Reviewing the Role of Insulin in Aging
The relationship between insulin metabolism and aging is one of the most studied areas of the field, with decades of researchers putting in time to deepen the understanding of the web of interactions surrounding insulin. Yet this has failed to lead to any practical outcome when it comes to slowing or reversing aging. Researchers now have an incrementally better idea as to why obesity, metabolic syndrome, and type 2 diabetes shorten life and worsen health, but that was well understood to be the case well prior to the advent of modern biotechnology.
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.