Genetic Analyses of Epigenetic Predictors that Estimate Aging, Metabolic Traits, and Lifespan

Abstract

AbstractDNA methylation (DNAm) remodeling is an important aspect of aging. Recently, a ‘pan-mammalian’ microarray was developed that provides a unifying platform to profile conserved CpGs across mammalian clades, and to develop universal biomarkers for aging. We used this array to measure DNAm in 339 predominantly female mice belonging to the BXD family. We computed epigenetic clocks and predicted maximum lifespan (predicted-maxLS), and tested associations with DNAm entropy, diet, weight, metabolic traits, and genetic variation. Epigenetic age acceleration (EAA) and predicted-maxLS were correlated with genotype-dependent lifespan of the BXD strains. Genetic analyses uncovered quantitative trait loci (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 and metabolic genes. The results highlight loci concordant in humans and mice, and demonstrate intimate links between metabolism, body weight, and epigenetic aging.