Distinct roles of chronotype, daytime napping, and sleep duration in biological and functional aging: a univariable and multivariable Mendelian randomization study

Sleep traits have been linked to aging, but observational designs cannot separate correlated sleep behaviors or establish causality. We used Mendelian randomization (MR) to estimate both total and direct effects of chronotype, daytime napping, and sleep duration on multidimensional aging outcomes. Two-sample MR used large GWAS instruments for the three sleep traits against leukocyte telomere length, facial ageing, epigenetic clocks (IEAA, HannumAge, PhenoAge, GrimAge), frailty index, and cognitive performance. Inverse-variance weighted (IVW) was primary, with MR-Egger, weighted median, and MR-PRESSO as sensitivity analyses. Univariable MR (UVMR) estimated total effects; multivariable MR (MVMR) estimated direct effects accounting for intercorrelations. In UVMR, napping was adversely associated with telomere length (β = − 0.11, 95% CI − 0.18 to − 0.05, PFDR = 0.002), facial ageing (β = 0.05, 0.01–0.09, PFDR = 0.036), GrimAge (β = 0.96, 0.09–1.83, PFDR = 0.048), frailty (β = 0.32, 0.20–0.45, PFDR < 0.001), and cognition (β = − 0.16, − 0.29 to − 0.03, PFDR = 0.036); HannumAge was nominal (β = 0.53, − 0.29–1.35, PFDR = 0.275). Chronotype related to HannumAge (β = 0.46, 0.15–0.78, PFDR = 0.032) with borderline links to IEAA (β = 0.36, 0.07–0.66, PFDR = 0.060) and poorer cognition (β = − 0.04, − 0.08 to − 0.01, PFDR = 0.060). Sleep duration was inversely associated with frailty (β = −0 .17, − 0.26 to − 0.08, PFDR = 0.001). In MVMR, napping retained associations with GrimAge (β = 1.08, 0.02–2.15, P = 0.046) and frailty (β = 0.29, 0.15–0.43, P < 0.001), while links to telomere length and cognition attenuated. Chronotype became protective for facial ageing (β = −0 .03, − 0.05 to − 0.01, P = 0.011) and cognition (β = 0.09, 0.01–0.17, P = 0.036) and showed no independent association with epigenetic clocks. The inverse association between sleep duration and frailty strengthened (β = − 0.36, − 0.49 to − 0.22, P < 0.001). Sleep traits show distinct, partly independent causal links with aging: excessive napping adversely influences GrimAge and frailty; longer sleep duration independently protects against frailty; and chronotype benefits facial ageing and cognition after accounting for other sleep behaviors.