BackgroundEpigenetic biomarkers of aging (the “epigenetic clock”) have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors.ResultsWe analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue.ConclusionsEpigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1030-0) contains supplementary material, which is available to authorized users.

Background Conventional coronary artery disease risk factors might potentially explain at least 90% of the attributable risk of coronary artery disease. To better understand the association between the pre-industrial lifestyle and low prevalence of coronary artery disease risk factors, we examined the Tsimane, a Bolivian population living a subsistence lifestyle of hunting, gathering, fishing, and farming with few cardiovascular risk factors, but high infectious inflammatory burden. Methods We did a cross-sectional cohort study including all individuals who self-identified as Tsimane and who were aged 40 years or older. Coronary atherosclerosis was assessed by coronary artery calcium (CAC) scoring done with non-contrast CT in Tsimane adults. We assessed the difference between the Tsimane and 6814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). CAC scores higher than 100 were considered representative of significant atherosclerotic disease. Tsimane blood lipid and inflammatory biomarkers were obtained at the time of scanning, and in some patients, longitudinally. Findings Between July 2, 2014, and Sept 10, 2015, 705 individuals, who had data available for analysis, were included in this study. 596 (85%) of 705 Tsimane had no CAC, 89 (13%) had CAC scores of 1–100, and 20 (3%) had CAC scores higher than 100. For individuals older than age 75 years, 31 (65%) Tsimane presented with a CAC score of 0, and only four (8%) had CAC scores of 100 or more, a five-fold lower prevalence than industrialised populations (p≤0-0001 for all age categories of MESA). Mean LDL and HDL cholesterol concentrations were 2.35 mmol/L (91 mg/dL) and 1.0 mmol/L (39.5 mg/dL), respectively; obesity, hypertension, high blood sugar, and regular cigarette smoking were rare. High- sensitivity C-reactive protein was elevated beyond the clinical cutoff of 3.0 mg/dL in 360 (51%) Tsimane participants. Interpretation Despite a high infectious inflammatory burden, the Tsimane, a forager-horticulturalist population of the Bolivian Amazon with few coronary artery disease risk factors, have the lowest reported levels of coronary artery disease of any population recorded to date. These findings suggest that coronary atherosclerosis can be avoided in most people by achieving a lifetime with very low LDL, low blood pressure, low glucose, normal body-mass index, no smoking, and plenty of physical activity. The relative contributions of each are still to be determined. Funding National Institute on Aging, National Institutes of Health; St Luke's Hospital of Kansas City; and Paleocardiology Foundation.

The Tsimane Health and Life History Project, an integrated bio‐behavioral study of the human life course, is designed to test competing hypotheses of human life‐history evolution. One aim is to understand the bidirectional connections between life history and social behavior in a high‐fertility, kin‐based context lacking amenities of modern urban life (e.g. sanitation, banks, electricity). Another aim is to understand how a high pathogen burden influences health and well‐being during development and adulthood. A third aim addresses how modernization shapes human life histories and sociality. Here we outline the project's goals, history, and main findings since its inception in 2002. We reflect on the implications of current findings and highlight the need for more coordinated ethnographic and biomedical study of contemporary nonindustrial populations to address broad questions that can situate evolutionary anthropology in a key position within the social and life sciences.

Background Amazonian populations are exposed to diverse parasites and pathogens, including protozoal, bacterial, fungal, and helminthic infections. Yet much of our understanding of the immune system is based on industrialised populations where these infections are relatively rare. Aim We examine distributions and age-related differences in 22 measures of immune function for Bolivian forager-horticulturalists and US and European populations. Subjects and Methods Subjects were 6,338 Tsimane aged 0–90 years. Blood samples collected between 2004–2014 were analysed for 5-part blood differentials, C-reactive protein, erythrocyte sedimentation rate (ESR), and total immunoglobulins E, G, A, and M. Flow cytometry was used to quantify naive and non-naïve CD4 and CD8 T cells, natural killer cells, and B cells. Results Compared to reference populations, Tsimane have elevated levels of most immunological parameters, particularly immunoglobulins, eosinophils, ESR, B cells, and natural killer cells. However, monocytes and basophils are reduced and naïve CD4 cells depleted in older age groups. Conclusion Tsimane ecology leads to lymphocyte repertoires and immunoglobulin profiles that differ from those observed in industrialised populations. These differences have consequences for disease susceptibility and co-vary with patterns of other life history traits, such as growth and reproduction.

We hypothesize that, ancestrally, sex-specific immune modulation evolved to facilitate survival of the pregnant person in the presence of an invasive placenta and an immunologically challenging pregnancy; an idea we term the Pregnancy Compensation Hypothesis. Further, we propose sex differences in immune function are mediated, at least in part, by the evolution of gene content and dosage on the sex chromosomes, and regulated by reproductive hormones. Finally, we propose that changes in reproductive ecology in industrialized environments exacerbate these evolved sex differences resulting in the increasing risk of autoimmune disease observed in females, and a counteracting reduction in diseases, such as cancer, that can be caught by heightened immune surveillance. The Pregnancy Compensation Hypothesis generates a series of expectations that can be tested empirically and may help identify mechanisms of sex differences in modern human diseases.

Infection with intestinal helminths results in immunological changes that influence the odds of comorbid infections, and might also affect fecundity by inducing immunological states supportive of conception and pregnancy. Here we investigate associations between intestinal helminths and fertility in human females, utilizing nine years of longitudinal data from 986 Bolivian forger-horticulturalists, experiencing natural fertility and a 70% helminth prevalence. We find that different species of helminth are associated with opposing effects on fecundity. Infection with roundworm (Ascaris lumbricoides) is associated with earlier first births and shortened interbirth intervals, while infection with hookworm is associated with delayed first pregnancy and extended interbirth intervals. Thus, helminths may have important, and sometimes contradictory effects on human fertility, reflecting the physiological and immunological consequences of infection with particular species.

Objectives Resting metabolic rate (RMR) reflects energetic costs of homeostasis and accounts for 60-75% of total energy expenditure (TEE). Lean mass and physical activity account for much RMR variability, but the impact of prolonged immune activation from infection on human RMR is unclear in naturalistic settings. We evaluate the effects of infection on mass-corrected RMR among Bolivian forager-horticulturalists, and assess whether RMR declines more slowly with age than in hygienic sedentary populations, as might be expected if older adults experience high pathogen burden. Materials and Methods RMR was measured by indirect calorimetry (Fitmate MED, Cosmed) in 1,300 adults aged 20-90 and TEE was measured using doubly labeled water (n= 40). Immune biomarkers, clinical diagnoses and anthropometrics were collected by the Tsimane Health and Life History Project. Results Tsimane have higher RMR and TEE than people in sedentary industrialized populations. Tsimane RMR is 18-47% (women) and 22-40% (men) higher than expected using six standard prediction equations. Tsimane mass-corrected TEE is similarly elevated compared to Westerners. Elevated leukocytes and helminths are associated with excess RMR in multivariate regressions, and jointly result in a predicted excess RMR of 10-15%. After age 40, RMR declines by 69 kcal/decade (p<0.0001). Controlling for lean mass and height accounts for 71% of age-related RMR decline, and adding indicators of infection minimally affects the age slope. The residual level of age-related decline from age 40 is 1.2% per decade. Conclusion High pathogen burden may lead to higher metabolic costs, which may be offset by smaller body mass or other energy-sparing mechanisms.

Background Traditional diets are often credited for the robust cardiometabolic health of subsistence populations. Yet, rural subsistence populations are undergoing nutrition transitions that have been linked to the increase in chronic noncommunicable diseases. Few studies have presented detailed dietary estimates in transitioning populations. Objectives We aimed to 1) characterize and compare dietary profiles of 2 neighboring subsistence populations in Bolivia who vary in market integration and 2) identify dietary factors contributing to low cardiovascular disease risk. Design We used a mixed longitudinal design to estimate nutrient intake via 24-h recall and dietary questionnaires among 1299 Tsimane (aged 30–91 y) and 229 Moseten (aged 30–84 y) men and women. We constructed population-level estimates of energy intake, dietary diversity, and nutrient shortfalls and analyzed dietary changes over time and space using multilevel models. Last, we compared Tsimane and Moseten dietary profiles with those of Americans (NHANES). Results The Tsimane diet was characterized by high energy (2422–2736 kcal/d), carbohydrate (376–423 g/d), and protein (119–139 g/d) intakes; low fat intake (40–46 g/d); and low dietary diversity relative to the average US diet. Most calories (64%) were derived from complex carbohydrates. Total energy and carbohydrate intake increased significantly during the 5-y study, particularly in villages near market towns. Tsimane consumption of food additives (lard, oil, sugar, salt) increased significantly [sugar (15.8 g ⋅ person−1 ⋅ d−1) and oil (4.9 mL ⋅ person−1 ⋅ d−1)] between 2010 and 2015. The more-acculturated Moseten consumed substantially more sugar (by 343%) and oil (by 535%) than the Tsimane. Conclusions A high-energy diet rich in complex carbohydrates is associated with low cardiovascular disease risk when coupled with a physically active lifestyle. A transition away from a high-fiber and low-fat, low-salt, and low-processed-sugar diet is a salient health risk for transitioning populations. Evidence of a nutrition transition in Bolivia parallels trends of increasing body fat and body mass index, which suggests that a low prevalence of cardiovascular disease may not persist.