The Role of mTOR Signaling in Controlling Mammalian Life Span: What a Fungicide Teaches Us About Longevity

Encouraging results with rapamycin suggest that the mammalian target of rapamycin (mTOR) is a promising pharmacological target for prolongevity intervention in mammals. In theory, such an approach mimics food, energy, and/or growth factor restriction, both of which have proven to be effective in animal models but are not practical for people interested in maximizing the healthy years of their life. In a recent mouse survival study conducted by the National Institute of Aging Intervention Testing Program (ITP) (1), mice were treated with rapamycin starting at late middle-aged (∼60 human years). In contrast to food restriction, which has variable, sometimes detrimental, effects in mice when initiated at an advanced age, rapamycin was effective in extending life span of genetically heterogeneous mice when treatment was begun in late life. Camardo has provided an excellent review of the early history of rapamycin (2). The story starts at Ayerst in Montreal, where scientists in the 1970s identified a macrocyclic lactone in a soil sample collected from Rapa Nui (Easter Island). Its original name was rapamycin after the source of the soil and was later designated as sirolimus, which is used in the medical literature. Rapamycin is a metabolite produced by Streptomyces hygroscopicus, a bacterium in the soil, and was first developed as an antifungal agent. Later, it was found to have immunosuppressive effects, which halted its potential use as an antifungal. Antitumor activity was first noted in 1975, but was not actively pursued by Wyeth Ayerst until 1997. Although it failed as a fungicide, rapamycin analogs (rapalogs) are used as an adjunctive therapy in clinics today to prevent host rejection in transplants, as a monotherapy for cancer treatments, and in drug-eluting stents to prevent restenosis of cardiac vessels. Because of the interesting and important effects it has on cells and organisms, much study has been devoted toward understanding its mode of action. Reports in the 1990s showed that adding rapamycin to yeast cultures whose media were replete with nutrients resulted in the cells ignoring the nutrients and entering a state resembling starvation (3). Thus, soil bacteria in an apparent strategy to compete for nutrients in their environment produce a compound whose effect on fungi is a starved phenotype. Could a similar pharmacological approach induce a state similar to caloric restriction in mammalian cells? An evolving understanding of the conserved target of rapamycin (TOR) system in small and large organisms suggested that it is feasible. The TOR in eukaryotic cells is a conserved member of the phosphatidylinositol kinase–related kinase family. Other members are kinases (eg, ataxia telangiectasia mutated; ataxia telangiectasia and Rad3 related; DNA-dependent protein kinase, catalytic subunit) involved in cellular responses to stress such as genomic insults. A unique feature of eukaryotic TOR proteins is an FKBP12/rapamycin-binding (FRB) domain (see Figure 1 and its legend for a description of other important functional domains). In mammalian cells, mTOR participates in two complexes with at least one common subunit, mLST8. Variable subunits that define substrates are Raptor in mammalian TOR complex 1 (mTORC1) and Rictor in mTORC2 (Figure 2). In mammals, mTORC1 is rapamycin sensitive, whereas mTORC2 is insensitive as assessed by Ser 473 phosphorylation, except for a subset of cell types such as U937 (lymphoma) and Jurkat (T-cell leukemia) (15). Eukaryotic translation initiation factor 4E–binding proteins (4EBP) and ribosomal S6 protein kinases (S6K1/2) are well known substrates of mTORC1, which control translation and cell growth (mass), and are probably important readouts for aging. Signaling pathways for mTORC1 are summarized in Figure 2 and its legend. Functional domains of mammalian target of rapamycin (mTOR). The N-terminal half of mTOR is dominated by HEAT (Huntington, Elongation factor 3A, A subunit of PP2A, and Tor1) repeats (green boxes), which likely mediate protein–protein interactions and are required for membrane localization of target of rapamycin (TOR) (4). Next are FAT (FRAP, ataxia telangiectasia mutated, and TTRAP) and FAT-C-terminal (FATC) regions (red boxes), which together likely regulate the Ptdins-3-kinase–related catalytic domain (blue box) (5). Unique to the eukaryotic TOR orthologs is the FKBP12/rapamycin-binding (FRB) domain (green box) to which the FKBP12–rapamycin complex binds to inhibit TOR function. Recent evidence indicates that rapamycin, rapalogs, and other small molecules can interact with the FRB without FKBP12 (6–9). The negative regulatory domain (yellow box) is a repressor domain (10), which is most likely phosphorylated by S6K1 (11). Amino acid coordinates are shown above the map. RAPA = rapamycin. Mamammalian target of rapamycin (mTOR) C1 signaling and theoretical underpinning for its ability to extend lifespan. Growth factors, such as IGF-I, activate mTOR complex 1 (mTORC1) via repression of the tuberous sclerosis complex (TSC)2. Nutrients, such as amino acids, also promote activation of mTORC1. A high AMP/ATP ratio inhibits mTORC1 activation via AMP-activated protein kinase (AMPK). Genotoxic stress will also inhibit mTORC1 via p53. Other cell stresses, such as oxidative stress reactive oxygen species and glucocorticoids (not shown), also will inhibit mTORC1. Under favorable conditions (replete nutrients and low stress inputs), mTORC1 promotes cell growth via regulation of protein synthesis by phosphorylating S6K1 (a kinase that phosphorylates the sixth ribosomal subunit) and 4E-Binding Protein 1 (4E-BP1, a translation repressor that binds the eukaryotic initiation factor 4E). This state is indicated by a larger arrow and is postulated to result in a normal life span with the usual age-related diseases. Calorie restriction (CR) is posited to exert its effect on life-span extension, at least in part, via an inhibition of mTORC1 (Sharp, Strong, and Nelson, in preparation). Likewise, growth factor restriction in pituitary dwarfs is also proposed to extend life span via repression of mTORC1 (12). In calorie-restricted Ames dwarf mice (13), the mTOR output is predicted to be even less activated than in ad-lib fed dwarf mice (not shown in this figure). Chronic treatment by the rapamycin–FK506BP12 complex is also proposed to decrease mTORC1 activity to partially mimic both CR and growth factors restriction (GFR) (14). The size of the arrows indicates each of these states. This figure does not attempt to illustrate the complexity of the mTORC1 and mTORC2 (not shown) signaling system, but rather focus on the elements that are directly related to the calorie and growth factor restriction. Excellent reviews on the mTOR pathways are cited in the main body of this article. GF = growth factors. The importance of mTOR in cell biology is related to the central role it plays in integrating responses to nutrients, changes in energy status, growth factor stimulation, and various types of stress (summarized in Table 1). Table 1 also illustrates the wide range of responses mediated by mTORC1, with new discoveries increasing at a rapid pace. Because of it central role in metabolism, mTOR function is essential for normal growth and development, and inhibition of its function during this period is detrimental to an organism. For the same reason, mTOR has important roles in diverse human diseases. Functions of mTORC1 Note: mTORC1 = mammalian target of rapamycin complex 1; UTR = untranslated region. Functions of mTORC1 Note: mTORC1 = mammalian target of rapamycin complex 1; UTR = untranslated region. Wyeth Ayerst aggressively pursued rapamycin as an antirejection drug, which was ultimately successful. For readers interested in the history of this episode of rapamycin’s history, Camardo (2) provided a detailed account. Its mechanism of action for this purpose is through mTOR, whereas other antirejection drugs such as cyclosporine and tacrolimus (FK 506) target calcineurin, and it is generally well tolerated, with side effects that can be managed clinically (30). A point to make here is that transplant patients, once started on the drug, will likely live the remainder of their lives on it, except if a surgery is anticipated at which time they will be taken off of it because of wound healing problems. This is also a side effect of calorie restriction (CR) (31). Another point is that some of the effects attributed to rapamycin may be due to interactions with other calcineurin-targeted suppressants. Despite its exploitation in many immunosuppressive protocols, a precise understanding of its mode of action in vivo in this setting is lacking. It is becoming clear that rapamycin is an immune modulator (reviewed in 32,33), rather than a strict immune suppressant. In immunity, mTOR has a crucial role in the activation and proliferation of effector T cells. The development of regulatory T cells (T-regs) is restrained by mTOR. In monocytes, macrophages, and peripheral dendritic cells, mTOR promotes anti-inflammatory and restricts proinflammatory responses. In plasmacytoid dendritic cells, mTOR encourages type I interferon production. Thus, as an inhibitor of mTORC1, rapamycin is thought to have varied effects on these vital responses. Further complicating rapamycin’s effects on immunity are reports that it enhances immune memory (34). Consistent with this picture is an article showing that rapamycin enhances, via autophagy, the efficacy of vaccination (35) and inhibits HIV infection (36). Mammalian TOR is a critical effector in the deregulated cell growth and proliferation signaling pathways associated with cancer (37–39), and several lines of investigation support linkages between mTOR and cancer. One unambiguous link between mTOR and cancer is the tuberous sclerosis complex (TSC) 1/2, which is an upstream inhibitor of mTORC1 (see Figure 2). Mutations in Tsc1 or Tsc2 lead to the hamartomatous syndrome TSC, providing a clear molecular connection between mTOR and cancer. These lesions are described as less aggressive compared with other types of cancer, which may be explained by a feedback loop that limits PI3K/Akt signaling (37). Shaw and Cantley (38) pointed out that a common target of two of the major signaling pathways disrupted in cancer is mTOR (Figure 3). Cellular responses to nutrients also target mTOR, emphasizing its role as an integrator of cell growth stimuli (Figure 3). An example is the inactivation of the gene encoding phosphatase and the tensin homolog deleted on chromosome 10 (Pten), that in TSC2-deficient lesions elevates AKT activity resulting in more aggressive tumors (40). Besides TSC, AKT signaling is also aberrant in numerous types of other cancers (41–43) and is critical for activation of mTOR (37). Skeen and colleagues (44) showed that partial ablation of AKT abrogated its tumorigenic potential in vitro and in vivo, an effect abrogated by hyperactivation of mTORC1. 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