Unravelling the SEX-frailty paradox: identification of SEX-specific determinants of frailty

The National Institute on Aging awarded the Institute For Systems Biology $1.345 million on July 1, 2026, under the Aging Research program (CFDA 93.866) to unravel the sex-frailty paradox and identify sex-specific determinants of frailty. The project runs through June 30, 2031, and is performed in Seattle, Washington.

The research pursues three integrated aims: benchmarking the performance and potential sex bias of commonly used frailty assessment tools across multiple large-scale global human datasets; identifying sex-specific, modifiable molecular and environmental drivers of frailty using AI-powered analysis of multi-omic and exposome data; and testing causal biological mechanisms of sex differences in frailty using genetically diverse UM-HET3 mice and four core genotype (4CG) mouse models. The project addresses the clinical observation that women exhibit higher frailty scores than men at comparable ages yet experience lower mortality—a phenomenon termed the sex-frailty paradox. The principal investigator, Kane, an early-career researcher, is supported by a team of experts in sex differences, large-scale clinical data analysis, and systems biology. Completion is intended to inform the development of precision tools and targeted interventions for detection, prevention, and treatment of frailty for all older adults.

Abstract

Frailty is a clinically significant indicator of biological aging and a strong predictor of adverse outcomes, including mortality. Notably, women tend to exhibit higher frailty scores than men at comparable ages, yet experience lower mortality-a phenomenon termed the SEX-frailty paradox. The biological and socio-environmental underpinnings of this paradox remain poorly understood. This project addresses the GAP by pursuing three integrated aims: (1) to benchmark the performance and potential SEX bias of commonly used frailty assessment tools across multiple large-scale, global human datasets; (2) to identify SEX-specific, modifiable molecular and environmental drivers of frailty using AI-powered analysis of multi-omic and exposome data; and (3) to test causal biological mechanisms of SEX differences in frailty using genetically diverse UM-HET3 mice and four core genotype (4CG) mouse models. As an early career researcher PI kane will be supported by a team of experts in SEX differences, large-scale clinical data analysis and systems biology. Completion of this project will result in better understanding of the SEX-frailty paradox and its underlying mechanisms, and inform the development of precision tools and targeted interventions for the detection, prevention and treatment of frailty for all older adults.