Biological aging clock from routine clinical and anthropometric measurements in diverse populations

Aging is accompanied by a progressive decline in physiological function that contributes to chronic disease development. Biological clocks estimated from high-dimensional clinical and biological measurements may provide more granular tracking of the aging processes. Current biological clocks, however, have limited cross-ancestry generalizability and clinical applicability. Here, we developed a multi-ancestry biological clock (ClinBAG) using 22 routine blood and anthropometric biomarkers in 14,328 age- and sex-balanced individuals from the All of Us Research Program. We tested the association of ClinBAG with 434 traits and evaluated its ability to predict incident disease in 152,733 non-overlapping individuals. We also conducted genome-wide association studies in European (N=74,675), African (N=22,315), and Admixed American ancestry individuals (N=19,940). Among 190 neurological phenotypes, elevated ClinBAG was associated with cognitive decline, increased incidence of dementia (HR=1.020, p=1.6x10-5) and Parkinson's disease (HR=1.014, p=0.023), and decreased risk of migraine (HR=0.991, p=8.7x10-4). We also identified common (NPRL3) and ancestry-specific genetic loci (HBB in African-ancestry and FADS1/FADS2 in European-ancestry) for ClinBAG. Single-cell enrichment revealed that ClinBAG-associated genes are overexpressed in double-negative (DN) T cells in an age-dependent manner. This study presents a clinically applicable multi-ancestry biological age clock predicting neurological disease risk. Our findings also uncover population-specific genetic drivers, particularly involving erythropoiesis and DN T-cell-mediated neuroinflammation.