Early melatonin supplementation partially delays gastrointestinal aging

Oxidative stress is a pivotal initiator of organismal aging. Targeted antioxidant interventions can effectively slow this process; however, the optimal timing for these interventions remains controversial. In this study, we observed that with advancing age, the gastrointestinal tract of mice exhibited a progressive increase in oxidative stress, which was accompanied by a gradual decline in connexin 43 expression in the gastrointestinal mesothelium, without any detectable loss of mesothelial cells. Notably, the decrease in mesothelial connexin 43 was observed beginning at 16 months of age in mice, roughly equivalent to 50 years in humans, and occurred prior to the loss of enteric neurons and interstitial cells of Cajal. The administration of the antioxidant melatonin to 16-month-old mice significantly ameliorated oxidative stress, mitigated reduction in connexin 43, and attenuated degenerative alterations in the gastrointestinal tract, suggesting that connexin 43 expression may serve as a candidate morphological indicator for assessing gastrointestinal aging and the effectiveness of early antioxidant interventions in the clinic. Our findings demonstrate that the early stage of gastrointestinal aging is characterized by reversible functional impairments; timely and appropriate interventions during this period can partially delay gastrointestinal aging trajectory.