DNA methylation (DNAm) clocks are accurate molecular biomarkers of aging. However, the clock mechanisms remain unclear. Here, we used a pan-mammalian microarray to assay DNAm in liver from 339 predominantly female mice belonging to the BXD family. We computed epigenetic clocks and maximum lifespan predictor (predicted-maxLS), and examined associations with DNAm entropy, diet, weight, metabolic traits, and genetic variation. The epigenetic age acceleration (EAA) derived from the clocks, and predicted-maxLS were correlated with lifespan of the BXD strains. Quantitative trait locus (QTL) analyses uncovered significant QTLs on chromosome (Chr) 11 that encompasses the Erbb2/Her2 oncogenic region, and on Chr19 that contains a cytochrome P450 cluster. Both loci harbor candidate genes associated with EAA in humans (STXBP4, NKX2-3, CUTC). Transcriptome and proteome analyses revealed enrichment in oxidation-reduction, metabolic, and mitotic genes. Our results highlight loci that are concordant in human and mouse, and demonstrate intimate links between metabolism, body weight, and epigenetic aging.
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