Increased Insulin Sensitivity is Not Required for Extension of Healthy Life Span in Mice via Calorie Restriction

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The biochemistry surrounding insulin and insulin signaling is very well studied in the context of aging. A number of ways to slow aging in laboratory species involve directly manipulating these signaling pathways. Calorie restriction, like a number of other methods of slowing aging, improves insulin sensitivity, and the consensus in the research community has been that some fraction of the benefits to health and longevity that result from a restricted calorie intake are derived from this change to insulin metabolism. Today’s open access paper provides evidence to suggest, surprisingly, that this is not in fact the case. It is possible to block this part of the calorie restriction response, and the effect on health and longevity is much the same.

What, then, are the mechanisms by which calorie restriction produces extension of life span in short-lived species? The evidence to date points towards upregulation of autophagy. Autophagy is the name given to a collection of processes responsible for recycling damaged or unwanted cellular structures and protein machinery. Many methods of slowing aging in laboratory species prominently feature increased autophagy; in principle, cells that are better maintained will experience fewer issues and this results in better tissue function and a slower decline into age-related degeneration. Certainly, it is the case that when autophagy is disabled, then calorie restriction no longer acts to extend life.

Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension

Calorie restriction (CR), a dietary regimen in which calories are reduced without causing malnutrition, extends the lifespan of many diverse species and is the gold standard for interventions that promote the health and longevity of mammals. Importantly, CR extends not only longevity but also healthspan. There has therefore been great interest in identifying the physiological and molecular mechanisms by which CR promotes health and longevity.

In mammals fed a CR diet, one of the most striking and broadly conserved effects is improved sensitivity to insulin. Many dietary and pharmaceutical interventions that extend mammalian lifespan and healthspan likewise promote insulin sensitivity, while conversely, there is a well-known association of insulin resistance with diabetes and poor health. Given the central role of the insulin signaling pathway in the lifespan of worms, flies, and mammals, improved insulin sensitivity has been proposed as an essential mechanism by which a CR diet extends mammalian lifespan. While the effects of CR are systemic, some of its most prominent effects are on adipose tissue; CR reduces adiposity in mammals, mobilizing fat stores in white adipose tissue (WAT) while also activating WAT lipogenesis, which is associated with improved systemic insulin sensitivity and metabolic health.

Despite the strong correlative evidence that CR promotes health and longevity through improved insulin sensitivity, there is clear evidence that insulin sensitivity may not necessarily be essential for healthy aging. Several genetically modified mouse models in which insulin resistance has been induced in one or more tissues have extended lifespan, while mice treated with rapamycin, an inhibitor of the mTOR (mechanistic target of rapamycin) protein kinase that extends lifespan, develop insulin resistance in multiple tissues.

Over the last decade, a critical role for mTOR complex 2 (mTORC2) in the control of organismal metabolism has become apparent. In contrast to the well-known mTOR complex 1 (mTORC1), which functions as a key integrator of many different environmental and hormonal cues, mTORC2 functions primarily as an effector of phosphatidylinositol 3-kinase (PI3K) signaling, contributing to the downstream activation of many kinases, including AKT, by insulin. Deletion of Rictor, which encodes an essential protein component of mTORC2, results in insulin resistance in tissues, including liver, adipose tissue, and skeletal muscle. The organismal consequences of inactivating adipose mTORC2 have been unclear.

While an important role for CR-induced insulin sensitivity in the health and survival benefits of CR has long been assumed, the contribution of improved insulin sensitivity to the benefits of CR has not been directly examined. Here, we have tested the role of CR-induced insulin sensitivity on the metabolic health, frailty, and longevity of mice by placing mice lacking adipose mTORC2 signaling (AQ-RKO) and their wild-type littermates on either ad libitum or CR diets. Critically, the insulin sensitivity of AQ-RKO mice does not improve on a CR diet, enabling us to discern the role of CR-induced insulin sensitivity in CR-induced phenotypes. Although the WAT of AQ-RKO mice has a blunted metabolic response to CR and female AQ-RKO mice fed an ad libitum diet have a slightly reduced lifespan, we find that AQ-RKO mice of both sexes fed a CR diet have increased fitness and extended lifespan. We conclude that the CR-induced increase in insulin sensitivity is dispensable for the effects of CR on fitness and longevity.

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