Hypothesis: Quantitative sensory testing (QST) of pressure and heat pain thresholds reflects the functional state of NAD+-dependent sirtuin activity in sensory neurons, and thus serves as a rapid, noninvasive proxy for epigenetic age acceleration driven by mitochondrial dysfunction and neuroinflammation. Specifically, we predict that individuals with lower pain thresholds exhibit elevated PARP-mediated NAD+ consumption, reduced SIRT1/3 signaling, and increased NLRP3 inflammasome activation in dorsal root ganglia, which concomitantly accelerates DNAmPhenoAge and DNAmGrimAge. Conversely, interventions that boost NAD+ (e.g., NR or NMN supplementation) or inhibit PARP will raise pain thresholds and decelerate epigenetic aging in parallel.

Mechanistic rationale: NAD+ is a cofactor for sirtuins that deacetylate NF‑κB and PGC‑1α, suppressing inflammatory transcription and promoting mitochondrial biogenesis. When NAD+ falls, PARP hyperactivation consumes the remaining pool, further suppressing sirtuins and triggering a vicious cycle of oxidative stress and senescence. Sensory neurons are especially vulnerable because they rely on axonal mitochondria for signal propagation; mitochondrial dysfunction lowers their activation threshold, manifesting as heightened pain sensitivity. At the same time, released ATP from damaged neurons activates P2X7 receptors on microglia, amplifying NLRP3 inflammasome signaling and IL‑1β release, which feeds back to epigenetically age‑associated clocks via histone acetylation changes. This dual pathway explains why clocks that weigh inflammation (DNAmGrimAge, EpInflammAge) correlate strongly with pain outcomes.

Testable predictions: 1) In a cohort of 200 adults aged 40‑70, baseline pressure and heat pain thresholds will negatively correlate with DNAmPhenoAge (r ≈ -0.5) and DNAmGrimAge (r ≈ -0.6) after adjusting for chronological age, sex, and BMI. 2) Participants in the lowest pain‑threshold quintile will show higher plasma NAD+ metabolites indicative of PARP activity (e.g., increased ADP‑ribose) and lower SIRT1 expression in peripheral blood mononuclear cells. 3) A 12‑week randomized trial of NR (500 mg bid) versus placebo will produce a statistically significant increase in pain thresholds (Δ ≥ 15 % change) coupled with a measurable decrease in epigenetic age acceleration (ΔDNAmPhenoAge ≤ -0.5 years) only in the NR arm. 4) Adding a PARP inhibitor (e.g., olaparib low dose) to NR will further amplify these effects, establishing causality.

Falsifiability: If NR fails to improve pain thresholds or epigenetic age despite raising NAD+ levels, or if pain threshold changes dissociate from epigenetic clock shifts, the hypothesis is refuted. Likewise, if PARP inhibition does not augment the NR effect, the proposed NAD+‑PARP‑sirtuin axis in sensory neurons is insufficient to explain the pain‑aging link.

This framework turns a simple bedside algometer into a functional biomarker of biological age, enabling real‑time monitoring of geroprotective interventions without blood draws.