Integrative analysis of brain-age acceleration: health associations and multi-omics profiles

The health impacts and biological mechanisms underlying Brain-Age Acceleration (BAA) remain incompletely understood. In this study, we estimated BAA using brain magnetic resonance imaging data from over 60,000 individuals in the UK Biobank. We found that accelerated brain aging was significantly associated with mortality and diseases affecting multiple organ systems. BAA also mediated the effects of lifestyle factors on health-related outcomes. A genome-wide association study (GWAS) identified multiple novel genetic risk loci for BAA. The polygenic risk score for BAA demonstrated significant associations with mortality and diseases across multiple systems in the non-GWAS cohort. Gene-drug interaction analysis based on genes mapped to BAA-associated loci revealed drugs with potential modulatory effects on brain aging. Analysis of brain single-cell transcriptomic data implicated specific cell types, including endothelial cells, pericytes, and astrocytes, as being closely associated with BAA. Integrative Summary-data-based Mendelian Randomization and Transcriptome-Wide Association Study analyses identified numerous genes with tissue-specific expression robustly associated with BAA. Proteomic and metabolomic profiling revealed a broad spectrum of circulating biomarkers associated with BAA, many of which have been found to mediate the effects of modifiable factors and genetic risk on brain aging. Together, our findings underscore the biological significance of BAA in human health and provide a multi-omic perspective on its mechanisms, offering potential targets for interventions aimed at slowing brain aging.