Intermittent fasting improves pain tolerance and decelerates epigenetic aging by enhancing mitochondrial resilience and vagal tone.

Recent work links higher pain sensitivity to accelerated epigenetic age, chronic inflammation, and reduced mitochondrial function 1 2. In older adults, painful stimuli trigger exaggerated and prolonged pro-inflammatory cytokine release, which correlates with shorter telomeres and altered immune profiles 3 4. These observations suggest that pain perception mirrors systemic aging processes that are not yet captured by routine blood panels.

We hypothesize that intermittent fasting (IF) simultaneously raises pain thresholds and slows epigenetic age acceleration through a mechanistic loop: fasting elevates intracellular NAD+, activates SIRT1 and SIRT3, thereby improving mitochondrial oxidative phosphorylation and reducing ROS-mediated NF-κB signaling 5 6. Lower mitochondrial ROS diminishes inflammasome activation, leading to attenuated cytokine spikes after nociceptive input. Concomitantly, fasting-induced increases in vagal afferent activity boost acetylcholine release, which further suppresses systemic inflammation via the cholinergic anti-inflammatory pathway and raises the threshold for pain perception. Improved mitochondrial efficiency also enhances ATP-dependent ion pump function in sensory neurons, decreasing ectopic firing and raising pain tolerance.

To test this, we propose a 12-week parallel-group RCT in sedentary adults aged 45-65. Participants will be randomized to either a time-restricted eating protocol (16 h fast/8 h feed) or an isocaloric control diet with matched macronutrients. Primary outcomes: change in pressure pain threshold (algometer) at the trapezius and tibialis anterior, and change in epigenetic age measured by the Horvath clock in peripheral blood mononuclear cells. Secondary outcomes: plasma IL-6, TNF-α, CRP; heart-rate variability (RMSSD) as a vagal tone index; mitochondrial ROS in isolated PBMCs measured by MitoSOX fluorescence.

We predict that the IF group will show a >=15 % increase in pain threshold and a >=1.2-year reduction in epigenetic age acceleration relative to baseline, whereas the control group will show no significant change. Mediation analysis will test whether changes in mitochondrial ROS and HRV significantly account for the effects on both pain tolerance and epigenetic age. Failure to observe these improvements, or demonstration that pain tolerance shifts without corresponding epigenetic changes (or vice versa), would falsify the hypothesis that IF couples pain modulation to aging through the proposed mitochondrial-vagal mechanism.