Sleep disorders and aging: Mendelian randomization analysis of epigenetic and frailty markers

Sleep disorders-including daytime sleepiness (DS), insomnia, and sleep apnea (SA)-have been linked to aging-related phenotypes, but their causal roles remain unclear. This study aimed to examine the potential causal effects of these sleep traits on biological aging using a Mendelian randomization (MR) approach.

We conducted two-sample MR analyses using genetic instruments from large-scale genome-wide association studies (GWAS) for DS, insomnia, and SA. The inverse-variance weighted (IVW) method was the primary analytical approach, with sensitivity analyses performed for validation. Aging-related outcomes included intrinsic epigenetic age acceleration (IEAA), GrimAge, HannumAge, PhenoAge, telomere length, facial aging, frailty index, and cognitive performance. False discovery rate (FDR) correction was applied for multiple testing.

DS was significantly associated with increased frailty index (β = 0.33, 95 % CI: 0.09-0.57, PFDR = 0.045). Insomnia showed significant associations with both IEAA (β = 1.57, 95 % CI: 0.40-2.73, PFDR = 0.035) and frailty index (β = 0.42, 95 % CI: 0.23-0.61, PFDR <0.001). SA was significantly associated with facial aging (β = 0.03, 95 % CI: 0.01-0.06, PFDR = 0.016) and frailty index (β = 0.09, 95 % CI: 0.02-0.16, PFDR = 0.028). No significant associations were found for telomere length, GrimAge, PhenoAge, or cognitive performance.

This MR study supports potential causal effects of insomnia on epigenetic aging and frailty. DS and SA were also linked to increased frailty, and SA further associated with facial aging. These findings underscore the importance of sleep health in mitigating age-related biological decline.