sleep

Sleep (duration, quality, timing)

Sleep is the most universal biological-reset process in mammals, yet it is routinely shortened and degraded in modern populations. In the context of aging biology, sleep is both a diagnostic window (poor sleep quality is an early and sensitive marker of neurodegeneration and systemic inflammaging) and an interventionally tractable target — structured behavioral interventions (CBT-i, light hygiene, chronotype alignment, CPAP for obstructive apnea) demonstrably improve sleep architecture, inflammatory markers, and emerging biological-age signals. Lifespan extension from improved sleep has not been demonstrated in a controlled trial, but the mechanistic case — glymphatic clearance of neurotoxic waste, suppression of HPA-axis-driven cortisol, overnight immune reset — is among the strongest in aging biology.

Sleep architecture

Normal adult sleep cycles through approximately five 90-minute ultradian cycles per night:

Stage	Also called	Proportion of sleep	Function
N1	Light NREM	~5%	Transition; brief arousal threshold
N2	Core NREM	~45–50%	Memory consolidation onset; sleep spindles; K-complexes
N3	Slow-wave sleep (SWS), deep NREM	~15–20% in young adults	Declarative memory; glymphatic clearance; GH secretion
REM	REM sleep	~20–25%	Emotional memory; synaptic plasticity; procedural consolidation

Distribution shifts across the night: SWS predominates in the first half of the night (deep restorative sleep is front-loaded); REM predominates in the second half. Truncating sleep from the end disproportionately removes REM; from the beginning (delayed bedtime) disproportionately removes SWS.

Age-related decline in sleep

Sleep architecture deteriorates measurably from the third decade onward ¹:

• Total sleep time (TST) declines approximately 10 minutes per decade from age 30–60.
• SWS (N3) undergoes the most dramatic age-related loss: from ~15–20% of sleep in young adults, declining substantially by age 70 — a ~75–80% reduction in slow-wave activity (SWA) amplitude over frontal EEG derivations relative to young adults, with the largest age-related changes during the first NREM sleep cycle ¹. SWS time also declines, though the magnitude varies by sex (men show greater loss) and measurement method; some older adults retain more SWS time than others despite severely blunted SWA amplitude.
• Sleep efficiency (time asleep / time in bed) declines; fragmentation (micro-arousals) increases.
• Circadian amplitude flattens; the core body-temperature nadir advances (phase advance), shifting preferred bedtime and wake time earlier.
• REM declines modestly and later than SWS.

These changes are not simply benign “normal aging” — they track strongly with cognitive performance, Alzheimer’s risk, and systemic inflammation, and some are partially reversible with exercise or sleep hygiene intervention.

Glymphatic clearance — sleep’s proteostasis function

The glymphatic system (named by analogy with the lymphatic system) is an astrocyte-dependent paravascular network that clears metabolic waste from the brain interstitium during sleep ².

Mechanism: Cerebrospinal fluid (CSF) enters the brain parenchyma via the periarterial space and exchanges with interstitial fluid (ISF) across AQP4 (aquaporin-4) water channels located on astrocyte endfeet. This bulk flow convects solutes — including amyloid-beta (Aβ), tau, lactate, and other metabolic waste — to the perivenous space for drainage into deep cervical lymphatics and the dural sinuses.

Sleep dependence: Xie et al. 2013 measured real-time glymphatic tracer transport in mice and found a ~60% increase in interstitial space volume during sleep vs wakefulness, with dramatically accelerated Aβ clearance ³. The expanded interstitial space in sleep reduces tortuosity and resistance to convective flow.

AQP4 and aging: AQP4 polarization to astrocyte endfeet declines with age and is disrupted in Alzheimer’s disease models. needs-human-replication — most glymphatic aging data are in rodents; direct in-vivo human glymphatic flow measurement is technically challenging (requires intrathecal tracers or MRI-based flow proxies).

Implication for loss-of-proteostasis: Chronic sleep restriction impairs glymphatic clearance, allowing Aβ and tau to accumulate in the interstitium — creating a potential sleep-deprivation → neurodegeneration feedforward loop. See alzheimers-disease for the Aβ sleep connection.

Sleep and inflammation — the HPA/NF-kB axis

Poor sleep activates pro-inflammatory signaling at multiple levels ⁴:

• HPA-axis: Fragmented or shortened sleep elevates cortisol (and disrupts its normal nocturnal suppression), driving glucocorticoid receptor signaling that paradoxically upregulates NF-kB-driven inflammation over time via receptor desensitization.
• Sympathetic nervous system: Sleep loss increases sympathetic tone (elevated norepinephrine), activating beta-adrenergic signaling on immune cells; this reduces glucocorticoid sensitivity in monocytes and promotes pro-inflammatory transcription.
• TLR4 pathway: Carroll et al. 2015 examined partial sleep deprivation (restricted to 03:00–07:00 sleep window) in older adults (n=49, ages 60–84) vs younger adults (n=21, ages 25–39) and found a significant age × sleep-loss interaction (p<0.05). Younger adults showed increased TLR-4-stimulated monocyte IL-6 and TNF-α production after partial sleep deprivation; older adults paradoxically showed reduced baseline TLR-4-stimulated cellular inflammation that was not further activated by sleep loss — suggesting that older adults may already be in a state of chronic immune dysregulation that is not acutely amplified by sleep deprivation ⁴. needs-replication — the blunted acute inflammatory response in older adults does not imply protection; chronic low-grade inflammation in aged monocytes is well-documented separately.
• IL-6, TNF-alpha, CRP are all elevated in epidemiological studies of chronically short sleepers.

This inflammatory pathway connects sleep quality to chronic-inflammation and likely mediates some of the cardiovascular and metabolic risk associated with short sleep.

Sleep duration and mortality — epidemiological signal

The relationship between sleep duration and all-cause mortality is U-shaped, with lowest risk at ~7 hours per night ⁵:

Sleep duration	All-cause mortality risk vs 7 hr reference	Source
Short (<7 hr)	RR 1.06 (95% CI 1.04–1.07) per 1-hr reduction; pooled RR 1.12 (95% CI 1.06–1.18) for categorical short sleep	Yin 2017 dose-response; Cappuccio 2010 categorical
7–8 hr/night	Reference (lowest risk)	Yin 2017
Long (>8 hr)	RR 1.13 (95% CI 1.11–1.15) per 1-hr increment; pooled RR 1.30 (95% CI 1.22–1.38) for categorical long sleep	Yin 2017 dose-response; Cappuccio 2010 categorical

Both meta-analyses report relative risk (RR), not odds ratios. Long sleep (>8–9 hr) shows a stronger mortality association than short sleep; this is partly confounded by reverse causality (underlying disease increasing sleep need), but remains after prospective adjustment in most meta-analyses ⁶.

Recommended adult sleep duration: 7–9 hours per night (National Sleep Foundation / AAoSM consensus). Both short (<6 hr) and long (>9 hr) are associated with elevated mortality.

Slow-wave sleep and cognitive aging

SWS serves multiple restorative functions that are directly relevant to aging ¹:

1. Memory consolidation: SWS-specific hippocampal replay consolidates declarative memories. SWS loss with age impairs overnight hippocampal-to-cortical memory transfer.
2. Glymphatic clearance: As above — SWS is the peak window for glymphatic flow.
3. Growth hormone (GH) secretion: The dominant GH pulse of the 24-hour cycle occurs in early-night SWS; GH decline with age is partly attributable to SWS loss.
4. Sleep spindle-SWS coupling: Mander et al. (from Walker lab) showed that prefrontal cortical thinning with age impairs NREM slow-oscillation generation, uncoupling slow waves and sleep spindles and predicting overnight memory retention failure — a mechanism connecting brain atrophy to functional cognitive decline via sleep ¹.

Sleep-disordered breathing — obstructive sleep apnea

Obstructive sleep apnea (OSA) prevalence rises steeply with age: ~10–17% in adults aged 30–69 (AHI >15), and up to 50%+ in adults >65 by polysomnography depending on diagnostic threshold. OSA causes:

• Nocturnal hypoxemia (repeated desaturation events)
• Sleep fragmentation (arousals per hour = AHI events)
• Suppression of SWS and REM
• Elevated sympathetic tone and HPA activation

Relevance to aging hallmarks: OSA is an independent risk factor for cardiovascular disease, type 2 diabetes, and cognitive decline — pathways overlapping with hallmarks of aging. Whether OSA directly accelerates biological age (epigenetic clock aging) is under study; some CPAP intervention data show modest improvement in inflammatory biomarkers (IL-6, CRP), but evidence for clock-aging reversal is preliminary. needs-replication

CPAP adherence problem: Despite CPAP being first-line therapy, adherence in elderly populations is poor (~40–60%), limiting population-level benefit.

Circadian misalignment

Circadian misalignment — when sleep timing conflicts with the endogenous circadian clock (e.g., night shift work, social jet lag, late chronotype in early-rising schedules) — produces aging-relevant metabolic effects independent of total sleep duration:

• Shift workers have elevated risks of metabolic syndrome, cancer (particularly breast and colorectal), and cardiovascular disease, consistent with disrupted circadian regulation of cell-cycle checkpoints, repair processes, and immune surveillance.
• Social jet lag (>1–2 hr difference between weekday and weekend sleep timing) correlates with higher BMI, elevated CRP, and insulin resistance in population studies — all hallmarks of accelerated aging. needs-replication for hard-endpoint evidence.
• Chronotype-aligned sleep (sleeping at one’s natural preferred time) is associated with lower cardiometabolic risk than chronotype-misaligned sleep of equal duration.

This mechanism is relevant to altered-intercellular-communication: circadian disruption impairs time-dependent intercellular signaling (e.g., glucocorticoid pulsatility, growth hormone rhythms, immune oscillations) that coordinate tissue-level homeostasis.

Interventional approaches

Approach	Target population	Evidence level	Notes
CBT-i (Cognitive Behavioral Therapy for Insomnia)	Chronic insomnia; any age	Strong — gold standard; outperforms pharmacotherapy long-term	Comprises sleep restriction therapy, stimulus control, sleep hygiene, relaxation; delivered 4–8 sessions; digital (dCBT-i) formats validated
Sleep hygiene	General population	Moderate — as standalone, weak; as adjunct, standard of care	Fixed wake time, darkness, temperature, caffeine cutoff, screen light minimization
Bright light therapy	Circadian phase disorders, delayed or advanced sleep phase, shift workers, seasonal mood	Moderate	Morning bright light (>10,000 lux) advances circadian phase; evening avoidance delays it
CPAP	OSA (AHI >15 or symptomatic)	Strong for symptomatic relief and cardiovascular risk; variable for mortality	Adherence is the rate-limiting factor
Chronotype-aligned scheduling	Social jet lag, shift work	Emerging	Aligning sleep timing to chronotype reduces misalignment burden; employer/school-schedule dependent
Pharmacological hypnotics	Short-term only; not recommended in elderly	Caution — benzodiazepines and Z-drugs associated with excess mortality, fall risk, cognitive impairment, and in the elderly with dementia risk in long-term use	NOT recommended as an aging intervention; opposite of restorative

CBT-i is first-line for chronic insomnia by AASM guidelines; pharmacological hypnotics should not be considered as aging-biology interventions.

Biological-age clock effects

The Waziry 2023 CALERIE trial established DunedinPACE as the clock most sensitive to metabolic lifestyle interventions; sleep-focused RCTs with DunedinPACE primary endpoints have not yet been completed ⁷. Observational data suggest:

• Short sleep (<6 hr) is associated with accelerated epigenetic aging by multiple clocks in cross-sectional analyses, but causal direction is uncertain.
• The proposed RCT (sleep extension + CBT-i, 18 months, DunedinPACE primary endpoint in short-sleeping middle-aged adults) would provide the cleanest causal evidence.

See dunedinpace-2022 for clock methodology and cross-intervention comparison. needs-replication — no RCT with biological-age-clock primary endpoint has been completed for sleep interventions as of 2026.

2025–2026 sleep × biological-age-clock cohort and MR evidence

The observational and Mendelian-randomization base for sleep × epigenetic clocks expanded substantially in 2025–2026:

Diao 2025 (Clin Epigenetics, Dongfeng-Tongji cohort, n=3,566 mean age 65.5 yr): Healthy sleep score (composite of bedtime, duration, quality, midday napping) inversely associated with PhenoAgeAccel (β=−0.208, p<0.05), GrimAgeAccel (β=−0.107), DunedinPACE (β=−0.008), and DNAm mortality risk score (β=−0.019). DunedinPACE mediated 6.2% (95% CI 0.8–11.5%) of the inverse association between healthier sleep and reduced all-cause mortality risk over 5.4 years follow-up ⁸. Stronger associations in older adults than younger (interaction p=0.027 for DunedinPACE). This is the first study to formally quantify the mediation fraction of sleep → mortality through DunedinPACE.

Wu 2025 (Aging (Albany NY), UK Biobank n=442,664): Restricted-cubic-spline + Mendelian-randomization analysis of self-reported sleep duration on PhenoAgeAccel, BioAgeAccel, and leukocyte telomere length ⁹. Observational analyses confirmed the U-shape (optimum ~7 h/d). MR analyses corroborated the deleterious impact of insufficient sleep but not excessive sleep, suggesting the long-sleep association is largely driven by reverse causation (illness → more sleep), while short sleep has a causal contribution. Cell-type enrichment linked short sleep to BioAgeAccel and LTL through muscle-maintenance and immune-function pathways. This refines the U-shape framing — for short sleep, the causal arrow is supported; for long sleep, residual confounding likely dominates.

Zhang 2026 (Clin Epigenetics, MR for chronotype, napping, sleep duration): Multivariable MR (MVMR) on chronotype, napping, and sleep duration vs telomere length, facial aging, IEAA/HannumAge/PhenoAge/GrimAge, frailty, and cognitive performance ¹⁰. Daytime napping had causal independent effects on GrimAge (β=+1.08, p=0.046) and frailty (β=+0.29, p<0.001); longer sleep duration independently protected against frailty (β=−0.36, p<0.001); chronotype (morningness) protected facial aging and cognition after MVMR adjustment. The napping-causal-on-GrimAge finding is novel and adds a sleep-trait dimension beyond duration.

O’Toole 2025 (medRxiv, MULTI study Sleep Chart): Across 23 biological-age clocks spanning 17 organ/tissue systems and 3 omics types, both short (<6 h) and long (>8 h) sleep durations associated with elevated biological-age gaps, with optimal varying by organ and sex (6.4–7.8 h) ¹¹. Preprint; provides multi-organ resolution beyond the single-clock framing typical of prior studies.

Implication for the U-shape: The pooled epidemiological U-shape (optimum 7 h) replicates across multiple modern cohorts, multi-organ clocks, and MR designs. The new MR work strengthens the causal interpretation for the short-sleep arm of the curve while attenuating it for the long-sleep arm. Mediation through DunedinPACE is now quantified at ~6% of the sleep → mortality effect.

Cross-organism extrapolation

Most foundational sleep-aging biology (especially glymphatic clearance) is from rodent models. Translation to humans is supported by the conservation of AQP4-expressing astrocytes and the paravascular anatomy, but direct human glymphatic flow quantification remains technically limited.

Dimension	Status	Notes
Pathway conserved in humans?	yes	Glymphatic system anatomically confirmed in humans; AQP4 present
Phenotype conserved in humans?	yes	Sleep deprivation → inflammation, cognitive impairment well-replicated in humans
Replicated in humans?	yes (observational); in-progress (intervention RCTs)	Epidemiological signal strong; mechanistic RCTs ongoing

Limitations and open gaps

• Causal vs correlational sleep-mortality relationship: Long sleep is likely partly explained by reverse causality (illness → more sleep). Short sleep’s causal contribution to mortality vs confounding by lifestyle (shift work, stress) is not fully resolved. contradictory-evidence
• Optimal sleep duration varies by individual: U-shaped curve pooled across populations; individual optima may differ by genetics (e.g., BHLHE41 “short-sleeper” variants), age, and health status. dose-response-unclear
• Glymphatic clearance in humans: Quantitative rates measured only indirectly; the “~60% increase in interstitial space volume during sleep” figure is from adult mouse studies (Xie et al. 2013, Nedergaard lab) and may not transfer quantitatively to humans ³. needs-human-replication
• OSA + aging-clock causation: Whether treating OSA with CPAP reverses epigenetic-age acceleration is unresolved. needs-replication
• Sleep as intervention vs marker: Poor sleep may be downstream of other aging processes (neurodegeneration, chronic pain, nocturia) as much as upstream. Disentangling the direction is essential for intervention design.
• No head-to-head RCT: CBT-i vs light therapy vs chronotype-alignment vs pharmacological sleep aid on aging-biology endpoints. needs-replication

Cross-references

• chronic-inflammation — inflammatory hallmark; sleep deprivation activates TLR4/NF-kB in monocytes
• loss-of-proteostasis — glymphatic Aβ/tau clearance is SWS-dependent
• altered-intercellular-communication — circadian disruption impairs pulsatile intercellular signaling
• mitochondrial-dysfunction — sleep deprivation acutely impairs mitochondrial respiratory efficiency; chronic short sleep linked to mitochondrial fragmentation unsourced
• autophagy — SWS may be a window of elevated autophagic flux; evidence in rodents needs-human-replication
• alzheimers-disease — glymphatic Aβ clearance connects sleep to AD risk
• neurodegeneration — broader neurodegenerative risk; REM sleep behavior disorder precedes alpha-synucleinopathy
• immunosenescence — sleep modulates NK cell activity and T-cell function with age
• frailty — short and long sleep duration both associated with frailty risk; bidirectional relationship
• dunedinpace-2022 — DunedinPACE proposed primary endpoint for sleep-extension RCT
• caloric-restriction — sibling lifestyle intervention; CALERIE DunedinPACE result context
• exercise — synergistic with sleep; exercise improves SWS depth
• intermittent-fasting — circadian-aligned eating (TRE) interacts with sleep timing
• time-restricted-eating — overlapping circadian-alignment mechanism

Footnotes

Footnotes

1. doi:10.1016/j.neuron.2017.02.004 · Mander BA, Winer JR, Walker MP · Neuron 2017 · review · model: human aging cohort studies + translational review · comprehensive review of SWS/SWA decline with aging: ~75–80% reduction in frontal SWA amplitude in older vs young adults (Figure 1B); spindle density and amplitude decline with age, largest in frontal regions; prefrontal cortical gray matter atrophy predicts severity of SWA impairment; slow-oscillation/spindle uncoupling with age predicts overnight hippocampal-neocortical memory consolidation failure; reviews “do older adults need less sleep?” debate — concludes impaired sleep-generating capacity rather than reduced need ↩ ↩² ↩³ ↩⁴

2. doi:10.1126/scitranslmed.3003748 · Iliff JJ, Wang M, Liao Y, et al. (Nedergaard lab) · Science Translational Medicine 2012;4(147):147ra111 · in-vivo (mouse) · model: adult C57BL/6 mice (8–12 weeks), Aqp4-null + NG2-DsRed + Tie2-GFP transgenics; 2-photon in-vivo microscopy + radiolabeled tracer clearance · discovered paravascular CSF-ISF bulk-flow exchange pathway (named “glymphatic system”) dependent on AQP4 water channels on astrocyte endfeet; CSF enters via periarterial space, exits via perivenous drainage; Aqp4 knockout reduced interstitial solute ([³H]mannitol) clearance by ~70%; demonstrated Aβ clearance via this pathway, reduced ~55% in Aqp4-null mice · verified against full PDF ↩

3. doi:10.1126/science.1241224 · Xie L, Kang H, Xu Q, et al. (Nedergaard lab) · Science 2013 · in-vivo (mouse) · model: adult mice; real-time two-photon imaging with fluorescent tracers + EEG recording · sleep increased interstitial space by ~60% vs wakefulness; dramatically accelerated Aβ clearance; glymphatic flow ~2x higher during NREM sleep vs wakefulness · note: PDF download failed (no OA copy available in archive); ~60% figure and attribution confirmed correct per cross-reference with citing literature, but quantitative claims not independently verified against full PDF no-fulltext-access ↩ ↩²

4. doi:10.5665/sleep.4398 · Carroll JE, Carrillo C, Olmstead R, Witarama T, et al. (Irwin lab) · Sleep 2015;38(2):205–211 · in-vivo (human) · experimental crossover (adaptation → baseline → partial sleep deprivation [03:00–07:00 window] → recovery) · n=70 total: 49 older adults (ages 60–84) + 21 younger adults (ages 25–39) · partial sleep deprivation vs baseline sleep; blood collected each morning for monocyte TLR4-stimulated IL-6/TNF-α · age × sleep-loss interaction significant (p<0.05): younger adults showed increased TLR4-stimulated inflammation after sleep deprivation; older adults showed REDUCED baseline TLR4-stimulated inflammation, not further activated by sleep loss · note: PDF download failed (bronze OA, URL mismatch); verified via publisher abstract only — quantitative values approximate ↩ ↩²

5. doi:10.1161/JAHA.117.005947 · Yin J, Jin X, Shan Z, et al. · Journal of the American Heart Association 2017 · meta-analysis · 67 articles (141 independent reports); n=3,582,016 total participants; 241,107 all-cause deaths · U-shaped dose-response: lowest all-cause mortality at ~7 hr/day; short sleep (<7 hr): pooled RR 1.06 (95% CI 1.04–1.07) per 1-hr reduction; long sleep (>7 hr): pooled RR 1.13 (95% CI 1.11–1.15) per 1-hr increment; cardiovascular events similar U-shaped pattern · nonlinear dose-response analysis; reference category 7 hr ↩

6. doi:10.1093/sleep/33.5.585 · Cappuccio FP, D’Elia L, Strazzullo P, Miller MA · Sleep 2010 · meta-analysis · n=1,382,999 across 16 studies (27 independent cohort samples); 112,566 deaths · short sleep (≤5–7 hr depending on study) RR 1.12 (95% CI 1.06–1.18); long sleep (>8 hr in most studies) RR 1.30 (95% CI 1.22–1.38) for all-cause mortality · results expressed as RR (relative risk), not OR ↩

7. Waziry R et al. 2023 — doi:10.1038/s43587-022-00357-y — CALERIE II DunedinPACE result: this was a caloric-restriction trial, not a sleep intervention. Cited here as methodological comparator for DunedinPACE sensitivity. See caloric-restriction § Biomarker effects for full detail. ↩

8. doi:10.1186/s13148-025-01898-w · Diao T, Liu K, Zhou L, Wang Q, Lyu J, Zhu Z, Chen F, Qin W, Yang H, Wang C, Zhang X, Wu T · Clin Epigenetics 2025;17(1):87 · cross-sectional + prospective cohort (Dongfeng-Tongji 2013–2018) · n=3,566 (mean age 65.5; 426 deaths over 5.4 yr) · sleep score (0–4: bedtime, duration, quality, midday napping) → PhenoAgeAccel β=−0.208, GrimAgeAccel β=−0.107, DunedinPACE β=−0.008, DNAm MS β=−0.019 (all p<0.05); stronger in older adults (interaction p=0.027 DunedinPACE); slower DunedinPACE mediated 6.2% (95% CI 0.8–11.5%) of sleep-score → all-cause-mortality association · PMID 40442824 · PMC12123996 ↩

9. doi:10.18632/aging.206306 · Wu X, Zhao X, Ge A, Han Z, Hou C, Hao Y, Xiao J, Fan M, Burgess S, Li J, Jiang X · Aging (Albany NY) 2025;17(8):2126–2151 · n=442,664 (UK Biobank) · multivariable linear regression + restricted cubic splines + Mendelian randomization · self-reported sleep duration → PhenoAgeAccel, BioAgeAccel, leukocyte telomere length · observational U-shape with optimum ~7 h/d; MR analyses corroborate deleterious effect of insufficient (short) sleep but not excessive (long) sleep, suggesting long-sleep effect partly reflects reverse causation; cell-type enrichment links short sleep to BioAgeAccel/LTL via muscle and immune-function pathways · PMID 40856643 · PMC12422793 ↩

10. doi:10.1186/s13148-026-02068-2 · Zhang Z, Wang X, Qiu H, Luo Q, Jiang C, Yang G · Clin Epigenetics 2026;18(1):43 · 2-sample MR (UVMR + MVMR) using GWAS instruments for chronotype, daytime napping, sleep duration · outcomes: telomere length, facial aging, IEAA/HannumAge/PhenoAge/GrimAge, frailty index, cognitive performance · UVMR napping → telomere β=−0.11 (p=0.002), facial aging β=+0.05 (p=0.036), GrimAge β=+0.96 (p=0.048), frailty β=+0.32 (p<0.001); MVMR napping retained associations with GrimAge (β=+1.08, p=0.046) and frailty (β=+0.29, p<0.001); chronotype (morningness) protected facial aging and cognition after MVMR; sleep duration independently protected against frailty (β=−0.36, p<0.001) · PMID 41821113 · PMC12980927 ↩

11. doi:10.1101/2025.08.08.25333313 · MULTI study; O’Toole CK, Song Z, Anagnostakis F, et al. (Wen J et al., includes Belsky DW, Ferrucci L, Resnick SM, Walker KA) · medRxiv preprint 2025 Aug 11 · cross-omics, cross-organ analysis of sleep duration vs 23 biological-age clocks across 17 organ/tissue systems and 3 omics types (imaging, proteomics, metabolomics) · U-shaped pattern across 9 brain/body systems and 3 omics; optimal sleep range varied by organ and sex (6.4–7.8 h); short and long sleep both associated with increased systemic disease risk and all-cause mortality; MR did not show strong reverse-causal effects from disease to sleep · interactive portal: labs-laboratory.com/sleepchart · preprint; not yet peer-reviewed · PMID 40832429 · PMC12363694 ↩