Insulin and aging - a disappointing relationship

Experimental studies in animal models of aging such as nematodes, fruit flies or mice have observed that decreased levels of insulin or insulin signaling promotes longevity. In humans, hyperinsulinemia and concomitant insulin resistance are associated with an elevated risk of age-related diseases suggestive of a shortened healthspan. Age-related disorders include neurodegenerative diseases, hypertension, cardiovascular disease, and type 2 diabetes. High ambient insulin concentrations promote increased lipogenesis and fat storage, heightened protein synthesis and accumulation of non-functional polypeptides due to limited turnover capacity. Moreover, there is impaired autophagy activity, and less endothelial NO synthase activity. These changes are associated with mitochondrial dysfunction and oxidative stress. The cellular stress induced by anabolic activity of insulin initiates an adaptive response aiming at maintaining homeostasis, characterized by activation of the transcription factor Nrf2, of AMP activated kinase, and an unfolded protein response. This protective response is more potent in the long-lived human species than in short-lived models of aging research resulting in a stronger pro-aging impact of insulin in nematodes and fruit flies. In humans, resistance to insulin-induced cell stress decreases with age, because of an increase of insulin and insulin resistance levels but less Nrf2 activation. These detrimental changes might be contained by adopting a lifestyle that promotes low insulin/insulin resistance levels and enhances an adaptive response to cellular stress, as observed with dietary restriction or exercise.

Automated summary

Experimental studies have shown that reduced levels of insulin or insulin signaling can promote longevity in animal models of aging, but in humans, high insulin and insulin resistance are associated with an increased risk of age-related diseases. These diseases include neurodegenerative diseases, hypertension, cardiovascular disease, and type 2 diabetes. High levels of insulin can lead to increased fat storage and impaired cell function. The synthesis and metabolism of insulin initiate an adaptive response to maintain homeostasis, which has a stronger pro-aging effect in humans compared to short-lived models. Conversely, adopting a lifestyle that promotes low insulin and insulin resistance levels, such as dietary restriction or exercise, can help mitigate these detrimental changes.