Aging differs significantly between sexes: women live longer but experience higher frailty and multimorbidity, while men face earlier mortality from cardiovascular and respiratory diseases. In women, menopause marks a pivotal midlife transition that affects multiple organs, where it likely accelerates aging, and increases risks for dementia, cardiovascular, and metabolic conditions. Despite this, most aging models ignore reproductive history and treat aging as a linear process, overlooking the non-linear and sex-specific nature of aging.
Recent studies using UK Biobank plasma proteomics have shown that aging affects different organs to varying degrees and that these patterns may differ by sex. However, sex-stratified, organ-specific analyses remain limited. Furthermore, while recent work has identified non-linear aging alterations using plasma proteomics, no study has systematically modeled organ aging as a non-linear process or considered menopause as a biological breakpoint influencing multi-organ aging.
This project will use plasma proteomic data from ~54,000 UK Biobank participants – and the upcoming expanded proteomics release on 500,000 participants – to build and compare sex-specific models of organ and immune system aging. Our objectives are to:
(1) Develop statistical methods to detect non-linear age-related protein trajectories;
(2) Identify how reproductive history and menopause influence aging dynamics and disease susceptibility in female reproductive and non-reproductive organs;
(3) Explore sex-specific immune aging and validate proteomic signatures of immunosenescence.
By identifying sex-specific and non-linear aging trajectories, this work will reveal how aging processes diverge between males and females, providing mechanistic insights into sex-biased disease risk. Ultimately, it will contribute toward developing personalized, sex-informed strategies to delay age-related decline and extend healthspan.
