Diminished mTOR signaling: a common mode of action for endocrine longevity factors

Abstract

Since the initial observation that a calorie-restricted (CR) diet can extend rodent lifespan, many genetic and pharmaceutical interventions that also extend lifespan in mammals have been discovered. The mechanism by which CR and these other interventions extend lifespan is the subject of significant debate and research. One proposed mechanism is that CR promotes longevity by increasing insulin sensitivity, but recent findings that dissociate longevity and insulin sensitivity cast doubt on this hypothesis. These findings can be reconciled if longevity is promoted not via increased insulin sensitivity, but instead via decreased PI3K/Akt/mTOR pathway signaling. This review presents a unifying hypothesis that explains the lifespan-extending effects of a variety of genetic mutations and pharmaceutical interventions and points towards new molecular pathways which may also be leveraged to promote healthy aging.

Keywords: Calorie restriction; Insulin resistance; Longevity; Rapamycin.

Figure 1

The PI3K/Akt/mTOR signaling pathway. Insulin, amino acids and glucose stimulate signaling through the PI3K/Akt/mTOR signaling pathway to regulate ribosomal biogenesis, translation, autophagy, and metabolism and stress resistance.

Figure 2

Regulation of PI3K/Akt/mTOR signaling by growth hormone, IGF-1, leptin and adiponectin. Growth hormone signaling promotes the expression of IGF-1 by the liver and adipose tissue, which signals through the insulin/IGF-1 receptor to promote PI3K/Akt/mTORC1 signaling and aging. Several mutant mice, such as the Ames Dwarf mouse, are deficient for the production of growth hormone, and consequently have low IGF-1 levels and low mTORC1 activity in IGF-1 sensitive tissues. Growth hormone also normally represses adiponectin, a hormone from white adipose tissue that inhibits mTORC1 activity by activating AMPK. Leptin promotes PI3K/Akt/mTOR signaling via the Jak2-mediated phosphorylation of insulin receptor substrate. Leptin also promotes IGF-1 signaling by stimulating the GH/IGF-1 axis. Functions such as translation and autophagy that impact aging are shown in a green box if stimulated by PI3K/Akt/mTORC1 activity, and gray box if inhibited by PI3K/Akt/mTORC1 activity.

Figure 3

The sexually dimorphic effect of rapamycin treatment. Rapamycin consistently has a stronger effect on average and maximum female lifespan than on male lifespan in both HET3 and C57BL/6 mice. Data taken from (Zhang et al. ; Miller et al. ; Harrison et al. ; Fok et al. 2014b); median lifespan not available for HET3 mice initiated on 14ppm rapamycin at 20 months of age, mean is shown instead.