Sleep Chart of Biological Aging Clocks in Middle and Late Life

CLINICAL QUESTION

How is self-reported sleep duration associated with biological aging across organs and omics platforms, subsequent systemic disease, all-cause mortality, and late-life depression?

BOTTOM LINE

Sleep duration had a U-shaped association with nine of 23 biological aging clocks, with the lowest age-gap values occurring between approximately 6.4 and 7.8 hours, depending on organ and sex. Both short and long sleep were associated with higher risks of systemic disease and all-cause mortality, although causality and reverse causation remain unresolved.

BACKGROUND: Insufficient and excessive sleep have both been associated with aging, chronic disease, and mortality. This study examined whether those relationships extend beyond the brain by evaluating biological aging clocks derived from imaging, plasma proteomics, and metabolomics across multiple organ systems.

STUDY DESIGN: Large-scale multimodal observational analysis using MULTI Consortium data. Generalized additive models assessed nonlinear relationships between self-reported sleep duration and 23 biological age-gap measures. Genetic correlation, time-to-incident disease, mortality, and structural equation analyses were also performed.

SETTING: The principal analysis used UK Biobank participants aged 37-84 years, supplemented by genetic and clinical datasets from the MULTI Consortium.

SYNOPSIS: Nine of 23 biological aging clocks showed significant nonlinear associations with sleep duration. These included proteomic age gaps for the brain, pulmonary system, liver, immune system, and skin; an endocrine metabolomic age gap; and MRI-derived age gaps for the brain, adipose tissue, and pancreas. The sleep duration associated with the lowest biological age gap ranged from 6.5 to 7.8 hours in women and 6.4 to 7.7 hours in men.

For downstream analyses, sleep was classified as short, less than six hours; normal, six to eight hours; or long, more than eight hours. Genetic correlation analyses identified 153 positive associations between abnormal sleep duration and systemic disease endpoints, with short sleep showing broader correlations across cardiovascular, metabolic, musculoskeletal, psychiatric, neurological, pulmonary, and gastrointestinal conditions. Long sleep showed a more focused genetic correlation pattern, particularly for neuropsychiatric traits.

Longitudinal analyses likewise identified 153 significant associations with subsequent disease endpoints. Compared with normal sleep, short sleep was associated with higher all-cause mortality (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.44 to 1.55), as was long sleep (HR, 1.40; 95% CI, 1.36 to 1.44).

Structural equation analyses suggested that short sleep was linked more directly with late-life depression, whereas associations with long sleep were more often mediated by MRI-based aging measures, particularly brain and adipose age gaps. Mendelian randomization analyses did not provide strong evidence that disease causally altered sleep duration, but reverse causality could not be excluded.

CITATION: O’Toole CK, et al. Sleep chart of biological ageing clocks in middle and late life. Nature. 2026. doi:10.1038/s41586-026-10524-5.