Abstract
Maintenance of cellular energy homeostasis, counterbalanced by cellular stress response and an adequate cellular housekeeping are the hallmarks of improved healthspan and lifespan. Mammalian target of rapamycin (mTOR) is a central cell growth regulator that integrates cellular growth and proliferation with nutrient status of the cell. It is an intracellular nutrient sensor that controls protein synthesis, cell growth and metabolism. mTOR turns off stress resistance and autophagy and activates translation. Available scientific evidence endorses that molecular inhibition of this pathway slows aging, extends lifespan and improves symptoms of diverse array of age-related diseases in wide range of species. Rapamycin, a small molecule inhibitor of the protein kinase mTOR, has been found to extend the lifespan of model organisms including mice. Many of such inhibitors of this pathway are already characterized and clinically approved. In the present chapter, we summarize current understanding of mTOR and its role in aging and age-related disease progression.
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References
Alvers AL, Wood MS, Hu D et al (2009) Autophagy is required for extension of yeast chronological life span by rapamycin. Autophagy 5:847–849. https://doi.org/10.4161/auto.8824
Anisimov VN, Zabezhinski MA, Popovich IG et al (2011) Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 10:4230–4236. https://doi.org/10.4161/cc.10.24.18486
Blagosklonny MV (2010) Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans). Cell Cycle 9:683–688. https://doi.org/10.4161/cc.9.4.10766
Blagosklonny MV (2012) Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging. Aging 4:159–165. https://doi.org/10.18632/aging.100443
Chen C, Liu Y, Liu Y, Zheng P (2009) mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2:ra75–ra75. https://doi.org/10.1126/scisignal.2000559
Demidenko ZN, Blagosklonny MV (2008) Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle 7:3355–3361. https://doi.org/10.4161/cc.7.21.6919
DeYoung MP, Horak P, Sofer A et al (2008) Hypoxia regulates TSC1/2 mTOR signaling and tumor suppression through REDD1-mediated 14 3 3 shuttling. Genes Dev 22:239–251. https://doi.org/10.1101/gad.1617608
Ehninger D, Neff F, Xie K (2014) Longevity, aging and rapamycin. Cell Mol Life Sci 71:4325–4346. https://doi.org/10.1007/s00018-014-1677-1
Fischer KE, Gelfond JAL, Soto VY et al (2015) Health effects of long-term rapamycin treatment: the impact on mouse health of enteric rapamycin treatment from four months of age throughout life. PLoS One 10:e0126644. https://doi.org/10.1371/journal.pone.0126644
Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221:3–12. https://doi.org/10.1002/path.2697
Goberdhan DCI, Wilson C, Harris AL (2016) Amino acid sensing by mTORC1: intracellular transporters mark the spot. Cell Metab 23:580–589. https://doi.org/10.1016/j.cmet.2016.03.013
Gwinn DM, Shackelford DB, Egan DF et al (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226. https://doi.org/10.1016/j.molcel.2008.03.003
Hansen M, Chandra A, Mitic LL et al (2008) A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 4:e24. https://doi.org/10.1371/journal.pgen.0040024
Harrison DE, Strong R, Sharp ZD et al (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. https://doi.org/10.1038/nature08221
He L, Lu J, Yue Z (2013) Autophagy in ageing and ageing-associated diseases. Acta Pharmacol Sin 34:605–611. https://doi.org/10.1038/aps.2012.188
Inoki K, Ouyang H, Li Y, Guan K-L (2005) Signaling by target of rapamycin proteins in cell growth control. Microbiol Mol Biol Rev 69:79–100. https://doi.org/10.1128/MMBR.69.1.79-100.2005
Inoki K, Ouyang H, Zhu T et al (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126:955–968. https://doi.org/10.1016/j.cell.2006.06.055
Johnson SC, Rabinovitch PS, Kaeberlein M (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493:338–345. https://doi.org/10.1038/nature11861
Kaplan B, Qazi Y, Wellen JR (2014) Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev 28:126–133. https://doi.org/10.1016/j.trre.2014.03.002
Kunz J, Henriquez R, Schneider U et al (1993) Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73:585–596
Lamming DW, Ye L, Sabatini DM, Baur JA (2013) Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Investig 123:980–989. https://doi.org/10.1172/JCI64099
Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293. https://doi.org/10.1016/j.cell.2012.03.017
Lee S-G, Kaya A, Avanesov AS et al (2017) Age-associated molecular changes are deleterious and may modulate life span through diet. Sci Adv 3:e1601833. https://doi.org/10.1126/sciadv.1601833
Mendoza MC, Er EE, Blenis J (2011) The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci 36:320–328. https://doi.org/10.1016/j.tibs.2011.03.006
Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016–1023. https://doi.org/10.1038/ncb2329
Miller RA, Harrison DE, Astle CM et al (2014) Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 13:468–477. https://doi.org/10.1111/acel.12194
Morris RE (1992) Rapamycins: antifungal, antitumor, antiproliferative, and immunosuppressive macrolides. Transplant Rev 6:39–87. https://doi.org/10.1016/S0955-470X(10)80014-X
Oh WJ, Jacinto E (2011) mTOR complex 2 signaling and functions. Cell Cycle 10:2305–2316. https://doi.org/10.4161/cc.10.14.16586
Pan Y, Schroeder EA, Ocampo A et al (2011) Regulation of yeast chronological life span by TORC1 via adaptive mitochondrial ROS signaling. Cell Metab 13:668–678. https://doi.org/10.1016/j.cmet.2011.03.018
Periyasamy-Thandavan S, Jiang M, Schoenlein P, Dong Z (2009) Autophagy: molecular machinery, regulation, and implications for renal pathophysiology. Am J Physiol Renal Physiol 297:F244–F256. https://doi.org/10.1152/ajprenal.00033.2009
Peterson TR, Laplante M, Thoreen CC et al (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137:873–886. https://doi.org/10.1016/j.cell.2009.03.046
Ruetenik A, Barrientos A (2015) Dietary restriction, mitochondrial function and aging: from yeast to humans. Biochim Biophys Acta (BBA) – Bioenerg 1847:1434–1447. https://doi.org/10.1016/j.bbabio.2015.05.005
Sabatini DM, Erdjument-Bromage H, Lui M et al (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78:35–43
Sabers CJ, Martin MM, Brunn GJ et al (1995) Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270:815–822
Sancak Y, Thoreen CC, Peterson TR et al (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25:903–915. https://doi.org/10.1016/j.molcel.2007.03.003
Sancak Y, Bar-Peled L, Zoncu R et al (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303. https://doi.org/10.1016/j.cell.2010.02.024
Saraswat K, Rizvi SI (2017) Novel strategies for anti-aging drug discovery. Expert Opin Drug Discov 12:955–966. https://doi.org/10.1080/17460441.2017.1349750
Schneider A, Younis RH, Gutkind JS (2008) Hypoxia-induced energy stress inhibits the mTOR pathway by activating an AMPK/REDD1 signaling Axis in head and neck squamous cell carcinoma. Neoplasia 10:1295–1302. https://doi.org/10.1593/neo.08586
Sengupta S, Peterson TR, Sabatini DM (2010) Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 40:310–322. https://doi.org/10.1016/j.molcel.2010.09.026
Showkat M, Beigh MA, Andrabi KI (2014) mTOR signaling in protein translation regulation: implications in cancer genesis and therapeutic interventions. Mol Biol Int 2014:1–14. https://doi.org/10.1155/2014/686984
Singh AK, Kashyap MP, Tripathi VK et al (2016) Neuroprotection through rapamycin-induced activation of autophagy and PI3K/Akt1/mTOR/CREB signaling against amyloid-β-induced oxidative stress, synaptic/neurotransmission dysfunction, and neurodegeneration in adult rats. Mol Neurobiol. https://doi.org/10.1007/s12035-016-0129-3
Singh AK, Garg G, Singh S, Rizvi SI (2017a) Synergistic effect of rapamycin and metformin against age-dependent oxidative stress in rat erythrocytes. Rejuvenation Res 20:420–429. https://doi.org/10.1089/rej.2017.1916
Singh AK, Singh S, Garg G, Rizvi SI (2017b) Rapamycin mitigates erythrocyte membrane transport functions and oxidative stress during aging in rats. Arch Physiol Biochem 1–9. https://doi.org/10.1080/13813455.2017.1359629
Tee AR, Manning BD, Roux PP et al (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 13:1259–1268. https://doi.org/10.1016/S0960-9822(03)00506-2
Thedieck K, Polak P, Kim ML et al (2007) PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One 2:e1217. https://doi.org/10.1371/journal.pone.0001217
Wang L, Harris TE, Roth RA, Lawrence JC (2007) PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 282:20036–20044. https://doi.org/10.1074/jbc.M702376200
Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484. https://doi.org/10.1016/j.cell.2006.01.016
Xu J, Ji J, Yan X-H (2012) Cross-talk between AMPK and mTOR in regulating energy balance. Crit Rev Food Sci Nutr 52:373–381. https://doi.org/10.1080/10408398.2010.500245
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Saraswat, K., Kumar, R., Rizvi, S.I. (2018). Inhibition of mTOR Signalling: A Potential Anti-aging Drug Strategy. In: Rizvi, S., Çakatay, U. (eds) Molecular Basis and Emerging Strategies for Anti-aging Interventions. Springer, Singapore. https://doi.org/10.1007/978-981-13-1699-9_10
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DOI: https://doi.org/10.1007/978-981-13-1699-9_10
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