Metabolite-predicted biological age acceleration and associations with oncologic, neurodegenerative, and adiposity-related endpoints in multi-ancestry populations

Chronologic age is widely understood as a significant risk factor for many chronic diseases and is frequently used in risk stratification to guide selective screening. However, for age-related diseases, chronological age alone may not accurately reflect the underlying heterogeneity in biological aging that contributes to disease risk. Using prospectively collected data from the Women’s Health Initiative (WHI), the Multiethnic Cohort (MEC), and the Wisconsin Registry for Alzheimer’s Prevention (WRAP), we developed statistical models to estimate biological age acceleration from untargeted LC/MS metabolomics data and evaluated associations with, primarily, breast and prostate cancer, cognitive function scores, and BMI. Additionally, we conducted pathway analyses to identify metabolic pathways significantly associated with chronologic age. Model performance was consistent across cohorts, with RMSE ranging from [5.36, 6.41] years. We did not find evidence of a statistically significant association between a 10-year increase in metabolite-predicted biological age acceleration and disease risk, including for any oncologic outcomes, cognitive scores, or BMI. We detected several enriched metabolic pathways across cohorts, including C21-steroid hormone biosynthesis and metabolism, urea cycle/amino acid group metabolism, and carnitine shuttle.