Post, Sasha R. (58168051500); Ryan, Calen P. (36128872500); Lee, Nanette R. (56446147800); Carba, Delia B. (55241184400); Bechayda, Sonny A. (57192306439); MacIsaac, Julie L. (59988654800); Dever, Kristy (57189977811); Lin, David T. S. (7403692025); Atashzay, Parmida (57701360700); Kobor, Michael S. (6603486133); Kuzawa, Christopher W. (6602265247)
Epigenetic clocks estimate biological aging through age-related DNA methylation patterns and are known to accelerate in response to adversity. While cortisol links stress experiences to cellular aging, the relationship between circadian cortisol and epigenetic age acceleration (EAA) remains unclear. To address this gap, we use data from the Cebu Longitudinal Health and Nutrition Survey (CLHNS) to explore linear relationships between diurnal salivary cortisol and a suite of epigenetic clocks. In 2005, when cohort members were 20–22 years old, saliva samples were obtained to measure bedtime cortisol, waking cortisol, and the cortisol awakening response (CAR). Additionally, DNA methylation was measured in whole blood to calculate EAA with multiple epigenetic clocks: principal components-based first-generation clocks trained on chronological age (PC Horvath, PC Hannum), second-generation clocks trained on chronological age and health markers (PC PhenoAge, PC GrimAge, PC DNAmTL), and DunedinPACE, a clock trained on the pace of change in aging-related biomarkers. Elevated bedtime cortisol and a blunted CAR—markers of chronic stress—significantly predicted EAA across second-generation clocks and DunedinPACE, even when stratifying by sex and adjusting for immune cell fractions. After multiple hypothesis test correction, elevated bedtime cortisol remained a significant predictor of EAA, although effect sizes were small. Associations were attenuated by adjusting for immune cell fractions, suggesting that links between chronic stress and EAA may operate through stress-related changes to the composition of the immune system. These findings indicate that, in the CLHNS cohort, cortisol-based measures of chronic stress already predict acceleration of multiple epigenetic clocks in young adulthood. © 2026 Wiley Periodicals LLC.
Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, United States; Robert N. Butler Columbia Aging Center, Mailman School of Public Health, Columbia University, New York, NY, United States; USC-Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines; Department of Anthropology, Sociology and History, University of San Carlos, Cebu City, Philippines; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; Child and Brain Development Program, Canadian Institute for Advanced Research, Toronto, ON, Canada; Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada
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