Inhibition of the Mechanistic Target of Rapamycin (mTOR)-Rapamycin and Beyond

Abstract

Rapamycin is a Food and Drug Administration (FDA)-approved immunosuppressant and anticancer agent discovered in the soil of Easter Island in the early 1970s. Rapamycin is a potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, which acts as a central integrator of nutrient signaling pathways. During the last decade, genetic and pharmaceutical inhibition of mTOR pathway signaling has been found to promote longevity in yeast, worms, flies, and mice. In this article, we will discuss the molecular biology underlying the effects of rapamycin and its physiological effects, evidence for rapamycin as an antiaging compound, mechanisms by which rapamycin may extend life span, and the potential limitations of rapamycin as an antiaging molecule. Finally, we will discuss possible strategies that may allow us to inhibit mTOR signaling safely while minimizing side effects, and reap the health, social, and economic benefits from slowing the aging process.

Figure 1.

The mechanistic target of rapamycin (mTOR) signaling pathway. Rapamycin is an acute inhibitor of mTOR complex 1 (mTORC1), which phosphorylates substrates including S6 kinase 1 (S6K1), eIF4E-binding protein 1 (4E-BP1), transcription factor EB (TFEB), unc-51-like autophagy-activating kinase 1 (Ulk1), and growth factor receptor-bound protein 10 (GRB-10). Rapamycin dosed chronically also inhibits mTOR complex 2 (mTORC2), which regulates the phosphorylation of Akt, serum/glucocorticoid regulated kinase (SGK), and members of the protein kinase C (PKC) family. mTORC2 is primarily responsive to insulin/insulin-like growth factor 1 (IGF-1) signaling, whereas mTORC1 is sensitive to insulin as well as amino acids and glucose. AMPK, Adenosine monophosphate-stimulated kinase.

Figure 2.

Sexually dimorphic impact of rapamycin and genetic interventions in the insulin/insulin-like growth factor 1 (IGF-1)/mechanistic target of rapamycin (mTOR)-signaling pathway. (A,B) Treatment with 14 ppm rapamycin begun at 9 mo of age extends the life span of genetically heterogeneous HET3 (A) males and (B) females. (C) Rapamycin and genetic interventions in the insulin/IGF-1/mTOR-signaling pathway that promote life span have a stronger effect on median female life span than on male life span (data from Holzenberger et al. 2003; Harrison et al. 2009; Selman et al. 2009, 2011; Lamming et al. 2012; Nojima et al. 2013; Fok et al. 2014b; Miller et al. 2014; Zhang et al. 2014). Mean life span is shown for HET3 mice initiated on 14 ppm rapamycin at 20 mo of age as median is not available. (Panels A and B from Miller et al. 2011a; reprinted by permission of Oxford University Press.)

Figure 3.

Haploinsufficiency of Rictor, but not Akt, significantly decreases male life span. (A) Kaplan–Meier plots showing life spans of male and female mice heterozygous for Rictor. (B) Kaplan–Meier survival plots showing life spans of mice heterozygous for Akt. (Panel A from Lamming et al. 2014b; reprinted, with permission, from the author. Panel B from Nojima et al. 2013; adapted, with permission, from the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium.)