how people learn and focus on an approach to effective pedagogy known as backward design. The goal of this session is to assist workshop participants in developing education resources for evolutionary medicine.

ABSTRACT. Momentum is growing for the inclusion of evolutionary medicine in classroom curriculum ranging from high school through medical school. Research in the learning sciences reveals that an important consideration for any curriculum is to have clear learning goals for students, alongside more specific and measurable learning objectives. To date, little information exists on what these goals are in existing evolutionary medicine courses, and no concerted effort has elicited what these goals should be. Creating a learning framework that outlines learning goals and associated objectives represents an important step for evolutionary medicine education. However, a ‘one-size-fits-all’ set of learning goals and objectives may not be appropriate or feasible in evolutionary medicine given 1) the multidisciplinary nature of evolutionary medicine, and 2) instruction of evolutionary medicine takes place across different educational levels and in different national systems of education. In this workshop, I will present on the structure and value of learning frameworks, what is known about learning objectives in evolutionary medicine, and lead a discussion about the potential creation of a learning framework in evolutionary medicine.

ABSTRACT. A variety of initiatives have been taken during the last decade to initiate graduate courses in evolutionary medicine. They appear to almost invariably have been within biology curricula, but no systematic evaluations have been done to answer questions like: 1. How many students sign up for these courses and what is their background? 2. How broad a course program do they get offered? 3. How useful (eye-opening) do students appreciate these courses to be? 4. What adjustment of course content might improve student interest in the future? 5. How much do answers to these questions vary across European countries and depend on whether evolutionary courses are taught under the auspices of a Natural Science or a Medical Faculty? Obtaining answers to questions like these may be particularly important because of the key differences between Europe and the USA in that European biology students almost never continue on a MD trajectory, but quite often obtain research positions in Medical Departments or hospitals. This may imply that optimal strategies for maximizing the impact of graduate courses in evolutionary medicine in Europe and the USA may not be identical. Here I intend to address and formulate tentative conclusions to the questions posed above, and engage in discussion with delegates to find out the best way to proceed with teaching evolutionary medicine in Europe.