Cellular and molecular mechanisms underlying aging-related gastric neuromuscular dysfunction

Aging is linked to a gradual decline in the gastric motor function, contributing to reduced food intake, and its association with frailty and sarcopenia. A key cellular change in the gastric neuromuscular apparatus is the loss of interstitial cells of Cajal (ICC), pacemaker cells of the gut. The ICC function as pacemakers that generate electrical slow waves and mediate enteric neurotransmission, playing a critical role in gastric motility. Aging-related ICC depletion leads to impaired gastric compliance and reduced slow wave activity, which contributes to early satiety and reduced food intake. Recent studies have elucidated the molecular and epigenetic mechanisms underlying aging-related ICC decline, highlighting the roles of ICC stem/precursor cells (ICC-SCs), transformation-related protein 53 (TRP53), extracellular signal-regulated kinase (ERK), and insulin-like growth factor 1 (IGF1) pathways, and epigenetic regulation mediated by the histone methyltransferase enhancer of zeste 2 (EZH2). By synthesizing the current findings, this review aims to provide a comprehensive understanding of the mechanisms driving ICC decline and to explore potential therapeutic strategies for preserving gastric motility in aging populations. Future research should aim to translate these discoveries into clinical applications to improve the gastric motor function and overall health in the aging population. Identifying effective interventions targeting ICC maintenance may ultimately help to alleviate age-related gastric motor dysfunction and its associated health burdens, including frailty, malnutrition, and impaired quality of life.