Hillard Kaplan

Paraspinal muscles support and move the spine, and reduced size and density of these muscles is associated with increased risk of vertebral fracture and back pain. We test the hypothesis that subsistence-oriented forager-horticulturalists (Bolivian Tsimane) have larger and denser paraspinal muscles, and smaller age-related differences in paraspinal muscle size and density, than more sedentary post-industrialized suburbanites (Framingham Heart Study [FHS]). We measured cross-sectional area (CSA) and density of trunk extensors and psoas major at L3 from computed tomography scans of 411 FHS and 330 Tsimane (50% women, aged 50–90 years). Sex-stratified linear regressions determined associations of muscle CSA and density with age and cohort (Tsimane or FHS [ref.]), with and without an age–cohort interaction term. Covariates were height and weight. After adjusting for covariates, Tsimane women had 11–14% larger and denser extensors, and 17–26% smaller and less-dense psoas major, than FHS women. Tsimane men had 8–21% smaller and less-dense psoas major than FHS men. The age-related difference in extensors density was 41% smaller for Tsimane men than for FHS men. There were no other significant age-related cohort differences in muscle CSA or density. We observed a different balance in the size and density of trunk extensors versus psoas major between Tsimane and FHS. A possible explanation for this observation is cohort differences in the amount and types of physical activity, although future work is required to determine the influence of lifestyle and environmental factors on paraspinal muscle size and density.

Background: Intracranial arteriosclerosis (large‐ and small‐vessel disease) is considered a risk factor for major neurological disorders, such as stroke, cognitive impairment, and dementia. While most studies investigating intracranial arteriosclerosis include individuals from industrialized populations, the prevalence and clinical meaning of intracranial vascular calcifications in populations with a subsistence lifestyle is unknown. Methods: In this population‐based study evaluating data collected between 2017 and 2019 from Tsimane and Moseten people, 2 indigenous populations of forager‐horticulturalists living in the Bolivian Amazon, we used computed tomography to determine the prevalence of vascular calcifications in the intracranial internal carotid arteries, vertebral arteries, and lenticulostriate arteries within the basal ganglia, and their association with demographic characteristics, brain atrophy, cognitive performance, and clinical factors. Results: Our analysis included 1232 individuals who underwent a head computed tomography scan. Intracranial vascular calcifications were found in most individuals (>90%) and their prevalence was higher than that reported for age‐equivalent industrialized populations. These calcifications were significantly associated with higher age, brain atrophy, worse cognitive performance, and parkinsonian symptoms. Conclusions: Despite the physically active subsistence lifestyle and the low rates of typical cardiovascular risk factors and coronary artery disease, intracranial vascular calcifications are common in these Bolivian Amerindian people, suggesting that alternative factors may contribute to intracranial arteriosclerosis and a novel dementia phenotype.

Oxytocin, a hormone linked to reproduction and health, may mediate life-history trade-offs across the human life course. Yet, how oxytocin naturally varies with age remains poorly understood. Here, working with the Tsimane, forager-horticulturalists of lowland Bolivia, we collected the largest sample of oxytocin measurements to date (n = 1,242 samples, n = 405 individuals, age = 2 to 84 y, 51% female), and i) examined how oxytocin varies throughout the life course in females and males, and ii) investigated potential drivers of age- and sex-specific variation. Our sample provides rare insight into the relationship between oxytocin and age in a context where energy is limited and trade-offs between reproduction and somatic maintenance are more salient. We found that oxytocin follows a nonlinear sex-specific trajectory throughout the life course. In females, oxytocin levels were high during the reproductive years and declined in the early to midforties, a pattern largely explained by breastfeeding and, to a lesser extent, childcare and good self-rated health. In males, oxytocin was low in early adulthood but high in old age, and although higher oxytocin was linked to good self-rated health, this did not explain the rise in oxytocin in later life. These findings suggest that oxytocin is instrumental for reproduction and caregiving in females and may also be associated with health in both males and females. Together, our work highlights oxytocin’s broader biological significance across the human life course, suggesting that it may play a pivotal role in coordinating age- and sex-specific trade-offs involving reproduction and health.

An increase in chronic systemic inflammation in later life, termed inflammaging, is implicated in health risk. However, it is unclear whether inflammaging develops in all human populations, or if it is the product of environmental mismatch. We assessed inflammaging in Tsimane forager-horticulturalists of the Bolivian Amazon, using serum cytokines in a primarily cross-sectional sample (1134 samples from n = 714 individuals, age 39–94, 51.3% female). IL-6 was positively associated with age ( β = 0.013, p < 0.01). However, other pro-inflammatory markers, including IL-1β and TNF-α, did not increase with age ( β = −0.005 and β = −0.001, respectively). We then compared the Moseten, a neighbouring population that has experienced greater market integration (423 samples from n = 380 individuals, age 39–85, 48.2% female). The Moseten also showed a positive age association for IL-6 that attenuated at later ages (age β = 0.025, p < 0.01; age ² β = −0.001, p < 0.05). Further, IL-1β and TNF-α were both positively associated with age ( β = 0.021, p < 0.05 and β = 0.011, p < 0.01, respectively). Our results demonstrate minimal inflammaging in the Tsimane, highlighting variation across populations in this age-related process. They also suggest that inflammaging is exacerbated by lifestyle shifts.

Explaining the rapid evolution of human cooperation and its role in our species’ biodemographic success remains a major evolutionary puzzle. To address this challenge, we tested a social drive hypothesis, which predicts that social plasticity and social selection in human groups cause indirect genetic effects that accelerate the adaptation of fitness, promoting population growth via feedback between the environmental causes and evolutionary consequences of cooperation. Using Bayesian multilevel models to analyze fertility data from a small-scale society, we demonstrate that density- and frequency-dependent indirect genetic effects on fitness promote the evolution of cooperation among neighboring women, increasing the rate of contemporary adaptation by ~5×. Our results show how interactions between the genetic and socioecological processes shaping cooperation in reproduction can drive rapid growth and social evolution in human populations.

Porous cranial lesions (cribra cranii and cribra orbitalia) are widely used by archaeologists as skeletal markers of poor child health. However, their use has not been validated with systematic data from contemporary populations, where there has been little evidence of these lesions or their health relevance. Using 375 in vivo computed tomography scans from a cohort-representative sample of adults aged 40+ years from the Bolivian Amazon, among food-limited, high-mortality forager-farmers, we identified cribra cranii on 46 (12.3%) and cribra orbitalia on 23 (6%). Cribra orbitalia was associated with several hallmarks of compromised immune function, including fewer B cells, fewer naïve CD4 ⁺ T cells, a lower CD4 ⁺ /CD8 ⁺ T cell ratio, and higher tuberculosis risk. However, neither lesion type predicted other physician-diagnosed respiratory diseases, other markers of cell-mediated immunity, or hemoglobin values. While cribra orbitalia shows promise as a skeletal indicator of health challenges, our findings do not support the continued practice of using these lesions to infer anemia in adults.

Background: Little is known about arterial stiffness in rural subsistence populations that experience few cardiovascular risk factors. We conducted a cross‐sectional study comparing 3 arterial stiffness metrics among Tsimane forager‐horticulturalists with 2 representative US cohorts. Methods: Arterial elasticity (the inverse of stiffness) markers C1 (large artery elasticity) and C2 (small artery elasticity) were measured using a tonometry device among 490 Tsimane adults (mean age, 51.2±10.1 years; 55% women), and compared with 6294 multiethnic US adults (mean age, 62.0±10.2 years; 52% women) from MESA (Multi‐Ethnic Study of Atherosclerosis). Carotid‐femoral pulse wave velocity was assessed using the foot‐to‐foot method in a smaller Tsimane sample (n=94) and compared with 3086 predominantly White US adults (mean age, 46.1±8.7 years; 54% women) from the FHS Gen3 (Framingham Heart Study Third Generation). Results: Tsimane participants exhibited superior arterial health compared with US cohorts, with higher elasticity (C1/C2) and lower stiffness (carotid‐femoral pulse wave velocity). Their C1 (mean 22.8±12.2 mL/mm Hg×10) and C2 (mean 7.5±4.0 mL/mm Hg×100) were 47.3% and 35.7% higher than MESA participants by age 40 years, respectively, and differences remained sustained throughout adulthood. Compared with participants in FHS Gen3, the carotid‐femoral pulse wave velocity in Tsimane participants (mean 6.2±1.2 m/s) was 33.9% lower and showed a minimal age‐related increase, with carotid‐femoral pulse wave velocity only higher by age 70+ (β=1.74±0.38; reference <40 years). Tsimane participants with ≥2 comorbidities (hypertension, obesity, and diabetes) had ≈25% higher arterial elasticity than healthy Americans with no comorbidities. Conclusions: Tsimane forager‐farmers of the Bolivian Amazon demonstrate substantially lower arterial stiffness throughout adulthood than more urbanized and sedentary populations, and the differences are only partially explained by conventional cardiometabolic risk factors.

Characterizing DNA methylation patterns is important for addressing key questions in evolutionary biology, development, geroscience, and medical genomics. While costs are decreasing, whole-genome DNA methylation profiling remains prohibitively expensive for most population-scale studies, creating a need for cost-effective, reduced representation approaches (i.e., assays that rely on microarrays, enzyme digests, or sequence capture to target a subset of the genome). Most common whole genome and reduced representation techniques rely on bisulfite conversion, which can damage DNA resulting in DNA loss and sequencing biases. Enzymatic methyl sequencing (EM-seq) was recently proposed to overcome these issues, but thorough benchmarking of EM-seq combined with cost-effective, reduced representation strategies is currently lacking. To address this gap, we optimized the Targeted Methylation Sequencing protocol (TMS)—which profiles ~4 million CpG sites—for miniaturization, flexibility, and multispecies use. First, we tested modifications to increase throughput and reduce cost, including increasing multiplexing, decreasing DNA input, and using enzymatic rather than mechanical fragmentation to prepare DNA. Second, we compared our optimized TMS protocol to commonly used techniques, specifically the Infinium MethylationEPIC BeadChip (n = 55 paired samples) and whole genome bisulfite sequencing (n = 6 paired samples). In both cases, we found strong agreement between technologies (R² = 0.97 and 0.99, respectively). Third, we tested the optimized TMS protocol in three non-human primate species (rhesus macaques, geladas, and capuchins). We captured a high percentage (mean = 77.1%) of targeted CpG sites and produced methylation level estimates that agreed with those generated from reduced representation bisulfite sequencing (R² = 0.98). Finally, we confirmed that estimates of 1) epigenetic age and 2) tissue-specific DNA methylation patterns are strongly recapitulated using data generated from TMS versus other technologies. Altogether, our optimized TMS protocol will enable cost-effective, population-scale studies of genome-wide DNA methylation levels across human and non-human primate species.