Insulin resistance, aging biology, and non- communicable chronic diseases: a narrative review of bidirectional mechanisms and translational implications.

BACKGROUND: Insulin resistance has been considered a metabolic disorder related to obesity, metabolic syndrome, and type 2 diabetes mellitus. Growing evidence points to possible interactions between insulin resistance and hyperinsulinemia and the biological aging process and age-related non-communicable diseases, like cardiovascular disease, neurodegenerative disorders, sarcopenia, frailty, adipose tissue dysfunction, chronic kidney disease, and liver disease. Most published associations lack causality, and some biological aging mechanisms may also independently increase the risk for both insulin resistance and chronic disease. AIM: In this narrative review, we summarize bidirectional connections between insulin resistance, compensatory hyperinsulinemia, aging biology, and age-related non-communicable diseases and the quality of existing data. METHODS: We performed a structured narrative literature review for mechanistic, translational, omics, epidemiologic, and intervention studies on the connection between insulin resistance and biological mechanisms of aging and chronic disease. RESULTS: Mechanisms of age-related disease that may be affected by insulin resistance include insulin/IGF-1 signaling disruption, hyperinsulinemia, mitochondria dysfunction, oxidative stress, endothelial dysfunction, adipokine imbalance, chronic low-grade inflammation, cell senescence, ectopic lipids accumulation, AGE-RAGE signaling, and autophagy impairment. Aging mechanisms, such as cell senescence, mitochondria dysfunction, inflammaging, altered nutrient sensing, impaired proteostasis, adipose tissue remodeling, and physical inactivity may contribute to insulin resistance. Quality of evidence differs from strong to associative and exploratory depending on disease domain. CONCLUSION: It is important to understand insulin resistance as an important mediator in reciprocal network of connections between metabolism, biological aging, and age-related chronic diseases, rather than one of the causes of aging.