An official website of the United States government
Sex differences in life span are widespread across animal taxa, but their causes remain unresolved. Alterations to the epigenome are hypothesized to contribute to vertebrate aging, and DNA methylation–based aging clocks allow for quantitative estimation of biological aging trajectories. Here, we investigate the influence of age, sex, and their interaction on genome-wide DNA methylation patterns in the brown anole (Anolis sagrei), a lizard with pronounced female-biased survival and longevity. We develop a series of age predictor models and find that, contrary to our predictions, rates of epigenetic aging were not slower in female lizards. However, methylation states at loci acquiring age-associated changes appear to be more “youthful” in young females, suggesting that female DNA methylomes are preemptively fortified in early life in opposition to the direction of age-related drift. Collectively, our findings provide insights into epigenetic aging in reptiles and suggest that early-life epigenetic profiles may be more informative than rates of change for predicting sex biases in longevity.
more »
« less
This content will become publicly available on July 18, 2026
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.
more »
« less
- Award ID(s):
- 2313953
- PAR ID:
- 10649279
- Author(s) / Creator(s):
- ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract The goal of this study is to examine the association between in utero drought exposure and epigenetic age acceleration (EAA) in a global climate change hot spot. Calculations of EAA in adults using DNA methylation have been found to accurately predict chronic disease and longevity. However, fewer studies have examined EAA in children, and drought exposure in utero has not been investigated. Additionally, studies of EAA in low-income countries with diverse populations are rare. We assess EAA using epigenetic clocks and two DNAm-based pace-of-aging measurements from whole saliva samples in 104 drought-exposed children and 109 same-sex sibling controls in northern Kenya. We find a positive association between in utero drought exposure and EAA in two epigenetic clocks (Hannum’s and GrimAge) and a negative association in the DNAm based telomere length (DNAmTL) clock. The combined impact of drought’s multiple deleterious stressors may reduce overall life expectancy through accelerated epigenetic aging.more » « less
-
Abstract Life history theory predicts that organisms allocate resources across physiological processes to maximize fitness. Under this framework, early life adversity (ELA)—which often limits energetic capital—could shape investment in growth and reproduction, as well as trade-offs between them, ultimately contributing to variation in evolutionary fitness. Using long-term demographic, behavioral, and physiological data for 2,100 females from a non-human primate population, we tested whether naturally-occurring ELA influences investment in the competing physiological demands of growth and reproduction. By analyzing ELA, growth, and reproduction in the same individuals, we also assessed whether adversity intensifies trade-offs between life history domains. We found that ELA influenced life history patterns, and was associated with modified growth, delayed reproductive maturity, and small adult body size. Different types of ELA sometimes had distinct reproductive outcomes—e.g., large group size was linked to faster reproductive rates, while low maternal rank predicted slower ones. Adversity also amplified trade-offs between growth and reproduction: small body size was a stronger predictor of delayed and reduced reproductive output in females exposed to ELA, compared to those not exposed. Finally, we examined how traits modified by ELA related to lifetime reproductive success. Across the population, starting reproduction earlier and maintaining a moderate reproductive rate conferred the greatest number of offspring surviving to reproductive maturity. These findings suggest that ELA impacts key life history traits as well as relationships between them, and can constrain individuals from adopting the most optimal reproductive strategy. Significance StatementEarly life adversity (ELA) can have lasting effects on evolutionary fitness (e.g., the number of surviving offspring an animal produces); however, the paths connecting ELA to fitness—for example by influencing growth, reproductive timing or rate, or trade-offs between these processes—remain unclear. Leveraging long-term behavioral, physiological, and demographic data from 2,100 female rhesus macaques, we found that ELA-exposed females exhibited growth and reproductive schedules associated with less-optimal lifetime fitness outcomes. Further, ELA intensified trade-offs between growth and reproduction, suggesting that affected individuals face steeper energetic constraints. Our findings highlight the long-lasting impacts of ELA on traits of evolutionary and biomedical importance in a non-human primate model with relevance to humans.more » « less
-
Synopsis Adverse experiences in early life are associated with aging-related disease risk and mortality across many species. In humans, confounding factors, as well as the difficulty of directly measuring experiences and outcomes from birth till death, make it challenging to identify how early life adversity impacts aging and health. These challenges can be mitigated, in part, through the study of non-human animals, which are exposed to parallel forms of adversity and can age similarly to humans. Furthermore, studying the links between early life adversity and aging in natural populations of non-human animals provides an excellent opportunity to better understand the social and ecological pressures that shaped the evolution of early life sensitivities. Here, we highlight ongoing and future research directions that we believe will most effectively contribute to our understanding of the evolution of early life sensitivities and their repercussions.more » « less
-
Changes in DNA methylation with age are observed across the tree of life. The stereotypical nature of these changes can be modeled to produce epigenetic clocks capable of predicting chronological age with unprecedented accuracy. Despite the predictive ability of epigenetic clocks and their utility as biomarkers in clinical applications, the underlying processes that produce clock signals are not fully resolved, which limits their interpretability. Here, we develop a computational approach to spatially resolve the within read variability or “disorder” in DNA methylation patterns and test if age-associated changes in DNA methylation disorder underlie signals comprising epigenetic clocks. We find that epigenetic clock loci are enriched in regions that both accumulate and lose disorder with age, suggesting a link between DNA methylation disorder and epigenetic clocks. We then develop epigenetic clocks that are based on regional disorder of DNA methylation patterns and compare their performance to other epigenetic clocks by investigating the influences of development, lifespan interventions, and cellular dedifferentiation. We identify common responses as well as critical differences between canonical epigenetic clocks and those based on regional disorder, demonstrating a fundamental decoupling of epigenetic aging processes. Collectively, we identify key linkages between epigenetic disorder and epigenetic clocks and demonstrate the multifaceted nature of epigenetic aging in which stochastic processes occurring at non-random loci produce predictable outcomes.more » « less
