Abstract
Frailty is an age-related geriatric syndrome with largely unknown mechanisms. We conducted a longitudinal study of aging C57BL/6JNIA mice (females; n = 40, male; n = 49), measured frailty index and derived DNA methylation data from PBMCs. We selected frailty-related differentially methylated CpGs and determined differentially methylated regions (DMRs), focusing on both age-independent and -dependent frailty, and using both mixed-sex and sex-stratified subgroups. We propose a joint set of 925 frailty-related DMRs, perform an association study with frailty outcomes, build epigenetic frailty clocks and validate in mice with interventions. Notably, age-independent frailty DMRs are enriched in nervous and endocrine pathways, distinct from signaling and lipid metabolism pathways identified from age-dependent DMRs. We observe hypermethylation in signaling pathways and hypomethylation in lipid metabolism and cytochrome P450 pathways with frailty progression. 36 DMRs show consistent associations in validation. These findings highlight distinct epigenetic signatures underlying frailty and aging, with potential sex-specific mechanisms.