Hypothesis

Individuals with the PER3^5/5 genotype experience greater phase‑advancing responses to morning light, which amplifies SCN‑driven sympathetic output and elevates hepatic NAMPT expression, boosting NAD+ levels and SIRT1 activity. This cascade reduces epigenetic age acceleration measured by GrimAge, whereas PER3^4/4 carriers show a blunted response.

Mechanistic Rationale

Morning light (≥30 min before 10 a.m.) entrains the circadian clock via ipRGCs → SCN, advancing melatonin offset and cortisol rise【https://pmc.ncbi.nlm.nih.gov/articles/PMC12502225】. The circadian system is most sensitive to phase‑advancing light within the first 30‑60 min after waking【https://www.bannerhealth.com/healthcareblog/teach-me/sun-gating-and-morning-light-for-better-sleep】. PER3 polymorphisms modulate sensitivity to light‑induced phase shifts【https://www.chronobiologyinmedicine.org/m/journal/view.php?number=167】. Enhanced SCN output increases sympathetic signaling to the liver, upregulating the NAD+ salvage enzyme NAMPT, raising intracellular NAD+ and activating SIRT1 deacetylase. SIRT1 deacetylates histone H3K9 and promotes DNA demethylation at age‑associated CpG sites, slowing epigenetic clocks such as GrimAge. Evening blue light (460‑480 nm) suppresses melatonin and delays the clock by ~2 h【https://www.cdc.gov/niosh/work-hour-training-for-nurses/longhours/mod2/19.html】, contributing to metabolic and cardiovascular risk when mistimed【https://www.health.harvard.edu/healthy-aging-and-longevity/blue-light-has-a-dark-side】. Because no human trials have directly linked optimized light exposure to epigenetic aging biomarkers【https://pmc.ncbi.nlm.nih.gov/articles/PMC12109716】, testing this mechanism fills a critical gap.

Testable Predictions

1. PER3^5/5 participants receiving 30 min of 10,000 lux broad‑spectrum light between 07:00‑09:00 for 4 weeks will show a ≥0.5‑year reduction in GrimAge acceleration relative to baseline, while PER3^4/4 participants will show <0.2‑year change.
2. The magnitude of GrimAge change will correlate with increase in morning salivary cortisol AUC and hepatic NAMPT expression (measured via circulating NAMPT peptide).
3. Evening blue‑light exposure (>2 h of 460‑480 nm light after 20:00) will attenuate or reverse the GrimAge benefit in PER3^5/5 carriers.

Experimental Design

• Population: 120 healthy adults aged 30‑50, stratified by PER3 genotype (60 5/5, 60 4/4).
• Intervention: Randomized crossover; 2‑week washout. Light condition: 10,000 lux broad‑spectrum (peak 460 nm) from 07:00‑09:00; control condition: dim red light (<10 lux) same timing.
• Outcomes: GrimAge acceleration (baseline vs post‑intervention), morning cortisol AUC, plasma NAMPT, melatonin onset, actigraphy‑derived sleep midpoint.
• Analysis: Mixed‑effects model with genotype, condition, and interaction as fixed effects; participant as random effect. Falsification: if no significant genotype‑condition interaction on GrimAge, the hypothesis is refuted.