Biology subjects

Watowich, M. M.

Publications and source records attributed to Watowich, M. M..

9 recordsLinked to original sources

bioRxiv2026

Divergent Biological Consequences of APOE Isoforms Across Industrialized and Non-Industrial Environments

The apolipoprotein {varepsilon}4 (APOE {varepsilon}4) isoform directly alters cholesterol and immune biology and is associated with an increased risk of neurodegenerative and cardiometabolic disease in industrialized settings; nevertheless, APOE {varepsilon}4--which is ancestral in humans--has persisted over evolutionary time. One potential explanation is that the costs and benefits of APOE {varepsilon}4 were significantly different in the environments in which humans evolved compared to those we experience today. In support, previous work has suggested that living in a high pathogen environment, engaging in high levels of physical activity, or eating a low fat diet can dampen the detrimental effects of APOE {varepsilon}4, and has revealed positive effects for fertility. However, direct tests of whether APOE isoforms are associated with different biological outcomes in non-industrial versus industrialized contexts are lacking. Working with the Turkana of Kenya and the Orang Asli of Peninsular Malaysia--two Indigenous groups in which individuals of shared ancestry span a continuum of subsistence, non-industrial to urban, industrialized lifestyles--we investigated how APOE genotypes impact cholesterol, immunological, and reproductive traits and tested for genotype x environment (GxE) interactions. First, we confirmed established genotype effects across lifestyles, showing that more APOE {varepsilon}4 alleles are associated with higher total cholesterol, higher LDL cholesterol, and lower HDL cholesterol. Second, we tested for lifestyle interactions, finding lifestyle-dependent effects of genotype on innate immune biomarkers in the Orang Asli but not Turkana. Finally, we show that more APOE {varepsilon}4 alleles are correlated with an extended reproductive lifespan, however this effect is relatively weak, is not consistent across populations, and does not correspond with a higher reproductive output. Together, our study provides evidence that industrialized environments can modify the biology of APOE {varepsilon}4; however, we find that APOE {varepsilon}4 is not universally beneficial in non-industrial contexts, highlighting the role of local environmental variation in determining its specific costs and benefits.

evolutionary biology↗

bioRxiv2025

Age and early life adversity shape heterogeneity of the epigenome across tissues in macaques

Age and early life adversity (ELA) are both key determinants of health, but whether they target similar physiological mechanisms across the body is unknown due to limited multi-tissue datasets from well-characterized cohorts. We generated DNA methylation (DNAm) profiles across 14 tissues in 237 semi-free ranging rhesus macaques, with records of naturally occurring ELA. We show that age-associated DNAm variation is predominantly tissue-dependent, yet tissue-specific epigenetic clocks reveal that the pace of epigenetic aging is relatively consistent within individuals. ELA effects on loci are adversity-dependent, but a given ELA has a coordinated impact across tissues. Finally, ELA targeted many of the same loci as age, but the direction of these effects varied, indicating that ELA does not uniformly contribute to accelerated age in the epigenome. ELA thus imprints a coordinated, tissue-spanning epigenetic signature that is both distinct from and intertwined with age-related change, advancing our understanding of how early environments sculpt the molecular foundations of aging and disease.

genomics↗

bioRxiv2025

Early life environments shape adult cardiometabolic health during rapid lifestyle change

Early life environments can have long-lasting impacts on health and fitness, but the evolutionary significance of these effects remains debated. Two major classes of explanations have been proposed: developmental constraints (DC) explanations posit that early life adversity limits optimal development, leading to long-term costs, while predictive adaptive response (PAR) explanations posit that organisms use early life cues to predict adult conditions, resulting in detriments when adult environments do not match expectations. We tested these hypotheses using anthropological and biomedical data for the Orang Asli--the Indigenous peoples of Peninsular Malaysia--who are undergoing a rapid but heterogenous transition from non-industrial, subsistence-based livelihoods to more industrialized, market-integrated conditions. Using questionnaire data, we show that this shift creates natural variation in the degree of similarity between early life and adult environments. Using anthropometric and health data, we find that, more rural, subsistence-based early life environments are associated with shorter stature but better adult cardiometabolic health. Applying a quadratic regression framework, we find support for DC but not PAR in explaining adult cardiometabolic health, echoing findings and conclusions from other long-lived species. Overall, our results suggest that early life conditions can provide additive protection against common health issues associated with urban, industrialized lifestyle exposure.

evolutionary biology↗

bioRxiv2024

Cost-effective solutions for high-throughput enzymatic DNA methylation sequencing

Characterizing DNA methylation patterns is important for addressing key questions in evolutionary biology, 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 has not yet been performed. To do so, we optimized Targeted Methylation Sequencing protocol (TMS)--which profiles [~]4 million CpG sites--for miniaturization, flexibility, and multispecies use at a cost of [~]$80. 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 (R{superscript 2} = 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 (R{superscript 2} = 0.98). Finally, we applied our protocol to profile age-associated DNA methylation variation in two subsistence-level populations--the Tsimane of lowland Bolivia and the Orang Asli of Peninsular Malaysia--and found age-methylation patterns that were strikingly similar to those reported in high income cohorts, despite known differences in age-health relationships between lifestyle contexts. 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.

genomics↗

bioRxiv2024

Sex differences in immune function and disease risk are not easily explained by an evolutionary mismatch

The "Pregnancy Compensation Hypothesis" (PCH) posits that sex differences in the mammalian immune system reflect the effects of selection on female immunity during pregnancy, during which increased immunomodulation is required to reduce immune responses to the fetus, while maintaining the ability to respond to pathogens. In humans, fewer pathogens and lower parity in urban, industrialized environments has been suggested to leave female immune systems under-stimulated, creating an "evolutionary mismatch" which exacerbates sex differences in immunity and increases female autoimmune disease risk. Yet, robust tests of this mismatch hypothesis have not been conducted. Here, we first confirmed a sex-bias in autoimmune disease prevalence in a large dataset of individuals from the United Kingdom (UK Biobank). Second, we asked whether sex differences in immune function are affected by shifts toward urban, lower-parity lifestyles in a single population--the Turkana people of northwest Kenya. We found that lifestyle alters sex differences in immune cell type proportions, but not in gene expression levels. Contrary to expectations from the PCH, parity did not predict immune physiology. We then tested for generalizable trends across natural fertility mammalian populations versus urban humans (data from Turkana, NHANES, GTEx, Batwa and Bakiga, yellow baboons, and macaques). We did not find consistent relationships between lifestyle and sex-biases in immune biomarkers or between parity and the same immune outcomes. Indeed, we found that parity predicts autoimmune disease risk in the opposite direction than expected from the PCH, with higher parity associated with higher autoimmune disease risk while adjusting for relevant socioeconomic variables in the UK Biobank. Taken together, our work suggests that while sex clearly influences immune physiology and disease risk in urban settings, these effects are not easily explained by an evolutionary mismatch. Future work addressing how sex interacts with lifestyle change to generate disease is needed.

evolutionary biology↗

bioRxiv2023

The biology of aging in a social world: insights from free-ranging rhesus macaques

Social adversity can increase the age-associated risk of disease and death, yet the biological mechanisms that link social adversities to aging remain poorly understood. Long-term naturalistic studies of nonhuman animals are crucial for integrating observations of social behavior throughout an individuals life with detailed anatomical, physiological, and molecular measurements. Here, we synthesize the body of research from one such naturalistic study system, Cayo Santiago Island, which is home to the worlds longest continuously monitored free-ranging population of rhesus macaques. We review recent studies of age-related variation in morphology, gene regulation, microbiome composition, and immune function. We also discuss ecological and social modifiers of age-markers in this population. In particular, we summarize how a major natural disaster, Hurricane Maria, affected rhesus macaque physiology and social structure and highlight the context-dependent and domain-specific nature of aging modifiers. Finally, we conclude by providing directions for future study, on Cayo Santiago and elsewhere, that will further our understanding of aging across different domains and how social adversity modifies aging processes.

immunology↗

bioRxiv2022

A generalizable epigenetic clock captures aging in two nonhuman primates.

Epigenetic clocks generated from DNA methylation array data provide important insights into biological aging, disease susceptibility, and mortality risk. However, these clocks cannot be applied to high-throughput, sequence-based datasets more commonly used to study nonhuman animals. Here, we built a generalizable epigenetic clock using genome-wide DNA methylation data from 493 free-ranging rhesus macaques. Using a sliding-window approach that maximizes generalizability across datasets and species, this model predicted age with high accuracy ({+/-} 1.42 years) in held-out test samples, as well as in two independent test sets: rhesus macaques from a captive population (n=43) and wild baboons in Kenya (n=271). Our model can also be used to generate insight into the factors hypothesized to alter epigenetic aging, including social status and exposure to traumatic events. Our results thus provide a flexible tool for predicting age in other populations and species and illustrate how connecting behavioral data with the epigenetic clock can uncover social influences on biological age.

evolutionary biology↗

bioRxiv2021

Sociodemographic effects on immune cell composition in a free-ranging non-human primate.

Increasing age is associated with dysregulated immune function and increased inflammation- patterns that are also observed in individuals exposed to chronic social adversity. Yet we still know little about how social adversity impacts the immune system and how it might promote age-related diseases. Here, we investigated how immune cell diversity varied with age, sex and social adversity (operationalized as low social status) in free-ranging rhesus macaques. We found age-related signatures of immunosenescence, including lower proportions of CD20+ B cells, CD20+/CD3+ ratio, and CD4+/CD8+ T cell ratio - all signs of diminished antibody production. Age was associated with higher proportions of CD3+/CD8+ Cytotoxic T cells, CD16+/CD3-Natural Killer cells, CD3+/CD4+/CD25+ and CD3+/CD8+/CD25+ T regulatory cells, and CD14+/CD16+/HLA-DR+ intermediate monocytes, and lower levels of CD14+/CD16-/HLA-DR+ classical monocytes, indicating greater amounts of inflammation and immune dysregulation. We also found an effect of exposure to social adversity (i.e., low social status) that was sex-dependent. High-status males, relative to females, had higher CD20+/CD3+ ratios and CD16+/CD3 Natural Killer cell proportions, and lower proportions of CD8+ Cytotoxic T cells. Further, low status females had higher proportions of cytotoxic T cells than high status females, while the opposite was observed in males. High status males had higher CD20+/CD3+ ratios than low status males. Together, our study identifies immune cell types that differ by age in a human-relevant primate model animal, and demonstrates a novel link between sex-dependent immunity and social adversity.

immunology↗

bioRxiv2020

Rhesus macaques as a tractable physiological model of human ageing

Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from shorter-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research due to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population.

genomics↗