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Chronic Mechanistic Target of Rapamycin Inhibition: Preventing Cancer to Delay Aging or Vice Versa?

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Abstract

Caloric restriction prolongs lifespan and healthspan in all model systems tested thus far, including yeasts, worms, flies, mice, rats, and monkeys (Rhesus macaques). Caloric restriction also improves healthspan, including reducing cancer development in mice and Rhesus macaques. Nonetheless, chronic caloric restriction to prolong life or healthspan, including cancer prevention, is unlikely to be popular or widely adopted for human clinical use. As caloric restriction inhibits mTOR, the pharmacologic mTOR inhibitor, rapamycin, was tested in lifespan extension and clearly prolonged lifespan and healthspan in mice even when started late in life. Although the types and prevalence of cancer in control and rapamycin-fed mice were similar, cancer-related deaths were delayed in mice fed rapamycin, demonstrating potential cancer prevention. Rapamycin and related pharmacologic mTOR inhibitors, collective dubbed “rapalogues,” are considered too dangerous for chronic human use for longevity extension or cancer prevention. Nonetheless, these data raise the interesting possibility that a pharmacologic intervention to suppress mTOR, or more specifically mTORC1, could prolong lifespan or healthspan in humans, including through cancer prevention, provided that a safe and effective agent for these purposes were identified. Many questions remain, including the specific mTOR-related pathway most appropriate for targeting, doses and schedules of specific agents for such purposes, and understanding specific mechanisms of action. The question arises as to whether rapalogues prolong life or delay aspects of aging by preventing cancer. This chapter will examine evidence to date and provide suggestions for major areas of needed research and possibilities for clinical trials and applications.

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References

  • Affara NI, Trempus CS, Schanbacher BL, Pei P, Mallery SR, Bauer JA, Robertson FM. Activation of Akt and Mtor in Cd34+/K15+ keratinocyte stem cells and skin tumors during multi-stage mouse skin carcinogenesis. Anticancer Res. 2006;26:2805–20.

    CAS  PubMed  Google Scholar 

  • Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R. Mtor regulates memory Cd8 T-cell differentiation. Nature. 2009;460:108–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Belsky DW, Huffman KM, Pieper CF, Shalev I, Kraus WE. Change in the rate of biological aging in response to caloric restriction: CALERIE Biobank Analysis. J Gerontol A Biol Sci Med Sci. 2017; https://doi.org/10.1093/gerona/glx096.

  • Berger NA, Savvides P, Koroukian SM, Kahana EF, Deimling GT, Rose JH, Bowman KF, Miller RH. Cancer in the elderly. Trans Am Clin Climatol Assoc. 2006;117:147–55. Discussion 155-6

    PubMed  PubMed Central  Google Scholar 

  • Brandhorst S, Longo VD. Fasting and caloric restriction in cancer prevention and treatment. Recent Results Cancer Res. 2016;207:241–66.

    Article  CAS  PubMed  Google Scholar 

  • Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions according to the Human Development Index (2008–2030): a population-based study. Lancet Oncol. 2012;13:790–801.

    Article  PubMed  Google Scholar 

  • Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 1994;369:756–8.

    Article  CAS  PubMed  Google Scholar 

  • Callejas-Valera JL, Iglesias-Bartolome R, Amornphimoltham P, Palacios-Garcia J, Martin D, Califano JA, Molinolo AA, Gutkind JS. Mtor inhibition prevents rapid-onset of carcinogen-induced malignancies in a novel inducible Hpv-16 E6/E7 mouse model. Carcinogenesis. 2016;37:1014–25.

    Article  CAS  PubMed  Google Scholar 

  • Carriere A, Romeo Y, Acosta-Jaquez HA, Moreau J, Bonneil E, Thibault P, Fingar DC, Roux PP. Erk1/2 phosphorylate Raptor to promote Ras-dependent activation of Mtor complex 1 (Mtorc1). J Biol Chem. 2011;286:567–77.

    Article  CAS  PubMed  Google Scholar 

  • Checkley LA, Rho O, Moore T, Hursting S, Digiovanni J. Rapamycin is a potent inhibitor of skin tumor promotion by 12-O-Tetradecanoylphorbol-13-acetate. Cancer Prev Res (Phila). 2011;4:1011–20.

    Article  CAS  Google Scholar 

  • Cheng CW, Adams GB, Perin L, Wei M, Zhou X, Lam BS, Da Sacco S, Mirisola M, Quinn DI, Dorff TB, Kopchick JJ, Longo VD. Prolonged fasting reduces Igf-1/Pka to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell. 2014;14:810–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christy B, Demaria M, Campisi J, Huang J, Jones D, Dodds SG, Williams C, Hubbard G, Livi CB, Gao X, Weintraub S, Curiel T, Sharp ZD, Hasty P. P53 and rapamycin are additive. Oncotarget. 2015;6:15802–13.

    Article  PubMed  PubMed Central  Google Scholar 

  • Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009;325:201–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun. 2014;5:3557.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dao V, Pandeswara S, Liu Y, Hurez V, Dodds S, Callaway D, Liu A, Hasty P, Sharp ZD, Curiel TJ. Prevention of carcinogen and inflammation-induced dermal cancer by oral Rapamycin includes reducing genetic damage. Cancer Prev Res (Phila). 2015;8:400–9.

    Article  CAS  Google Scholar 

  • Dao V, Liu Y, Pandeswara S, Svatek RS, Gelfond JA, Liu A, Hurez V, Curiel TJ. Immune-stimulatory effects of Rapamycin are mediated by stimulation of antitumor Gammadelta T cells. Cancer Res. 2016;76:5970–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Fijter JW. Cancer and Mtor inhibitors in transplant recipients. Transplantation. 2017;101:45–55.

    Article  PubMed  Google Scholar 

  • Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD. The Mtor kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30:832–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD. The kinase Mtor regulates the differentiation of helper T cells through the selective activation of signaling by Mtorc1 and Mtorc2. Nat Immunol. 2011;12:295–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Demaria S, Pikarsky E, Karin M, Coussens LM, Chen YC, El-Omar EM, Trinchieri G, Dubinett SM, Mao JT, Szabo E, Krieg A, Weiner GJ, Fox BA, Coukos G, Wang E, Abraham RT, Carbone M, Lotze MT. Cancer and inflammation: promise for biologic therapy. J Immunother. 2010;33:335–51.

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng CW, Cacciottolo M, Martin-Montalvo A, De Cabo R, Wei M, Morgan TE, Longo VD. Fasting-mimicking diet reduces Ho-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell. 2016;30:136–46.

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, Russo M, Cancelliere C, Zecchin D, Mazzucchelli L, Sasazuki T, Shirasawa S, Geuna M, Frattini M, Baselga J, Gallicchio M, Biffo S, Bardelli A. Deregulation of the Pi3k and Kras signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest. 2010;120:2858–66.

    Article  PubMed  PubMed Central  Google Scholar 

  • Digiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther. 1992;54:63–128.

    Article  CAS  PubMed  Google Scholar 

  • Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi DR, Dunlop MG. Aspirin inhibits Mtor signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology. 2012;142:1504–15. E3.

    Google Scholar 

  • Fontana L, Partridge L, Longo VD. Extending healthy life span – from yeast to humans. Science. 2010;328:321–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fontana L, Adelaiye RM, Rastelli AL, Miles KM, Ciamporcero E, Longo VD, Nguyen H, Vessella R, Pili R. Dietary protein restriction inhibits tumor growth in human xenograft models. Oncotarget. 2013;4:2451–61.

    Article  PubMed  PubMed Central  Google Scholar 

  • Goldberg EL, Romero-Aleshire MJ, Renkema KR, Ventevogel MS, Chew WM, Uhrlaub JL, Smithey MJ, Limesand KH, Sempowski GD, Brooks HL, Nikolich-Zugich J. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell. 2015;14(1):130–138

    Google Scholar 

  • Gupta M, Hendrickson AE, Yun SS, Han JJ, Schneider PA, Koh BD, Stenson MJ, Wellik LE, Shing JC, Peterson KL, Flatten KS, Hess AD, Smith BD, Karp JE, Barr S, Witzig TE, Kaufmann SH. Dual Mtorc1/Mtorc2 inhibition diminishes Akt activation and induces puma-dependent apoptosis in lymphoid malignancies. Blood. 2012;119:476–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. 2008;4:E24.

    Article  PubMed  PubMed Central  Google Scholar 

  • Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hasty P, Livi CB, Dodds SG, Jones D, Strong R, Javors M, Fischer KE, Sloane L, Murthy K, Hubbard G, Sun L, Hurez V, Curiel TJ, Sharp ZD. Erapa restores a normal life span in a Fap mouse model. Cancer Prev Res (Phila). 2014;7:169–78.

    Article  CAS  Google Scholar 

  • Havenith SH, Yong SL, Van Donselaar-Van Der Pant KA, Van Lier RA, Ten Berge IJ, Bemelman FJ. Everolimus-treated renal transplant recipients have a more robust cmv-specific Cd8+ T-cell response compared with cyclosporine- or Mycophenolate-treated patients. Transplantation. 2013;95:184–91.

    Article  CAS  PubMed  Google Scholar 

  • Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG. The ancient drug salicylate directly activates Amp-activated protein kinase. Science. 2012;336:918–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herbert TP, Tee AR, Proud CG. The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4e-Bp1 at multiple sites. J Biol Chem. 2002;277:11591–6.

    Article  CAS  PubMed  Google Scholar 

  • Hiller J, Vallejo C, Betthauser L, Keesling J. Characteristic patterns of cancer incidence: epidemiological data, biological theories, and multistage models. Prog Biophys Mol Biol. 2017;124:41–8.

    Article  PubMed  Google Scholar 

  • Hurez V, Daniel BJ, Sun L, Liu AJ, Ludwig SM, Kious MJ, Thibodeaux SR, Pandeswara S, Murthy K, Livi CB, Wall S, Brumlik MJ, Shin T, Zhang B, Curiel TJ. Mitigating age-related immune dysfunction heightens the efficacy of tumor immunotherapy in aged mice. Cancer Res. 2012;72:2089–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hurez V, Dao V, Liu A, Pandeswara S, Gelfond J, Sun L, Bergman M, Orihuela CJ, Galvan V, Padron A, Drerup J, Liu Y, Hasty P, Sharp ZD, Curiel TJ. Chronic Mtor inhibition in mice with Rapamycin alters T, B, myeloid, and innate lymphoid cells and gut Flora and prolongs life of immune-deficient mice. Aging Cell. 2015;14:945–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hursting SD, Lavigne JA, Berrigan D, Perkins SN, Barrett JC. Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu Rev Med. 2003;54:131–52.

    Article  CAS  PubMed  Google Scholar 

  • Johnson SC, Rabinovitch PS, Kaeberlein M. Mtor is a key modulator of ageing and age-related disease. Nature. 2013;493:338–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalaany NY, Sabatini DM. Tumours with Pi3k activation are resistant to dietary restriction. Nature. 2009;458:725–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keating R, Hertz T, Wehenkel M, Harris TL, Edwards BA, Mcclaren JL, Brown SA, Surman S, Wilson ZS, Bradley P, Hurwitz J, Chi H, Doherty PC, Thomas PG, Mcgargill MA. The kinase Mtor modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat Immunol. 2013;14:1266–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kennedy BK, Pennypacker JK. Drugs that modulate aging: the promising yet difficult path ahead. Transl Res. 2014;163:456–65.

    Article  PubMed  Google Scholar 

  • Kenyon CJ. The genetics of ageing. Nature. 2010;464:504–12.

    Article  CAS  PubMed  Google Scholar 

  • Komarova EA, Antoch MP, Novototskaya LR, Chernova OB, Paszkiewicz G, Leontieva OV, Blagosklonny MV, Gudkov AV. Rapamycin extends lifespan and delays tumorigenesis in heterozygous P53+/− mice. Aging (Albany NY). 2012;4:709–14.

    Article  CAS  Google Scholar 

  • Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA. Rapamycin-induced insulin resistance is mediated by Mtorc2 loss and uncoupled from longevity. Science. 2012;335:1638–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and Mtor inhibitors as anti-aging therapeutics. J Clin Invest. 2013;123:980–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laplante M, Sabatini DM. Mtor signaling in growth control and disease. Cell. 2012;149:274–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee C, Longo VD. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene. 2011;30:3305–16.

    Article  CAS  PubMed  Google Scholar 

  • Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, Fontana L, Mirisola MG, Guevara-Aguirre J, Wan J, Passarino G, Kennedy BK, Wei M, Cohen P, Crimmins EM, Longo VD. Low protein intake is associated with a major reduction in Igf-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab. 2014;19:407–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Pandeswara S, Dao V, Padron A, Drerup JM, Lao S, Liu A, Hurez V, Curiel TJ. Biphasic Rapamycin effects in lymphoma and carcinoma treatment. Cancer Res. 2017;77:520–31.

    Article  CAS  PubMed  Google Scholar 

  • Livi CB, Hardman RL, Christy BA, Dodds SG, Jones D, Williams C, Strong R, Bokov A, Javors MA, Ikeno Y, Hubbard G, Hasty P, Sharp ZD. Rapamycin extends life span of Rb1+/− mice by inhibiting neuroendocrine tumors. Aging (Albany NY). 2013;5:100–10.

    Article  CAS  Google Scholar 

  • Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci. 2010;31:89–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, De Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L. Interventions to slow aging in humans: are we ready? Aging Cell. 2015;14:497–510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB. Mtor inhibition improves immune function in the elderly. Sci Transl Med. 2014;6:268ra179.

    Article  PubMed  Google Scholar 

  • Markowicz-Piasecka M, Sikora J, Szydlowska A, Skupien A, Mikiciuk-Olasik E, Huttunen KM. Metformin – a future therapy for neurodegenerative diseases. Pharm Res. 2017. https://doi.org/10.1007/s11095-017-2199-y.

  • Martin DE, Hall MN. The expanding tor signaling network. Curr Opin Cell Biol. 2005;17:158–66.

    Article  CAS  PubMed  Google Scholar 

  • Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, De Cabo R. Metformin improves Healthspan and lifespan in mice. Nat Commun. 2013;4:2192.

    Article  PubMed  PubMed Central  Google Scholar 

  • Marz AM, Fabian AK, Kozany C, Bracher A, Hausch F. Large Fk506-binding proteins shape the pharmacology of Rapamycin. Mol Cell Biol. 2013;33:1357–67.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, De Cabo R. Impact of caloric restriction on health and survival in rhesus monkeys from the Nia study. Nature. 2012;489:318–21.

    Article  CAS  PubMed  Google Scholar 

  • Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2016;39:46–58.

    Google Scholar 

  • Mccay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition. 1989;5:155–71. Discussion 172

    CAS  PubMed  Google Scholar 

  • Mendoza MC, Er EE, Blenis J. The Ras-Erk and Pi3k-Mtor pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36:320–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, De Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2011;66:191–201.

    Article  PubMed  Google Scholar 

  • Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13:468–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mirsoian A, Bouchlaka MN, Sckisel GD, Chen M, Pai CC, Maverakis E, Spencer RG, Fishbein KW, Siddiqui S, Monjazeb AM, Martin B, Maudsley S, Hesdorffer C, Ferrucci L, Longo DL, Blazar BR, Wiltrout RH, Taub DD, Murphy WJ. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. J Exp Med. 2014;211:2373–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer Immunoediting and its three component phases – elimination, equilibrium and escape. Curr Opin Immunol. 2014;27:16–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Modi BG, Neustadter J, Binda E, Lewis J, Filler RB, Roberts SJ, Kwong BY, Reddy S, Overton JD, Galan A, Tigelaar R, Cai L, Fu P, Shlomchik M, Kaplan DH, Hayday A, Girardi M. Langerhans cells facilitate epithelial DNA damage and squamous cell carcinoma. Science. 2012;335:104–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Novelle MG, Ali A, Dieguez C, Bernier M, De Cabo R. Metformin: a hopeful promise in aging research. Cold Spring Harb Perspect Med. 2016;6:A025932.

    Article  PubMed  Google Scholar 

  • Parrella E, Maxim T, Maialetti F, Zhang L, Wan J, Wei M, Cohen P, Fontana L, Longo VD. Protein restriction cycles reduce Igf-1 and phosphorylated Tau, and improve behavioral performance in an Alzheimer’s disease mouse model. Aging Cell. 2013;12:257–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patlolla JM, Kopelovich L, Qian L, Zhang Y, Kumar G, Madka V, Mohammed A, Biddick L, Sadeghi M, Lightfoot S, Rao CV. Early and delayed intervention with rapamycin prevents Nnk-induced lung adenocarcinoma in A/J mice. Oncol Rep. 2015;34:2925–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pedicord VA, Cross JR, Montalvo-Ortiz W, Miller ML, Allison JP. Friends not foes: Ctla-4 blockade and Mtor inhibition cooperate during Cd8+ T cell priming to promote memory formation and metabolic readiness. J Immunol. 2015;194:2089–98.

    Article  CAS  PubMed  Google Scholar 

  • Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by Mtor. Annu Rev Immunol. 2012;30:39–68.

    Article  CAS  PubMed  Google Scholar 

  • Riaz H, Riaz T, Hussain SA. Mtor inhibitors: a novel class of anti-cancer agents. Infect Agent Cancer. 2012;7(1):1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richman IB, Owens DK. Aspirin for primary prevention. Med Clin North Am. 2017;101:713–24.

    Article  PubMed  Google Scholar 

  • Rosner M, Hengstschlager M. Cytoplasmic and nuclear distribution of the protein complexes Mtorc1 and Mtorc2: rapamycin triggers dephosphorylation and delocalization of the Mtorc2 components Rictor and Sin1. Hum Mol Genet. 2008;17:2934–48.

    Article  CAS  PubMed  Google Scholar 

  • Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377:31–41.

    Article  CAS  PubMed  Google Scholar 

  • Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. Raft1: a mammalian protein that binds to Fkbp12 in a rapamycin-dependent fashion and is homologous to yeast Tors. Cell. 1994;78:35–43.

    Article  CAS  PubMed  Google Scholar 

  • Saha A, Blando J, Tremmel L, Digiovanni J. Effect of metformin, rapamycin, and their combination on growth and progression of prostate tumors in Himyc mice. Cancer Prev Res (Phila). 2015;8:597–606.

    Article  CAS  Google Scholar 

  • Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM. Prolonged rapamycin treatment inhibits Mtorc2 assembly and Akt/Pkb. Mol Cell. 2006;22:159–68.

    Article  CAS  PubMed  Google Scholar 

  • Shahbazian D, Roux PP, Mieulet V, Cohen MS, Raught B, Taunton J, Hershey JW, Blenis J, Pende M, Sonenberg N. The Mtor/Pi3k and Mapk pathways converge on Eif4b to control its phosphorylation and activity. EMBO J. 2006;25:2781–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

    Article  PubMed  Google Scholar 

  • Society, A. C. Cancer facts & figures 2012. Atlanta: American Cancer Society; 2012.

    Google Scholar 

  • Soefje SA, Karnad A, Brenner AJ. Common toxicities of mammalian target of rapamycin inhibitors. Target Oncol. 2011;6:125–9.

    Article  PubMed  Google Scholar 

  • Soukas AA, Kane EA, Carr CE, Melo JA, Ruvkun G. Rictor/Torc2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 2009;23:496–511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stelzer MK, Pitot HC, Liem A, Lee D, Kennedy GD, Lambert PF. Rapamycin inhibits anal carcinogenesis in two preclinical animal models. Cancer Prev Res (Phila). 2011;3:1542–51.

    Article  Google Scholar 

  • Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016;16:275–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • United Nations, D. O. E. A. S. A., Population Division 2011. World population prospects: the 2010 revision, volume I: comprehensive tables. St/Esa/Ser.A/313.

    Google Scholar 

  • Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F. Genetics: influence of tor kinase on lifespan in C. Elegans. Nature. 2003;426:620.

    Article  CAS  PubMed  Google Scholar 

  • Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, Groshen S, Mack WJ, Guen E, Di Biase S, Cohen P, Morgan TE, Dorff T, Hong K, Michalsen A, Laviano A, Longo VD. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017;9:eaai8700.

    Article  PubMed  Google Scholar 

  • Yuan HX, Guan KL. Structural insights of Mtor complex 1. Cell Res. 2016;26:267–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zoncu R, Efeyan A, Sabatini DM. Mtor: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2010;12:21–35.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zoncu R, Efeyan A, Sabatini DM. Mtor: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12:21–35.

    Article  CAS  PubMed  Google Scholar 

  • Zou Z, Chen J, Yang J, Bai X. Targeted inhibition of Rictor/Mtorc2 in cancer treatment: a new era after rapamycin. Curr Cancer Drug Targets. 2016;16:288–304.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. The Graduate School of Biomedical Sciences, University of Texas Health, San Antonio, TX, USA

    Heather G. Hambright & Tyler J. Curiel

  2. Department of Medicine, University of Texas Health, San Antonio, TX, USA

    Vincent Hurez & Tyler J. Curiel

  3. Cancer Therapy & Research Center, University of Texas Health, San Antonio, TX, USA

    Tyler J. Curiel

  4. Barshop Institute for Longevity and Aging Studies, University of Texas Health, San Antonio, TX, USA

    Tyler J. Curiel

Authors
  1. Heather G. Hambright
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  2. Vincent Hurez
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  3. Tyler J. Curiel
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Correspondence to Heather G. Hambright .

Editor information

Editors and Affiliations

  1. Senior Adult Oncology Program, Moffitt Cancer Center, Tampa, Florida, USA

    Martine Extermann

Section Editor information

  1. Research Center on Aging, Department of Medicine, Immunology Graduate Programme, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada

    Tamas Fulop

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© 2018 Springer International Publishing AG

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Hambright, H.G., Hurez, V., Curiel, T.J. (2018). Chronic Mechanistic Target of Rapamycin Inhibition: Preventing Cancer to Delay Aging or Vice Versa?. In: Extermann, M. (eds) Geriatric Oncology . Springer, Cham. https://doi.org/10.1007/978-3-319-44870-1_81-1

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  • DOI: https://doi.org/10.1007/978-3-319-44870-1_81-1

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-44870-1

  • Online ISBN: 978-3-319-44870-1

  • eBook Packages: Springer Reference MedicineReference Module Medicine

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