Low pain tolerance predicts accelerated epigenetic aging, but the underlying signal may reflect a shared collapse of proteostasis in sensory neurons and pancreatic β‑cells. Both cell types rely heavily on the unfolded protein response (UPR) to manage secretory load, and aging impairs UPR signaling in neurons, leading to small fiber neuropathy and heightened pain perception. We hypothesize that individuals with low experimental pain thresholds exhibit concurrent UPR insufficiency in islets, resulting in chronic ER stress, reduced insulin biosynthesis, and a metabolic age that outpaces chronological age. This mechanistic link would make pain sensitivity a non‑invasive readout of systemic proteostatic capacity, especially for tissues that depend on robust UPR function like the islet.

To test this, we propose a longitudinal cohort of middle‑aged adults without diabetes. At baseline we would measure:

1. Heat pain threshold (HPT) and conditioned pain modulation (CPM) as quantitative pain phenotypes.
2. Epigenetic age using DNAmGrimAge, which is most sensitive to pain intensity and neuropathic features.
3. Islet proteostatic stress via circulating biomarkers: the ratio of proinsulin to insulin (reflecting ER folding efficiency), plasma CHOP and spliced XBP1 (XBP1s) levels, and exosomal miR‑375 enriched for islet origin.
4. Mitochondrial function in peripheral blood mononuclear cells (Seurat OCR/ECAR) and vagal tone (heart‑rate variability) to control for confounding autonomic influences.

We would follow participants for three years, tracking incident prediabetes (HbA1c ≥ 5.7 %) and changes in β‑cell function (fasting C‑peptide, acute insulin response during an OGTT). The primary prediction is that baseline low HPT (high pain sensitivity) will correlate with higher baseline proinsulin/insulin ratio and elevated CHOP/XBP1s, independent of age, sex, BMI, and epigenetic age. Moreover, the pain phenotype will predict faster decline in C‑peptide secretion and greater rise in HbA1c over follow‑up, even after adjusting for DNAmGrimAge. Conversely, if pain sensitivity merely reflects peripheral neuropathy without islet involvement, we would expect no association between HPT and islet stress markers after accounting for SFN severity (skin biopsy intraepidermal nerve fiber density).

A positive result would support a model where sensory neuron pain thresholds serve as a proxy for the cell‑autonomous UPR capacity that governs systemic metabolic aging. It would also suggest that interventions aimed at bolstering proteostasis—such as selective PERK activators or ER‑stress mitigators—might simultaneously improve pain tolerance and preserve β‑cell function, offering a dual‑benefit strategy for aging‑related metabolic decline.