Genetic loci and metabolic states associated with murine epigenetic aging

Abstract

Changes in DNA methylation (DNAm) are linked to aging. 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. We use a 'pan-mammalian' microarray that provides a common platform for assaying the methylome across mammalian clades. We computed epigenetic clocks and tested associations with DNAm entropy, diet, weight, metabolic traits, and genetic variation. We describe the multifactorial variance of methylation at these CpGs, and show that high fat diet augments the age-associated changes. Entropy increases with age. The progression to disorder, particularly at CpGs that gain methylation over time, was predictive of genotype-dependent life expectancy. The longer-lived BXD strains had comparatively lower entropy at a given age. 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. Both loci harbor genes associated with EAA in humans including STXBP4, NKX2-3, and CUTC. Transcriptome and proteome analyses revealed associations with oxidation-reduction, metabolic, and immune response pathways. Our results highlight concordant loci for EAA in humans and mice, and demonstrate a tight coupling between the metabolic state and epigenetic aging.

Stress induced aging in mouse eye

“…We used the Mammalian Methylation 320 k Array designed for mouse methylation studies (Arneson et al, 2022 ; Lu et al, 2021 ). We used previously published pan‐tissue mouse clock as well as tissue specific clocks for liver, blood, brain, muscle, heart, cortex, striatum, cerebellum, tail, kidney, skin, and fibroblasts (Mozhui et al, 2022 ). Since there is no retina‐specific DNA methylation clock, our primary analysis focused on the PanTissue mouse clock and the universal pan mammalian clock that applies to all mammalian species (Lu et al, 2021 ).…”

Genome-Wide DNA Methylation Profile Indicates Potential Epigenetic Regulation of Aging in the Rhesus Macaque Thymus

“…Previously, many age–methylation clocks were reported based on multiple tissues of multiple species [ 38 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ], but these studies did not include the thymus. When combining the reported data and the 431 thymus age-related methylated genes in the present study, we identified 3965 age-related homologous genes in humans, rhesus macaques, mice and dogs.…”

“…We downloaded about 11,700 age–methylation clock CpG sites and 137 age-related DMRs from multiple mammals, including humans [ 51 , 53 , 79 , 80 , 81 ], rhesus macaques [ 32 ], mice [ 54 , 55 , 57 , 59 ] and dogs [ 58 ]. These CpG sites and DMRs were mapped to the genomes of the corresponding species (human: GRCH38.p13; rhesus macaque: Mmul_10; mouse: GRCm39; dog: ROS_Cfam_1.0) using the Ensembl BioMart web server (Ensemble Genes 107) [ 82 , 83 ].…”

Small extracellular vesicles from young adipose-derived stem cells prevent frailty, improve health span, and decrease epigenetic age in old mice

“…Multiple mouse age predictors (epigenetic clocks) were used to estimate the age of the animals. The mouse clocks were trained/developed in a separate dataset ( 73 ). The age predictors were grouped into general and intervention clocks.…”