Ticking Differently: Elucidating Sexual Dimorphism in Human Aging through Metabolomics, Proteomics and Genomics

That males and females age differently has been overlooked while developing aging clocks. Here, we developed a sex-specific metabolic aging clock in 390,941 individuals from the UK Biobank and integrated it with genetic, proteomic and epidemiological data to identify mechanisms accelerating/decelerating metabolic aging in males and females. Our findings reveal dysregulation of cholesterol metabolism, immune system, hemostasis, and cell growth, survival and apoptosis as common mechanisms accelerating metabolic aging in males and females, and upregulation of oxidative stress detoxification, cellular resilience and tissue integrity as common mechanisms decelerating metabolic aging. In females, a further dysregulation of carbohydrate/glucose metabolism, circadian rhythm and hormone metabolism accelerating metabolic aging is observed, while dysregulation of energy metabolism, cancer and longevity pathway is specifically observed in males. Among reproductive factors, late puberty and higher parity manifest as protective factors, decelerating metabolic aging in both sexes, and additionally childbirth at older age decelerating metabolic aging in women. Accelerated metabolic age strongly predicted morbidity and mortality in both sexes, except that the magnitude of association was several folds higher in males, and obesity explained most of the disease associations in females, suggesting that obesity influences metabolic aging and subsequent health outcomes differently in males and females. Consistent with the upregulation of molecular mechanisms involved in cancer in males, accelerated metabolic aging predicted several common cancers in males but not females. Our study provides novel insights into the biological mechanisms underlying aging and disease susceptibility in males and females, underscoring the importance of considering sex differences in healthcare strategies and public health policies.