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

Daytime napping was adversely associated with telomere length in univariable Mendelian randomization analysis.

• β = -0.11, 95% CI -0.18 to -0.05, PFDR = 0.002
• This association attenuated in multivariable MR after accounting for intercorrelations with other sleep traits
• Analysis used inverse-variance weighted (IVW) as primary method with MR-Egger, weighted median, and MR-PRESSO as sensitivity analyses
• Leukocyte telomere length was used as the biological aging outcome

Daytime napping was adversely associated with facial ageing in univariable Mendelian randomization.

• β = 0.05, 95% CI 0.01 to 0.09, PFDR = 0.036
• This association was not retained in multivariable MR as an independent direct effect of napping
• In multivariable MR, chronotype became protective for facial ageing (β = -0.03, 95% CI -0.05 to -0.01, P = 0.011)

Daytime napping was adversely associated with GrimAge epigenetic clock in both univariable and multivariable MR.

• UVMR: β = 0.96, 95% CI 0.09 to 1.83, PFDR = 0.048
• MVMR: β = 1.08, 95% CI 0.02 to 2.15, P = 0.046
• The association with GrimAge was retained and slightly strengthened after accounting for chronotype and sleep duration in MVMR
• HannumAge association with napping was only nominal (β = 0.53, 95% CI -0.29 to 1.35, PFDR = 0.275)

Daytime napping was adversely associated with frailty index in both univariable and multivariable MR.

• UVMR: β = 0.32, 95% CI 0.20 to 0.45, PFDR < 0.001
• MVMR: β = 0.29, 95% CI 0.15 to 0.43, P < 0.001
• The frailty association was retained after accounting for other sleep behaviors in MVMR

Daytime napping was adversely associated with cognitive performance in univariable MR, but this association attenuated in multivariable MR.

• UVMR: β = -0.16, 95% CI -0.29 to -0.03, PFDR = 0.036
• The association with cognition attenuated in MVMR after accounting for other sleep traits
• In MVMR, chronotype showed a beneficial association with cognition (β = 0.09, 95% CI 0.01 to 0.17, P = 0.036)

Chronotype was associated with HannumAge epigenetic clock and showed borderline associations with IEAA and cognition in univariable MR.

• HannumAge: β = 0.46, 95% CI 0.15 to 0.78, PFDR = 0.032
• IEAA: β = 0.36, 95% CI 0.07 to 0.66, PFDR = 0.060 (borderline)
• Cognition: β = -0.04, 95% CI -0.08 to -0.01, PFDR = 0.060 (borderline)
• In MVMR, chronotype showed no independent association with epigenetic clocks but became protective for facial ageing (β = -0.03, P = 0.011) and cognition (β = 0.09, P = 0.036)

Longer sleep duration was inversely associated with frailty in both univariable and multivariable MR, with the association strengthening in MVMR.

• UVMR: β = -0.17, 95% CI -0.26 to -0.08, PFDR = 0.001
• MVMR: β = -0.36, 95% CI -0.49 to -0.22, P < 0.001
• The inverse association between sleep duration and frailty strengthened after accounting for napping and chronotype in MVMR

The study used a two-sample Mendelian randomization design with large GWAS instruments to estimate both total and direct effects of sleep traits on multidimensional aging outcomes.

• Three sleep traits examined: chronotype, daytime napping, and sleep duration
• Aging outcomes included leukocyte telomere length, facial ageing, epigenetic clocks (IEAA, HannumAge, PhenoAge, GrimAge), frailty index, and cognitive performance
• Univariable MR (UVMR) estimated total effects; multivariable MR (MVMR) estimated direct effects accounting for intercorrelations among sleep traits
• IVW was the primary method with MR-Egger, weighted median, and MR-PRESSO as sensitivity analyses
• FDR correction was applied to account for multiple comparisons in UVMR