Reviewing What is Known of Insulin in Aging

When it comes to the mechanisms by which the operation of metabolism determines natural variations in longevity, few areas are as well studied as the role of insulin and insulin-like growth factor (IGF-1). This is no doubt in part due to the size and influence of the type 2 diabetes research community, but it is also the case that most of the methods so far demonstrated to slow aging and extend life in mice, such as calorie restriction, appear to act at least partially through alterations to insulin metabolism and related systems. Here is a review on this topic, with a focus on the brain:

Insulin is the most powerful anabolic hormone discovered to date. Besides the well-established action of insulin in peripheral organs, such as liver, muscle, and adipose tissue, it is becoming increasingly clear that insulin affects important features of glucose metabolism via central mechanisms. Insulin signaling has been linked to longevity in organisms ranging from nematodes to mammals.

There is an impressive body of literature implicating insulin/IGF-1 like ligands and insulin/IGF-1 signaling in the regulation of metabolism, development, and longevity in the roundworm C. elegans. In response to food or the perception of food, multiple insulin-like ligands are secreted from neurosecretory cells in the brain of C. elegans and D. melanogaster, indicating that in these invertebrates, the central nervous system (CNS) plays a key role in insulin signaling mediated regulation of physiology and lifespan in response to environmental cues. In mammals, the insulin/insulin-like growth factor-1 signaling cascade exhibits some striking differences compared to the insulin/insulin-like growth factor-1 signaling cascade in invertebrates. These differences include the acquisition of growth hormone as a main regulator of IGF-1 production by the liver, and the acquisition of separate receptors for insulin and IGF-1. Again, several of the existing long-lived mammalian mutants with defects in insulin/IGF-1 signaling point to a role of the CNS in the regulation of mammalian longevity.

Also in humans, preserved insulin sensitivity has been associated with longevity. Insulin resistance has been shown to predict the development of age-related diseases, including hypertension, coronary heart disease, stroke, cancer, and type 2 diabetes. In the general population, the association between aging and decline in insulin sensitivity has been demonstrated in several studies. Mechanisms suggested to contribute to decreased insulin sensitivity in the elderly include (i) age-related receptor and post-receptor defects in insulin action, (ii) an age-related decrease in insulin stimulated whole body glucose oxidation, (iii) an age-related reduction in beta cell response to glucose, and (iv) impaired insulin-mediated glucose uptake, and inability to suppress hepatic glucose output. In contrast, centenarians, which exhibit exceptional longevity, seem protected against the age-related decline in insulin sensitivity when compared to a group of advanced middle-aged individuals.

We speculate that healthy longevity is associated with preserved brain insulin action. Enhanced insulin efficacy might occur through measures aimed at minimizing inflammation; and enhanced delivery might be promoted to the brain areas that are crucial for healthy longevity. Inflammation, including that occurring in the hypothalamus, has been linked to age-related decline in insulin sensitivity. Physical exercise is known to be protective against numerous diseases and reduction of inflammation has been implicated in the health benefits conferred by exercise. Notably, a lower intake of calories and food that is rich in saturated fat and carbohydrates has been shown to reduce inflammaging. Future research may focus on hypothalamic microglia as relevant targets for prevention and treatment of metabolic disorders.



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