Insulin as an Accelerator and Brake of Aging: From Molecular Landscape to Clinical Interventions

Population aging poses a significant threat to quality of life and contributes to an increasing medical burden. The concept of healthy aging has emerged to represent an aging process that is relatively well controlled. However, due to the multifaceted hallmarks and complex mechanisms underlying aging, there is a need for novel therapeutic targets to promote healthy aging comprehensively. As a fundamental hormone regulating nutrient anabolism and cell proliferation, insulin plays a central role in the aging process. Insulin resistance (IR), which triggers compensatory insulin secretion, along with β-cell dysfunction and impaired insulin clearance, is an established aging phenotype. These alterations of insulin synergistically contribute to the decline in insulin level and sensitivity during aging, making hyperglycemia a prominent risk factor for healthy aging. The decline of insulin signaling with age is associated with pro-aging effects, particularly by promoting dysregulated nutrient sensing and cellular senescence. Current hypoglycemic agents necessitate careful consideration of their potential pro-aging effects due to the overactivation of insulin signaling. Thus, a critical challenge for targeted interventions is to preserve the hypoglycemic benefits of insulin signaling while mitigating its downstream pro-aging effects. Herein, we analyzed current evidence on the complex changes in insulin synthesis, function, and clearance during aging, concentrating on the roles of insulin in hepatocytes, skeletal muscle cells, and adipocytes in the aging process. Additionally, current anti-aging interventions and their mechanisms were discussed from the perspective of regulating insulin signaling, aiming to provide new strategies and pharmacological targets for promoting healthy aging.