Sex-specific biological aging clocks across organs and omics

Abstract

Sex differentially shapes aging, neurodevelopment, and neurodegenerative diseases such as Alzheimer’s disease (AD). Yet, most biological aging clocks (AI-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance. Here, we develop 38 sex-specific biological aging clocks across 15 organ systems and 4 omics layers. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references, and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine, and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular, and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex- and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular, and clinical signatures that pooled models may obscure. Together, these findings reveal sex-specific biological aging signatures in aging, AD, and systemic health, highlighting the need for explicitly sex-stratified modelling approaches.