Multimodal circadian reinforcement slows epigenetic aging by coupling central SCN entrainment with peripheral clock‑driven inflammasome suppression

Combining morning bright light, evening blue‑light restriction, time‑restricted feeding, high‑fiber intake, and melatonin supplementation will reduce epigenetic age acceleration more than any single component.

**Mechanistic rationale

The suprachiasmatic nucleus (SCN) synchronizes peripheral clocks via neural and hormonal signals. Morning bright light (>1000 lux within an hour of waking) reinforces SCN output, enhancing BMAL1‑CLOCK transcription in peripheral tissues such as liver, muscle and immune cells 1. Evening avoidance of blue‑rich light prevents melatonin suppression, preserving the nocturnal signal that stabilizes SCN rhythm 2. Time‑restricted feeding confined to an 8‑12 hour daytime window restores peripheral clock gene oscillations in liver and muscle, lowering inflammatory cytokines 1. High‑fiber diets increase colonic short‑chain fatty acid (SCFA) production; butyrate acts as a histone deacetylase inhibitor, promoting BMAL1 expression and shifting chronotype earlier 1. Melatonin, whether supplemented or obtained from tart cherries, scavenges free radicals and amplifies SCN‑driven antioxidant pathways, further protecting clock proteins from oxidative damage 3.

When these cues are delivered together, we predict a synergistic increase in the amplitude of BMAL1 oscillations in peripheral blood mononuclear cells (PBMCs). Robust BMAL1 activity suppresses the NLRP3 inflammasome by reducing ROS‑mediated activation and by promoting transcription of anti‑inflammatory genes such as IL‑10. Simultaneously, elevated fecal butyrate raises systemic HDAC inhibition, which stabilizes PER/CRY complexes and dampens NF‑κB signaling. The combined effect lowers circulating IL‑1β and CRP, decreasing the inflammatory load that drives epigenetic clocks such as GrimAge.

**Testable hypothesis

In a 12‑week parallel‑group randomized controlled trial, participants receiving the full multimodal circadian regimen will exhibit a statistically significant reduction in DNAm GrimAge (Δ ≥ ‑0.5 years) relative to an active control receiving standard sleep hygiene advice. Secondary outcomes will include: (1) increased BMAL1 transcriptional amplitude measured by qPCR in PBMCs collected every 4 h over 24 h at baseline and week 12; (2) higher fecal butyrate concentrations assessed by GC‑MS; (3) lower plasma IL‑1β and NLRP3 activity measured by ELISA and caspase‑1 assay. We will conduct mediation analysis to test whether changes in BMAL1 amplitude and fecal butyrate levels account for >50 % of the GrimAge reduction. Failure to observe these changes would falsify the hypothesis that combined circadian entrainment slows epigenetic aging via peripheral clock‑inflammasome coupling.