Sirtuins as Molecular Mediators of Caloric Restriction in the Pancreas: Implications for β-Cell Function, Metabolism,...

Caloric restriction (CR), defined as a 30-60% decrease in ad libitum food intake without malnutrition, has emerged as one of the most robust non-pharmacological interventions for promoting metabolic health and longevity in various species, including yeast, worms, flies, rodents, and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer, and cardiovascular disorders) in mammals. Among the key organs influenced by CR, the pancreas-particularly the insulin-producing β-cells-plays a central role in maintaining glucose homeostasis and metabolic balance. A growing body of evidence suggests that CR exerts its beneficial effects, at least in part, through the modulation of nutrient-sensing pathways and epigenetic regulators. Sirtuins, a family of NAD⁺-dependent deacetylases and ADP-ribosyltransferases, have gained attention as pivotal molecular mediators of CR. By responding to changes in cellular energy status, sirtuins regulate diverse processes including gene expression, oxidative stress response, mitochondrial function, and autophagy. In the pancreas, sirtuins such as SIRT1, SIRT3, and SIRT6 have been implicated in preserving β-cell function, enhancing insulin secretion, and protecting against metabolic stress and inflammation. This review critically examines current evidence regarding the role of individual sirtuins in mediating the pancreatic response to caloric restriction, with particular emphasis on β-cell physiology, insulin secretion, mitochondrial function, autophagy, oxidative stress, and inflammatory signaling. We further discuss how these molecular mechanisms contribute to systemic metabolic homeostasis and may influence healthy longevity. Importantly, we integrate experimental findings with emerging clinical evidence demonstrating the recovery of β-cell function following dietary energy restriction and identify current controversies, limitations, and key knowledge gaps that should guide future translational research. Collectively, available evidence suggests that sirtuins represent central molecular links between caloric restriction and β-cell adaptation, highlighting their potential as therapeutic targets for preserving pancreatic function and preventing metabolic disease.