mTOR is a key modulator of ageing and age-related disease (original) (raw)

• Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Stanfel, M. N., Shamieh, L. S., Kaeberlein, M. & Kennedy, B. K. The TOR pathway comes of age. Biochim. Biophys. Acta 1790, 1067–1074 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012). This study uses genetic models to confirm that reduced mTORC1 activity extends lifespan in mammals, and reports that the insulin resistance associated with chronic mTORC1 inhibition is caused by altered mTORC2 signalling and is not causally involved in lifespan extension.
  Article ADS CAS PubMed PubMed Central Google Scholar
• Fabrizio, P., Pozza, F., Pletcher, S. D., Gendron, C. M. & Longo, V. D. Regulation of longevity and stress resistance by Sch9 in yeast. Science 292, 288–290 (2001).
  Article ADS CAS PubMed Google Scholar
• Jia, K., Chen, D. & Riddle, D. L. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897–3906 (2004).
  Article CAS PubMed Google Scholar
• Vellai, T. et al. Influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003).
  Article ADS CAS PubMed Google Scholar
• Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005).
  Article ADS CAS PubMed Google Scholar
• Powers, R. W. III, Kaeberlein, M., Caldwell, S. D., Kennedy, B. K. & Fields, S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20, 174–184 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Medvedik, O., Lamming, D. W., Kim, K. D. & Sinclair, D. A. MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae. PLoS Biol. 5, e261 (2007).
  Article PubMed PubMed Central CAS Google Scholar
• Robida-Stubbs, S. et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15, 713–724 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). This study reports lifespan extension from mTORC1 inhibition in a mammal.
  Article ADS CAS PubMed PubMed Central Google Scholar
• Miller, R. A. et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J. Gerontol. A Biol. Sci. Med. Sci. 66, 191–201 (2011).
  Article PubMed CAS Google Scholar
• Anisimov, V. N. et al. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 10, 4230–4236 (2011).
  Article CAS PubMed Google Scholar
• Fontana, L., Partridge, L. & Longo, V. D. Extending healthy lifespan — from yeast to humans. Science 328, 321–326 (2010).
  Article ADS CAS PubMed PubMed Central Google Scholar
• Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95–110 (2007).
  Article CAS PubMed Google Scholar
• Zid, B. M. et al. 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell 139, 149–160 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).
  Article ADS CAS PubMed Google Scholar
• Takano, A. et al. Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin. Mol. Cell. Biol. 21, 5050–5062 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Khatri, S., Yepiskoposyan, H., Gallo, C. A., Tandon, P. & Plas, D. R. FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1. J. Biol. Chem. 285, 15960–15965 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Tettweiler, G., Miron, M., Jenkins, M., Sonenberg, N. & Lasko, P. F. Starvation and oxidative stress resistance in Drosophila are mediated through the eIF4E-binding protein, d4E-BP. Genes Dev. 19, 1840–1843 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Guertin, D. A. et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1. Dev. Cell 11, 859–871 (2006).
  Article CAS PubMed Google Scholar
• Pan, K. Z. et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 6, 111–119 (2007).
  Article CAS PubMed Google Scholar
• Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P. S. & Curtis, R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 18, 3004–3009 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Onken, B. & Driscoll, M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS ONE 5, e8758 (2010).
  Article ADS PubMed PubMed Central CAS Google Scholar
• Anisimov, V. N. Metformin for aging and cancer prevention. Aging (Albany NY) 2, 760–774 (2010).
  Article CAS Google Scholar
• Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).
  Article CAS PubMed Google Scholar
• Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Mair, W. et al. Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470, 404–408 (2011).
  Article ADS CAS PubMed PubMed Central Google Scholar
• Leiser, S. F. & Kaeberlein, M. The hypoxia-inducible factor HIF-1 functions as both a positive and negative modulator of aging. Biol. Chem. 391, 1131–1137 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Hudson, C. C. et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol. Cell. Biol. 22, 7004–7014 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Mehta, R. et al. Proteasomal regulation of the hypoxic response modulates aging in C. elegans. Science 324, 1196–1198 (2009).
  Article ADS CAS PubMed PubMed Central Google Scholar
• Zhang, Y., Shao, Z., Zhai, Z., Shen, C. & Powell-Coffman, J. A. The HIF-1 hypoxia-inducible factor modulates lifespan in C. elegans. PLoS ONE 4, e6348 (2009).
  Article ADS PubMed PubMed Central CAS Google Scholar
• Leiser, S. F., Begun, A. & Kaeberlein, M. HIF-1 modulates longevity and healthspan in a temperature-dependent manner. Aging Cell 10, 318–326 (2011).
  Article CAS PubMed Google Scholar
• Chen, D., Thomas, E. L. & Kapahi, P. HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans. PLoS Genet. 5, e1000486 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian lifespan. Science 326, 140–144 (2009). This study shows that knockout of the mTORC1 substrate S6K1 extends lifespan in mice.
  Article ADS CAS PubMed PubMed Central Google Scholar
• Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).
  Article ADS CAS PubMed PubMed Central Google Scholar
• Fries, J. F. Aging, natural death, and the compression of morbidity. N. Engl. J. Med. 303, 130–135 (1980).
  Article CAS PubMed Google Scholar
• Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell 11, 675–682 (2012).
  Article CAS PubMed Google Scholar
• Halloran, J. et al. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience 223, 102–113 (2012).
  Article CAS PubMed Google Scholar
• Majumder, S. et al. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1β and enhancing NMDA signaling. Aging Cell 11, 326–335 (2012). References 41 and 42 report that rapamycin improves cognitive function and protects against age-related cognitive decline in mice.
  Article CAS PubMed Google Scholar
• Kaeberlein, M. & Kennedy, B. K. Hot topics in aging research: protein translation and TOR signaling. Aging Cell 10, 185–190 (2011).
  Article CAS PubMed Google Scholar
• Smith, E. D. et al. Quantitative evidence for conserved longevity pathways between divergent eukaryotic species. Genome Res. 18, 564–570 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kaeberlein, M. & Kennedy, B. K. Protein translation. Aging Cell 6, 731–734 (2007).
  Article CAS PubMed Google Scholar
• Blagosklonny, M. V. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle 5, 2087–2102 (2006).
  Article CAS PubMed Google Scholar
• Steffen, K. K. et al. Yeast lifespan extension by depletion of 60S ribosomal subunits is mediated by Gcn4. Cell 133, 292–302 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Rogers, A. N. et al. Lifespan extension via eIF4G inhibition is mediated by post-transcriptional remodeling of stress response gene expression in C. elegans. Cell Metab. 14, 55–66 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012).
  Article ADS CAS PubMed PubMed Central Google Scholar
• Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008).
  Article ADS CAS PubMed PubMed Central Google Scholar
• Cuervo, A. M. Autophagy and aging: keeping that old broom working. Trends Genet. 24, 604–612 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Hansen, M. et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. 4, e24 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Alvers, A. L. et al. Autophagy is required for extension of yeast chronological life span by rapamycin. Autophagy 5, 847–849 (2009).
  Article CAS PubMed Google Scholar
• Wei, M. et al. Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet. 4, e13 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Bishop, N. A. & Guarente, L. Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 447, 545–549 (2007).
  Article ADS CAS PubMed Google Scholar
• Steinbaugh, M. J., Sun, L. Y., Bartke, A. & Miller, R. A. Activation of genes involved in xenobiotic metabolism is a shared signature of mouse models with extended lifespan. Am. J. Physiol. Endocrinol. Metab. 303, E488–E495 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Cunningham, J. T. et al. mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex. Nature 450, 736–740 (2007).
  Article ADS CAS PubMed Google Scholar
• Bonawitz, N. D., Chatenay-Lapointe, M., Pan, Y. & Shadel, G. S. Reduced TOR signaling extends chronological lifespan via increased respiration and upregulation of mitochondrial gene expression. Cell Metab. 5, 265–277 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Pan, Y., Schroeder, E. A., Ocampo, A., Barrientos, A. & Shadel, G. S. Regulation of yeast chronological lifespan by TORC1 via adaptive mitochondrial ROS signaling. Cell Metab. 13, 668–678 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Polak, P. et al. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab. 8, 399–410 (2008).
  Article CAS PubMed Google Scholar
• Chung, H. Y. et al. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res. Rev. 8, 18–30 (2009).
  Article CAS PubMed Google Scholar
• Morgan, T. E., Wong, A. M. & Finch, C. E. Anti-inflammatory mechanisms of dietary restriction in slowing aging processes. Interdiscip. Top. Gerontol. 35, 83–97 (2007).
  CAS PubMed Google Scholar
• Liu, Y. Rapamycin and chronic kidney disease: beyond the inhibition of inflammation. Kidney Int. 69, 1925–1927 (2006).
  Article CAS PubMed Google Scholar
• Nuhrenberg, T. G. et al. Rapamycin attenuates vascular wall inflammation and progenitor cell promoters after angioplasty. FASEB J. 19, 246–248 (2005).
  Article PubMed CAS Google Scholar
• Chen, W. Q. et al. Oral rapamycin attenuates inflammation and enhances stability of atherosclerotic plaques in rabbits independent of serum lipid levels. Br. J. Pharmacol. 156, 941–951 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Abdulrahman, B. A. et al. Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis. Autophagy 7, 1359–1370 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Sharpless, N. E. & DePinho, R. A. How stem cells age and why this makes us grow old. Nature Rev. Mol. Cell Biol. 8, 703–713 (2007).
  Article CAS Google Scholar
• Chen, C., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009).
  PubMed PubMed Central Google Scholar
• Yilmaz, O. H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012). This study shows that rapamycin protects against loss of intestinal stem-cell function during ageing by preserving the stem-cell niche.
  Article ADS CAS PubMed PubMed Central Google Scholar
• Cerletti, M., Jang, Y. C., Finley, L. W., Haigis, M. C. & Wagers, A. J. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell 10, 515–519 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ramos, F. J. & Kaeberlein, M. A healthy diet for stem cells. Nature 486, 477–478 (2012).
  Article ADS CAS PubMed Google Scholar
• Singh-Manoux, A. et al. Timing of onset of cognitive decline: results from Whitehall II prospective cohort study. Br. Med. J. 344, d7622 (2012).
  Article Google Scholar
• Benjamin, D., Colombi, M., Moroni, C. & Hall, M. N. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nature Rev. Drug Discov. 10, 868–880 (2011).
  Article CAS Google Scholar
• Syntichaki, P., Troulinaki, K. & Tavernarakis, N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. Nature 445, 922–926 (2007).
  Article ADS CAS PubMed Google Scholar
• Curran, S. P. & Ruvkun, G. Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet. 3, e56 (2007).
  Article PubMed PubMed Central CAS Google Scholar
• Chiocchetti, A. et al. Ribosomal proteins Rpl10 and Rps6 are potent regulators of yeast replicative life span. Exp. Gerontol. 42, 275–286 (2007).
  Article CAS PubMed Google Scholar
• Malagelada, C., Jin, Z. H., Jackson-Lewis, V., Przedborski, S. & Greene, L. A. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease. J. Neurosci. 30, 1166–1175 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Tain, L. S. et al. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nature Neurosci. 12, 1129–1135 (2009).
  Article CAS PubMed Google Scholar
• Majumder, S., Richardson, A., Strong, R. & Oddo, S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS ONE 6, e25416 (2011).
  Article ADS CAS PubMed PubMed Central Google Scholar
• Spilman, P. et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. PLoS ONE 5, e9979 (2010).
  Article ADS PubMed PubMed Central CAS Google Scholar
• Wang, I. F. et al. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc. Natl Acad. Sci. USA 109, 15024–15029 (2012).
  Article ADS CAS PubMed PubMed Central Google Scholar
• Garber, K. Targeting mTOR: something old, something new. J. Natl Cancer Inst. 101, 288–290 (2009).
  Article CAS PubMed Google Scholar
• Shioi, T. et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation 107, 1664–1670 (2003).
  Article CAS PubMed Google Scholar
• McMullen, J. R. et al. Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109, 3050–3055 (2004).
  Article CAS PubMed Google Scholar
• Ding, Y. et al. Haploinsufficiency of target of rapamycin attenuates cardiomyopathies in adult zebrafish. Circ. Res. 109, 658–669 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Ramos, F. J. et al. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci. Transl. Med. 4, 144ra103 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Um, S. H. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200–205 (2004).
  Article ADS CAS PubMed Google Scholar
• Yang, S. B. et al. Rapamycin ameliorates age-dependent obesity associated with increased mTOR signaling in hypothalamic POMC neurons. Neuron 75, 425–436 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Jagannath, C. & Bakhru, P. Rapamycin-induced enhancement of vaccine efficacy in mice. Methods Mol. Biol. 821, 295–303 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Amiel, E. et al. Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. J. Immunol. 189, 2151–2158 (2012).
  Article CAS PubMed Google Scholar
• Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).
  Article ADS CAS PubMed PubMed Central Google Scholar
• Lieberthal, W. & Levine, J. S. Mammalian target of rapamycin and the kidney. II. Pathophysiology and therapeutic implications. Am. J. Physiol. Renal Physiol. 303, F180–F191 (2012).
  Article CAS PubMed Google Scholar
• Kolosova, N. G. et al. Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats. Am. J. Pathol. 181, 472–477 (2012).
  Article CAS PubMed Google Scholar
• Yin, L., Ye, S., Chen, Z. & Zeng, Y. Rapamycin preconditioning attenuates transient focal cerebral ischemia/reperfusion injury in mice. Int. J. Neurosci. 122, 748–756 (2012).
  Article CAS PubMed Google Scholar
• Tsai, P. T. et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488, 647–651 (2012).
  Article ADS CAS PubMed PubMed Central Google Scholar
• Ryther, R. C. & Wong, M. Mammalian target of rapamycin (mTOR) inhibition: potential for antiseizure, antiepileptogenic, and epileptostatic therapy. Curr. Neurol. Neurosci. Rep. 12, 410–418 (2012).
  Article CAS PubMed Google Scholar
• Yamaki, K. & Yoshino, S. Preventive and therapeutic effects of rapamycin, a mammalian target of rapamycin inhibitor, on food allergy in mice. Allergy 67, 1259–1270 (2012).
  Article CAS PubMed Google Scholar
• Pierdominici, M., Vacirca, D., Delunardo, F. & Ortona, E. mTOR signaling and metabolic regulation of T cells: new potential therapeutic targets in autoimmune diseases. Curr. Pharm. Des. 17, 3888–3897 (2011).
  Article CAS PubMed Google Scholar
• Nussenblatt, R. B. et al. A randomized pilot study of systemic immunosuppression in the treatment of age-related macular degeneration with choroidal neovascularization. Retina 30, 1579–1587 (2010).
  Article PubMed PubMed Central Google Scholar
• Cao, K. et al. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson–Gilford progeria syndrome cells. Sci. Transl. Med. 3, 89ra58 (2011).
  CAS PubMed Google Scholar