Influence of body weight at young adulthood on the epigenetic clock and lifespan in the BXD murine family

Background: The DNA methylation landscape is shaped by genetic and environmental factors and is modulate by aging. Here we evaluate the "aging methylome" in 12 recombinant inbred mouse strains from the BXD family that have more than two-fold variation in longevity. We examine relations among body weight, diet, lifespan, and DNA methylation-based rate of biological aging. We used affinity capture with the methyl-CpG binding domain (MBD) protein, followed by deep sequencing (MBD-seq), to assay DNA methylation in 70 mostly female liver samples, ranging in age from 6 to 25 months from mice maintained either on low fat chow or high fat diet (HFD). Results: Genetic background among strains is a major source of variation in genome-wide DNA methylation patterns. Surprisingly, body weight at young adulthood had a stronger association with the methylome than age itself. Nonetheless, age also had a strong effect on methylation at well-defined CpG regions largely located within genes. We used subsets of age-informative CpGs to build versions of the epigenetic clock and as expected, these were strongly correlated with chronological age. Both high initial body weight and the HFD were associated with accelerated epigenetic aging. A DNA methylation clock model built using CpGs associated with body weight correlated with longevity of strains rather than chronological age, implying an underlying lifespan clock. Complementary mRNA clocks were also informative of chronological age. Conclusion: Our results support the known association between body mass and lifespan, and indicate that the methylome provides a mechanistic link to accelerated aging.