Hypothesis: Chronic circadian disruption (shift work, social jet lag) accelerates epigenetic aging not merely through sleep loss but via desynchronization of NAD+ salvage pathway oscillations from the core CLOCK/BMAL1 transcriptional cycle, creating a feedforward loop of epigenetic drift.

Mechanism: NAMPT (rate-limiting NAD+ salvage enzyme) is transcriptionally regulated by CLOCK/BMAL1. NAD+ oscillations in turn regulate SIRT1 deacetylase activity, which modulates CLOCK acetylation and PER2 deacetylation. When external zeitgebers desynchronize from endogenous oscillators, NAMPT expression loses circadian amplitude, flattening NAD+ oscillations. This reduces peak SIRT1 activity during the active phase, impairing maintenance DNA methylation fidelity at CpG sites normally protected by SIRT1-DNMT1 interactions.

Testable prediction: (1) Shift workers with >10 years exposure will show Horvath epigenetic clock acceleration of 2.5-6 years versus matched day workers, with acceleration correlating to NAMPT circadian amplitude measured in PBMCs. (2) NMN supplementation timed to the biological morning (peak NAMPT window) will attenuate epigenetic clock acceleration by >50% compared to evening-dosed NMN in a crossover design over 6 months. (3) Single-cell ATAC-seq on circadian-disrupted mouse hepatocytes will show loss of rhythmic chromatin accessibility specifically at SIRT1-dependent enhancers, with concurrent gain of H3K9ac (SIRT1 substrate) at these loci.

Intersection with aging-autoimmunity: Circadian NAD+ depletion disproportionately affects regulatory T-cell SIRT1-dependent FOXP3 stabilization, potentially explaining the 2-3x increased autoimmune disease incidence in chronic shift workers. This links geroscience to rheumatic disease through a shared epigenetic-metabolic axis.

Falsification criteria: If NAMPT circadian amplitude shows no correlation with epigenetic age acceleration in shift worker cohorts (r < 0.15, p > 0.2), or if time-of-day NMN dosing shows equivalent epigenetic effects, the oscillation-coupling mechanism is refuted.