Chronic pain sensitivity reflects more than peripheral injury; it mirrors systemic aging processes that are not yet captured by standard clinical panels. We hypothesize that an individual's composite pain threshold across thermal, pressure, and ischemic modalities predicts their intrinsic biological age, as measured by next‑generation epigenetic clocks and inflammaging markers, because low pain thresholds signal mitochondrial NAD+ depletion and NLRP3 inflammasome activation in sensory neurons, which in turn drives a systemic inflammatory milieu and accelerates epigenetic aging.

The mechanistic chain begins with age‑related decline in mitochondrial oxidative phosphorylation in dorsal root ganglia, reducing NAD+ availability. Low NAD+ activates PARP1, consuming cellular NAD+ further and triggering SIRT1 inhibition. This shift promotes NF‑κB signaling and NLRP3 inflammasome assembly, leading to caspase‑1‑dependent release of IL‑1β and IL‑18. These cytokines spill into circulation, raising systemic inflammaging markers (IL‑6, TNF‑α, CRP) and altering DNA methylation patterns tracked by GrimAge and DunedinPoAm. Simultaneously, reduced vagal tone (lower HRV) diminishes cholinergic anti‑inflammatory feedback, creating a feed‑forward loop that amplifies both pain perception and biological aging.

We predict that participants with lower heat, cold, pressure, and ischemic pain thresholds will show: (1) higher GrimAge and DunedinPoAm acceleration independent of chronological age; (2) elevated plasma IL‑6, TNF‑α, CRP; (3) lower resting heart‑rate variability; and (4) increased mitochondrial DNA copy number variance and 8‑oxo‑dG in peripheral blood mononuclear cells. Importantly, these associations should persist after adjusting for comorbid conditions, medication use, and lifestyle factors.

To test this, we will recruit a longitudinal cohort of 500 adults aged 40‑80 years from community centers. At baseline, quantitative sensory testing will determine thresholds for four modalities (heat 44 °C, cold 20 °C, pressure 4 kg, ischemic cuff inflation). Blood will be drawn for epigenetic arrays (Illumina EPIC), inflammaging ELISA panels, mtDNA copy number qPCR, and 8‑oxo‑dG assay. Heart‑rate variability will be recorded during a 5‑minute resting ECG. Follow‑up assessments at 12 and 24 months will repeat the epigenetic clocks and inflammaging panel to compute pace‑of‑change.

Statistical analysis will use mixed‑effects models with pain threshold scores as fixed effects, random intercepts for participants, and covariates for sex, BMI, smoking, and analgesic use. A significant negative association between composite pain threshold score and epigenetic age acceleration (p<0.01 after FDR correction) will support the hypothesis. Conversely, if no relationship remains after full adjustment, the hypothesis is falsified, indicating that pain sensitivity does not uniquely track biological aging beyond conventional risk factors.

This approach integrates neuro‑immunometabolic mechanisms with practical phenotyping, offering a low‑cost, non‑invasive tool that could complement or outperform existing biological age clocks in longitudinal aging research and clinical risk stratification.