At 500 days, animals on a HFD typically gain four times as much weight as control, but variation in weight gain does not correlate with lifespan. Initial body weight and early weight gains account for longevity differences of roughly 4–6 days per gram. HFD feeding shortens lifespan by 12%: equivalent to a decade in humans. We further generate key metabolic data in a parallel cohort euthanized at four time points. Here we quantify the impact of differences in diet on lifespan in a genetically diverse family of female mice, split into matched isogenic cohorts fed a low-fat chow diet (CD, n = 663) or a high-fat diet (HFD, n = 685). How lifespan and body weight vary as a function of diet and genetic differences is not well understood. Our results highlight concordant loci for EAA in humans and mice, and demonstrate a tight coupling between the metabolic state and epigenetic aging. Transcriptome and proteome analyses revealed associations with oxidation-reduction, metabolic, and immune response pathways. Both loci harbor genes associated with EAA in humans including STXBP4, NKX2- 3, and CUTC. We identified two genetic loci that modulate rates of epigenetic age acceleration (EAA): one on chromosome (Chr) 11 that encompasses the Erbb2/Her2 oncogenic region, and a second on Chr19 that contains a cytochrome P450 cluster. The longer-lived BXD strains had comparatively lower entropy at a given age. The progression to disorder, particularly at CpGs that gain methylation over time, was predictive of genotype-dependent life expectancy. We describe the multifactorial variance of methylation at these CpGs, and show that high fat diet augments the age-associated changes. We computed epigenetic clocks and tested associations with DNAm entropy, diet, weight, metabolic traits, and genetic variation. We use a 'pan-mammalian' microarray that provides a common platform for assaying the methylome across mammalian clades. Here, we profile highly conserved CpGs in 339 predominantly female mice belonging to the BXD family for which we have deep longevity and genomic data. Furthermore, we demonstrate that the measure of epigenetic aging derived from age‐DMRs can predict genotype and diet‐induced differences in life span among female BXD members.Ĭhanges in DNA methylation (DNAm) are linked to aging. Our results highlight the age‐accelerating effect of heavier BW. Both higher BW and the HFD were associated with accelerated epigenetic aging. An epigenetic clock defined from age‐DMRs revealed accelerated aging in mice belonging to strains with shorter life spans. CpG regions associated with life span were linked to genes involved in life span modulation, including the telomerase reverse transcriptase gene, Tert, which had both lower methylation and higher expression in long‐lived strains. CpG regions associated with BW were enriched in introns, tended to have lower methylation in mice with higher BW, and were inversely correlated with gene expression (i.e., higher mRNA levels in mice with higher BW). These age‐associated differentially methylated CpG regions (age‐DMRs) featured distinct genomic characteristics, with DNAm gains over time occurring in sites such as promoters and exons that have high CpG density and low average methylation. We defined subsets of CpG regions associated with age, BW at young adulthood, and strain‐by‐diet‐dependent life span. Genome‐wide DNAm was assayed in 70 liver specimens from predominantly female cases, 6–25 months old, that were maintained on normal chow or high‐fat diet (HFD). Here, we examine interrelations between epigenetic aging, body weight (BW), and life span in 12 isogenic strains from the BXD family of mice that exhibit over twofold variation in longevity. DNA methylation (DNAm) is shaped by genetic and environmental factors and modulated by aging.