Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
Open accessAbstract
Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
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Rapamycin and rapalogs suppress the SASP by inhibiting mTOR and appear to extend healthspan and lifespan in mice.
“Rapamycin and its analogs (so-called ‘rapalogs’) suppress the SASP by inhibiting mTOR and appear to extend healthspan and lifespan in mice105,108,109.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [108]
The Abstract (page unavailable) reports that rapamycin inhibits the mTOR pathway and extends median and maximal lifespan in genetically heterogeneous mice. It does not report SASP suppression, effects of rapalogs, or an extension of healthspan; it says that whether mTOR inhibition alters other aspects of ageing remains to be tested. (LLM, conf=0.90)
Experimental — accuracy not yet measuredRapamycin treatment extended lifespan and postponed some ageing-related dysfunctions in mice.
“Additionally, rapamycin treatment increased lifespan and delayed certain ageing-related dysfunctions in mice234.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [234]
The Abstract reports that rapamycin extended median and maximal lifespan in mice. It does not establish that ageing-related dysfunctions were delayed; the paper says that demonstrating altered ageing would require testing age-dependent changes in multiple organs and processes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRapamycin's inhibition of SASP factors might explain its beneficial impact on longevity.
“which might explain its beneficial impact on longevity [121,122].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [122]
The Abstract reports that rapamycin extended median and maximal lifespan in mice. It discusses possible anti-neoplastic and cellular-stress mechanisms, but does not mention SASP factors or show that inhibiting them explains the longevity benefit (searched: SASP, senescence-associated secretory phenotype, senescent cells). (LLM, conf=0.88)
Experimental — accuracy not yet measuredMice treated with rapamycin, a well-characterized inhibitor of mTOR, show marked increase in lifespan and enhanced health-span.
“marked increase in lifespan and enhance health-span in mice treated with rapamycin, a well-characterized inhibitor of mTOR (Harrison et al., 2009)”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Harrison et al., 2009
The Abstract (page not provided) reports that rapamycin inhibits the mTOR pathway and extends median and maximal lifespan in male and female mice. It does not establish enhanced health-span: disease patterns did not differ from controls, and the authors say that determining whether ageing was slowed would require testing age-dependent changes in multiple tissues and processes. (LLM, conf=0.90)
Experimental — accuracy not yet measuredRapamycin inhibits the production of SASP factors.
“a well-known inhibitor of mTOR, rapamycin, inhibits the production of SASP factors”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [122]
The Abstract reports that rapamycin reduced phosphorylation of an mTOR-pathway target in mice, but it does not address production of SASP factors. Searches for SASP, senescence-associated secretory phenotype, and secretion by senescent cells found no passage supporting that specific claim in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measured
mTOR signaling is involved in regulating mammalian lifespan.
“mTOR signaling has been demonstrated to be involved in regulating mammalian lifespan (Harrison et al., 2009).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Harrison et al., 2009
Rapamycin, an inhibitor of the mTOR pathway, was shown to significantly extend the lifespan of mammals in 2009.
“In 2009, rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) pathway, was shown to significantly extend the lifespan of mammals.58”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [58]
AMPK activators and the mTOR signalling pathway inhibitor rapamycin have considerable ramifications for longevity and managing age-related illnesses.
“AMPK activators and the mTOR signalling pathway inhibitor rapamycin have considerable ramifications for longevity and managing age-related illnesses.58,402–404”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [58]
Animal models have determined that rapamycin and rapalogs can extend lifespan.
“Animal models exploring the effect of rapamycin and rapalogs on longevity have determined their ability to extend lifespan167-169.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [169]
The TOR inhibitor rapamycin extends lifespan in mice even when treatment is initiated late in life.
“Moreover, it was recently shown that the TOR inhibitor rapamycin extends lifespan in mice even when treatment is initiated late in life (58).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [58]
Genetic regulation of mTOR signal transduction can slow the aging of many organisms.
“Much of the literature suggests that the genetic regulation of mTOR signal transduction can slow the aging of many organisms [183–185].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [184]
Inhibition of the mTOR pathway (using rapamycin), which extends lifespan in a variety of model organisms, is an effective SASP suppressor.
“For instance, inhibition of the mTOR pathway (using the drug rapamycin), which has been shown to extend lifespan in a variety of model organisms (de Magalhaes et al., 2012;Harrison et al., 2009), is an effective SASP suppressor (Correia-Melo et al., 2016;Herranz et al., 2015;Laberge et al., 2015).”
From Stress, cell senescence and organismal ageing (2018) · cites this paper as Harrison et al., 2009
Reducing ribosome subunits or interfering with the TOR/ribosomal protein S6 kinase pathway changes lifespan in many species, including mammals.
“Depletion of ribosome subunits or interference with the target of rapamycin/ribosomal protein S6 kinase pathway, which functions to activate protein translation, were found to alter the lifespan of a variety of species including mammals (54–56).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [54]
Rapamycin has earned great interest over the years to prolong lifespan, even when administered to aged animals.
“Additionally, rapamycin has earned great interest over the years to prolong lifespan (195, 280), even when administered to aged animals (281).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [281]
Middle-aged mice on a diet supplemented with rapamycin survived significantly longer.
“Middle-aged mice on a diet supplemented with rapamycin survived significantly longer (Harrison et al., 2009); however, reports of the potent immunosuppressive properties of rapamycin suggest that the drug is unsuitable for lifespan extension in humans.”
From The Search for Antiaging Interventions: From Elixirs to Fasting Regimens (2014) · cites this paper as Harrison et al., 2009
Rapamycin selectively activates autophagy through inhibiting the mTOR pathway and can extend the lifespan of mice.
“Rapamycin selectively activates autophagy through inhibiting the mTOR pathway [60] and can extend the lifespan of mice [79].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [79]
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Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302 · see citing works
TOR signaling in growth and metabolism
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787 · see citing works
Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway
Kapahi, P., Zid, B. M., Harper, T., Koslover, D., Sapin, V., & Benzer, S. (2004) · Current Biology · doi:10.1016/j.cub.2004.03.059 · Cited by 1,293 · see citing works
Regulation of Yeast Replicative Life Span by TOR and Sch9 in Response to Nutrients
Kaeberlein, M., Powers, R. W., Steffen, K. K., Westman, E. A., Hu, D., Dang, N., Kerr, E. O., Kirkland, K. T., Fields, S., & Kennedy, B. K. (2005) · Science · doi:10.1126/science.1115535 · Cited by 1,293 · see citing works
Influence of TOR kinase on lifespan in C. elegans
Vellai, T., Takacs-Vellai, K., Zhang, Y., Kovacs, A. L., Orosz, L., & Müller, F. (2003) · Nature · doi:10.1038/426620a · Cited by 1,057 · see citing works
Overview of caloric restriction and ageing
Masoro, E. J. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.03.012 · Cited by 1,054 · see citing works
The Mouse in Biomedical Research
(1983) · Elsevier eBooks · doi:10.1016/c2013-0-10677-0 · Cited by 1,021 · see citing works
Extension of Chronological Life Span in Yeast by Decreased TOR Pathway Signaling
Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K., & Fields, S. (2006) · Genes & Development · doi:10.1101/gad.1381406 · Cited by 982 · see citing works
Mouse Models in Aging Research
Flurkey, K., MCURRER, J., & HARRISON, D. (2007) · Elsevier eBooks · doi:10.1016/b978-012369454-6/50074-1 · Cited by 904 · see citing works
Self-citationJia, K., Chen, D., & Riddle, D. L. (2004) · Development · doi:10.1242/dev.01255 · Cited by 705 · see citing works
Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice
Strong, R., Miller, R. A., Astle, C. M., Floyd, R. A., Flurkey, K., Hensley, K. L., Javors, M. A., Leeuwenburgh, C., Nelson, J. F., Ongini, E., et al. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2008.00414.x · Cited by 349 · see citing works
Self-citationReiling, J. H., & Sabatini, D. M. (2006) · Oncogene · doi:10.1038/sj.onc.1209889 · Cited by 338 · see citing works
Cancer risks among BRCA1 and BRCA2 mutation carriers
Levy‐Lahad, E., & Friedman, E. (2007) · British Journal of Cancer · doi:10.1038/sj.bjc.6603535 · Cited by 327 · see citing works
Temporal linkage between the phenotypic and genomic responses to caloric restriction
Dhahbi, J. M., Kim, H.-J., Mote, P. L., Beaver, R. J., & Spindler, S. R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0305300101 · Cited by 259 · see citing works
New modes of translational control in development, behavior, and disease.
Sonenberg, N., & Hinnebusch, A. (2007) · Molecules and Cells · doi:10.1016/j.molcel.2007.11.018 · Cited by 240 · see citing works
mTOR signaling: implications for cancer and anticancer therapy
Petroulakis, E., Mamane, Y., Bacquer, O. L., Shahbazian, D., & Sonenberg, N. (2005) · British Journal of Cancer · doi:10.1038/sj.bjc.6602902 · Cited by 239 · see citing works
An aging Interventions Testing Program: study design and interim report
Miller, R. A., Harrison, D. E., Astle, C. M., Floyd, R. A., Flurkey, K., Hensley, K., Javors, M. A., Leeuwenburgh, C., Nelson, J. F., Ongini, E., et al. (2007) · Aging Cell · doi:10.1111/j.1474-9726.2007.00311.x · Cited by 217 · see citing works
Self-citationStatistical methods for testing effects on “maximum lifespan”
Wang, C., Li, Q., Redden, D. T., Weindruch, R., & Allison, D. B. (2004) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.07.003 · Cited by 208 · see citing works
Extending Life: Scientific Prospects and Political Obstacles
Miller, R. A. (2002) · Milbank Quarterly · doi:10.1111/1468-0009.00006 · Cited by 168 · see citing works
Self-citationDesign of aging intervention studies: the NIA interventions testing program
Nadon, N. L., Strong, R., Miller, R. A., Nelson, J. F., Javors, M. A., Sharp, Z. D., Peralba, J. M., & Harrison, D. E. (2008) · AGE · doi:10.1007/s11357-008-9048-1 · Cited by 156 · see citing works
Self-citationKohn, R. R. (1971) · Prentice Hall eBooks · Cited by 150 · see citing works
Sharp, Z. D., & Bartke, A. (2005) · The Journals of Gerontology Series A · doi:10.1093/gerona/60.3.293 · Cited by 140 · see citing works
Self-citationBlumenthal, H. T. (1979) · Journal of Gerontology · doi:10.1093/geronj/34.3.446a · Cited by 102 · see citing works
In pursuit of the longevity dividend
Olshansky, S. J., Perry, D. P., Miller, R. A., & Butler, R. N. (2006) · The Scientist (Philadelphia, Pa. Online)/The Scientist · Cited by 94 · see citing works
Self-citationRapamycin's Resurrection: A New Way to Target the Cancer Cell Cycle
Garber, K. (2001) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/93.20.1517 · Cited by 82 · see citing works
Phelan, J., & Austad, S. N. (1994) · Journal of Gerontology · doi:10.1093/geronj/49.1.b1 · Cited by 74 · see citing works
Schneider, E. L., & Reed, J. D. (1985) · New England Journal of Medicine · doi:10.1056/nejm198505023121805 · Cited by 60 · see citing works
Lorberg, A., & Hall, M. N. (2004) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-18930-2_1 · Cited by 57 · see citing works
Akt/PKB and p38 MAPK signaling, translational initiation and longevity in Snell dwarf mouse livers
Hsieh, C.-C., & Papaconstantinou, J. (2004) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.07.008 · Cited by 56 · see citing works
Archer, J. R., & Harrison, D. E. (1996) · The Journals of Gerontology Series A · doi:10.1093/gerona/51a.6.b448 · Cited by 35 · see citing works
Self-citationMaximum Life Spans in Mice are Extended by Wild Strain Alleles
Klebanov, S., Astle, C. M., Roderick, T. H., Flurkey, K., Archer, J. R., & Chen, J. (2001) · Experimental Biology and Medicine · doi:10.1177/153537020122600908 · Cited by 33 · see citing works
Self-citationSELECTION FOR RADIATION RESISTANCE IN MICE
Roderick, T. H. (1963) · Genetics · doi:10.1093/genetics/48.2.205 · Cited by 26 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982 · see citing works
mTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509 · see citing works
mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555 · see citing works
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941 · see citing works
Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty
Ferrucci, L., & Fabbri, E. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0064-2 · Cited by 3,690 · see citing works
Extending Healthy Life Span—From Yeast to Humans
Fontana, L., Partridge, L., & Longo, V. D. (2010) · Science · doi:10.1126/science.1172539 · Cited by 3,023 · see citing works
mTOR at the nexus of nutrition, growth, ageing and disease
Liu, G. Y., & Sabatini, D. M. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0199-y · Cited by 2,737 · see citing works
Kenyon, C. J. (2010) · Nature · doi:10.1038/nature08980 · Cited by 2,739 · see citing works
Cellular senescence in ageing: from mechanisms to therapeutic opportunities
Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00314-w · Cited by 2,277 · see citing works
Hoeijmakers, J. H. J. (2009) · New England Journal of Medicine · doi:10.1056/nejmra0804615 · Cited by 2,239 · see citing works
Rubinsztein, D. C., Mariño, G., & Kroemer, G. (2011) · Cell · doi:10.1016/j.cell.2011.07.030 · Cited by 2,107 · see citing works
Induction of autophagy by spermidine promotes longevity
Eisenberg, T., Knauer, H., Schauer, A., Büttner, S., Ruckenstuhl, C., Carmona-Gutierrez, D., Ring, J., Schroeder, S., Magnes, C., Antonacci, L., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1975 · Cited by 1,680 · see citing works
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622 · see citing works
mTOR is a key modulator of ageing and age-related disease
Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013) · Nature · doi:10.1038/nature11861 · Cited by 1,676 · see citing works
The intersection between aging and cardiovascular disease
North, B. J., & Sinclair, D. A. (2012) · Circulation Research · doi:10.1161/circresaha.111.246876 · Cited by 1,585 · see citing works
Kinaan, M., Ding, H., & Triggle, C. R. (2015) · Medical Principles and Practice · doi:10.1159/000381643 · Cited by 1,515 · see citing works
Metformin improves healthspan and lifespan in mice
Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., Gomes, A. P., Ward, T. M., Minor, R. K., Blouin, M.-J., et al. (2013) · Nature Communications · doi:10.1038/ncomms3192 · Cited by 1,445 · see citing works
From discoveries in ageing research to therapeutics for healthy ageing
Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019) · Nature · doi:10.1038/s41586-019-1365-2 · Cited by 1,389 · see citing works
Autophagy modulation as a potential therapeutic target for diverse diseases
Rubinsztein, D. C., Codogno, P., & Levine, B. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3802 · Cited by 1,429 · see citing works
Stine, Z. E., Walton, Z. E., Altman, B. J., Hsieh, A. L., & Dang, C. V. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0507 · Cited by 1,375 · see citing works
Mechanisms of implantation: strategies for successful pregnancy
Cha, J., Sun, X., & Dey, S. K. (2012) · Nature Medicine · doi:10.1038/nm.3012 · Cited by 1,363 · see citing works
Neural mechanisms of ageing and cognitive decline
Bishop, N. A., Lu, T., & Yankner, B. A. (2010) · Nature · doi:10.1038/nature08983 · Cited by 1,323 · see citing works
Autophagy in healthy aging and disease
Aman, Y., Schmauck-Medina, T., Hansen, M., Morimoto, R. I., Simon, A. K., Bjedov, I., Palikaras, K., Simonsen, A., Johansen, T., Tavernarakis, N., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00098-4 · Cited by 1,313 · see citing works
The twilight of immunity: emerging concepts in aging of the immune system
Nikolich-Žugich, J. (2018) · Nature Immunology · doi:10.1038/s41590-017-0006-x · Cited by 1,240 · see citing works
Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States
Mattson, M. P., & Arumugam, T. V. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.05.011 · Cited by 1,242 · see citing works
Rapamycin: one drug, many effects
Li, J., Kim, S. G., & Blenis, J. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.01.001 · Cited by 1,287 · see citing works
Senescence and aging: Causes, consequences, and therapeutic avenues
McHugh, D., & Gil, J. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201708092 · Cited by 1,233 · see citing works
Mitochondria and the Autophagy–Inflammation–Cell Death Axis in Organismal Aging
Green, D. R., Galluzzi, L., & Kroemer, G. (2011) · Science · doi:10.1126/science.1201940 · Cited by 1,245 · see citing works
Regulation of the mTOR Complex 1 Pathway by Nutrients, Growth Factors, and Stress
Sengupta, S., Peterson, T. R., & Sabatini, D. M. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.026 · Cited by 1,234 · see citing works
Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity
Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., Davis, J. G., Salmon, A. B., Richardson, A., Ahima, R. S., et al. (2012) · Science · doi:10.1126/science.1215135 · Cited by 1,199 · see citing works
HIV Infection, Inflammation, Immunosenescence, and Aging
Deeks, S. G. (2011) · Annual Review of Medicine · doi:10.1146/annurev-med-042909-093756 · Cited by 1,349 · see citing works
Autophagy in malignant transformation and cancer progression
Galluzzi, L., Pietrocola, F., Bravo‐San Pedro, J. M., Amaravadi, R. K., Baehrecke, E. H., Cecconi, F., Codogno, P., Debnath, J., Gewirtz, D. A., Karantza, V., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490784 · Cited by 1,182 · see citing works
Laberge, R.-M., Sun, Y., Orjalo, A. V., Patil, C. K., Freund, A., Zhou, L., Curran, S. C., Davalos, A. R., Wilson-Edell, K. A., Liu, S., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3195 · Cited by 1,160 · see citing works
Self-citationSpermidine in health and disease
Madeo, F., Eisenberg, T., Pietrocola, F., & Kroemer, G. (2018) · Science · doi:10.1126/science.aan2788 · Cited by 1,154 · see citing works
Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span
Selman, C., Tullet, J. M. A., Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., Claret, M., Al-Qassab, H., Carmignac, D., Ramadani, F., et al. (2009) · Science · doi:10.1126/science.1177221 · Cited by 1,120 · see citing works
Fat tissue, aging, and cellular senescence
Tchkonia, T., Morbeck, D. E., Von Zglinicki, T., Van Deursen, J., Lustgarten, J., Scrable, H., Khosla, S., Jensen, M. D., & Kirkland, J. L. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00608.x · Cited by 1,094 · see citing works
Metformin as a tool to target aging
Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.011 · Cited by 1,096 · see citing works
Cellular senescence and senolytics: the path to the clinic
Chaib, S., Tchkonia, T., & Kirkland, J. L. (2022) · Nature Medicine · doi:10.1038/s41591-022-01923-y · Cited by 1,105 · see citing works
Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology
Forrester, S. J., Booz, G. W., Sigmund, C. D., Coffman, T. M., Kawai, T., Rizzo, V., Scalia, R. G., & Eguchi, S. (2018) · Physiological Reviews · doi:10.1152/physrev.00038.2017 · Cited by 1,106 · see citing works
Mitonuclear protein imbalance as a conserved longevity mechanism
Houtkooper, R. H., Mouchiroud, L., Ryu, D., Moullan, N., Katsyuba, E., Knott, G., Williams, R. W., & Auwerx, J. (2013) · Nature · doi:10.1038/nature12188 · Cited by 1,035 · see citing works
The sirtuin SIRT6 regulates lifespan in male mice
Kanfi, Y., Naiman, S., Amir, G., Peshti, V., Zinman, G., Nahum, L., Bar-Joseph, Z., & Cohen, H. Y. (2012) · Nature · doi:10.1038/nature10815 · Cited by 1,059 · see citing works
Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila Melanogaster
Bjedov, I., Toivonen, J. M., Kerr, F., Slack, C., Jacobson, J., Foley, A., & Partridge, L. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2009.11.010 · Cited by 1,057 · see citing works
Cellular senescence: a translational perspective
Kirkland, J. L., & Tchkonia, T. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.04.013 · Cited by 1,013 · see citing works
Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., Richardson, A., Strong, R., & Galvan, V. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009979 · Cited by 1,033 · see citing works
Self-citationRegulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks
Magnuson, B., Ekim, B., & Fingar, D. C. (2012) · Biochemical Journal · doi:10.1042/bj20110892 · Cited by 1,015 · see citing works
Epigenetic mechanisms of longevity and aging
Sen, P., Shah, P. P., Nativio, R., & Berger, S. L. (2016) · Cell · doi:10.1016/j.cell.2016.07.050 · Cited by 956 · see citing works
Rapamycin passes the torch: a new generation of mTOR inhibitors
Benjamin, D., Colombi, M., Moroni, C., & Hall, M. N. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3531 · Cited by 981 · see citing works
Solon-Biet, S. M., McMahon, A. C., Ballard, J. W. O., Ruohonen, K., Wu, L. E., Cogger, V. C., Warren, A., Huang, X., Pichaud, N., Melvin, R. G., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.02.009 · Cited by 904 · see citing works
Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control
Loewith, R., & Hall, M. (2011) · Genetics · doi:10.1534/genetics.111.133363 · Cited by 894 · see citing works
Targeting mTOR for cancer therapy
Hua, H., Kong, Q.-B., Zhang, H., Wang, J., Luo, T., & Jiang, Y.-F. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0754-1 · Cited by 772 · see citing works
Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice
Miller, R. A., Harrison, D. E., Astle, C. M., Baur, J. A., Boyd, A. R., de Cabo, R., Fernandez, E., Flurkey, K., Javors, M. A., Nelson, J. F., et al. (2011) · The Journals of Gerontology: Series A · doi:10.1093/gerona/glq178 · Cited by 896 · see citing works
Self-citationMolecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau
Caccamo, A., Majumder, S., Richardson, A., Strong, R., & Oddo, S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.100420 · Cited by 881 · see citing works
Self-citationβ-Hydroxybutyrate: A Signaling Metabolite
Newman, J. C., & Verdin, E. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064916 · Cited by 872 · see citing works
“Inhibition of the TOR (target of rapamycin) signaling complex by rapamycin (46), activation of AMPK by metformin (81), or provision of NAD+ precursors (161) recapitulates some of the beneficial effects of dietary restriction on diseases of aging and longevity.”
Brandhorst, S., Choi, I. Y., Wei, M., Cheng, C. W., Sedrakyan, S., Navarrete, G., Dubeau, L., Yap, L. P., Park, R., Vinciguerra, M., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.012 · Cited by 850 · see citing works
Metabolic control of autophagy
Galluzzi, L., Pietrocola, F., Levine, B., & Kroemer, G. (2014) · Cell · doi:10.1016/j.cell.2014.11.006 · Cited by 855 · see citing works
AMP-Activated Protein Kinase (AMPK) Controls the Aging Process via an Integrated Signaling Network
Salminen, A., & Kaarniranta, K. (2012) · Ageing Research Reviews · doi:10.1016/j.arr.2011.12.005 · Cited by 860 · see citing works
Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH
Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., & Cai, D. (2013) · Nature · doi:10.1038/nature12143 · Cited by 834 · see citing works
Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles
Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R., & Kroemer, G. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.22 · Cited by 842 · see citing works
Mitochondria as a therapeutic target for common pathologies
Murphy, M. P., & Hartley, R. C. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.174 · Cited by 832 · see citing works
The mTOR Signalling Pathway in Human Cancer
Pópulo, H., Lopes, J. M., & Soares, P. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13021886 · Cited by 830 · see citing works
The Critical Role of Metabolic Pathways in Aging
Barzilai, N., Huffman, D. M., Muzumdar, R. H., & Bartke, A. (2012) · Diabetes · doi:10.2337/db11-1300 · Cited by 803 · see citing works
Regulation and metabolic functions of mTORC1 and mTORC2.
Szwed, A., Kim, E., & Jacinto, E. (2021) · Physiological Reviews · doi:10.1152/physrev.00026.2020 · Cited by 723 · see citing works
Senescence and aging: the critical roles of p53
Rufini, A., Tucci, P., Celardo, I., & Melino, G. (2013) · Oncogene · doi:10.1038/onc.2012.640 · Cited by 798 · see citing works
mTOR inhibition improves immune function in the elderly
Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., Lonetto, M. A., Maecker, H. T., Kovarik, J., Carson, S., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009892 · Cited by 786 · see citing works
Mitochondria are required for pro-ageing features of the senescent phenotype
Correia‐Melo, C., Marques, F. D., Anderson, R., Hewitt, G., Hewitt, R., Cole, J., Carroll, B. M., Miwa, S., Birch, J., Merz, A., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201592862 · Cited by 796 · see citing works
mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype
Herranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C. J., Raguz, S., Acosta, J. C., Innes, A. J., Banito, A., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3225 · Cited by 788 · see citing works
Self-citationMetabolic Control of Longevity
López-Otín, C., Galluzzi, L., Freije, J. M. P., Madeo, F., & Kroemer, G. (2016) · Cell · doi:10.1016/j.cell.2016.07.031 · Cited by 753 · see citing works
Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease
Smith, R. L., Soeters, M. R., Wüst, R. C. I., & Houtkooper, R. H. (2018) · Endocrine Reviews · doi:10.1210/er.2017-00211 · Cited by 787 · see citing works
Human iPSC-based modeling of late-onset disease via progerin-induced aging
Miller, J. D., Ganat, Y. M., Kishinevsky, S., Bowman, R. L., Liu, B., Tu, E. Y., Mandal, P. K., Vera, E., Shim, J.-W., Kriks, S., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.11.006 · Cited by 777 · see citing works
Speakman, J. R., & Mitchell, S. E. (2011) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2011.07.001 · Cited by 769 · see citing works
Molecular mechanisms of dietary restriction promoting health and longevity
Green, C. L., Lamming, D. W., & Fontana, L. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00411-4 · Cited by 714 · see citing works
Lipton, J. O., & Şahin, M. (2014) · Neuron · doi:10.1016/j.neuron.2014.09.034 · Cited by 732 · see citing works
Mechanistic Pathways of Sex Differences in Cardiovascular Disease
Regitz‐Zagrosek, V., & Kararigas, G. (2016) · Physiological Reviews · doi:10.1152/physrev.00021.2015 · Cited by 738 · see citing works
Translational Regulation of Gene Expression during Conditions of Cell Stress
Spriggs, K. A., Bushell, M., & Willis, A. E. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.028 · Cited by 721 · see citing works
Overexpression of Atg5 in mice activates autophagy and extends lifespan
Pyo, J.-O., Yoo, S.-M., Ahn, H.-H., Nah, J., Hong, S.-H., Kam, T.-I., Jung, S., & Jung, Y.-K. (2013) · Nature Communications · doi:10.1038/ncomms3300 · Cited by 721 · see citing works
Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease
Donato, A. J., Machin, D. R., & Lesniewski, L. A. (2018) · Circulation Research · doi:10.1161/circresaha.118.312563 · Cited by 699 · see citing works
The role of protein clearance mechanisms in organismal ageing and age-related diseases
Vı́lchez, D., Sáez, I., & Dillin, A. G. (2014) · Nature Communications · doi:10.1038/ncomms6659 · Cited by 684 · see citing works
TOR Signaling and Rapamycin Influence Longevity by Regulating SKN-1/Nrf and DAF-16/FoxO
Robida-Stubbs, S., Glover-Cutter, K., Lamming, D. W., Mizunuma, M., Narasimhan, S. D., Neumann-Haefelin, E., Sabatini, D. M., & Blackwell, T. K. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.007 · Cited by 648 · see citing works
mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells
Chen, C., Liu, Y., Liu, Y., & Zheng, P. (2009) · Science Signaling · doi:10.1126/scisignal.2000559 · Cited by 680 · see citing works
Wilkinson, J. E., Burmeister, L., Brooks, S. V., Chan, C., Friedline, S., Harrison, D. E., Hejtmancik, J. F., Nadon, N. L., Strong, R., Wood, L. K., et al. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00832.x · Cited by 682 · see citing works
Self-citationFang, E. F., Xie, C., Schenkel, J. A., Wu, C., Long, Q., Cui, H., Aman, Y., Frank, J., Liao, J., Zou, H., et al. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101174 · Cited by 704 · see citing works
Metabolic Plasticity in Stem Cell Homeostasis and Differentiation
Folmes, C. D. L., Dzeja, P. P., Nelson, T. J., & Terzic, A. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.10.002 · Cited by 664 · see citing works
Regulation of mTORC1 and its impact on gene expression at a glance
Laplante, M., & Sabatini, D. M. (2013) · Journal of Cell Science · doi:10.1242/jcs.125773 · Cited by 665 · see citing works
With TOR, Less Is More: A Key Role for the Conserved Nutrient-Sensing TOR Pathway in Aging
Kapahi, P., Chen, D., Rogers, A. N., Katewa, S. D., Li, P. W.-L., Thomas, E., & Kockel, L. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.05.001 · Cited by 663 · see citing works
mTORC1 controls fasting-induced ketogenesis and its modulation by ageing
Sengupta, S., Peterson, T. R., Laplante, M., Oh, S., & Sabatini, D. M. (2010) · Nature · doi:10.1038/nature09584 · Cited by 646 · see citing works
SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans
Blackwell, T. K., Steinbaugh, M. J., Hourihan, J. M., Ewald, C. Y., & Isik, M. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.008 · Cited by 622 · see citing works
Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells
Xian, L., Wu, X., Pang, L., Lou, M., Rosen, C. J., Qiu, T., Crane, J., Frassica, F., Zhang, L., Rodriguez, J. P., et al. (2012) · Nature Medicine · doi:10.1038/nm.2793 · Cited by 631 · see citing works
Mitochondria-Ros Crosstalk in the Control of Cell Death and Aging
Marchi, S., Giorgi, C., Suski, J. M., Agnoletto, C., Bononi, A., Bonora, M., Marchi, E. D., Missiroli, S., Patergnani, S., Poletti, F., et al. (2011) · Journal of Signal Transduction · doi:10.1155/2012/329635 · Cited by 639 · see citing works
Aging and age‐related diseases: from mechanisms to therapeutic strategies
Li, Z., Zhang, Z., Ren, Y., Wang, Y., Fang, J., Yue, H., Ma, S., & Guan, F. (2021) · Biogerontology · doi:10.1007/s10522-021-09910-5 · Cited by 668 · see citing works
Madeo, F., Carmona-Gutierrez, D., Hofer, S. J., & Kroemer, G. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.018 · Cited by 630 · see citing works
mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review
Weichhart, T. (2018) · Gerontology · doi:10.1159/000484629 · Cited by 596 · see citing works
Anti-apoptosis and cell survival: A review
Portt, L., Norman, G., Clapp, C., Greenwood, M., & Greenwood, M. T. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.10.010 · Cited by 640 · see citing works
The ageing haematopoietic stem cell compartment
Geiger, H., de Haan, G., & Florian, M. C. (2013) · Nature Reviews Immunology · doi:10.1038/nri3433 · Cited by 604 · see citing works
Targeting cellular senescence with senotherapeutics: senolytics and senomorphics
Zhang, L. J., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022) · FEBS Journal · doi:10.1111/febs.16350 · Cited by 648 · see citing works
Intermittent metabolic switching, neuroplasticity and brain health
Mattson, M. P., Moehl, K., Ghena, N., Schmaedick, M., & Cheng, A. (2018) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.156 · Cited by 624 · see citing works
Miller, R. A., Harrison, D. E., Astle, C. M., Fernández, E., Flurkey, K., Han, M. L., Javors, M. A., Li, X., Nadon, N. L., Nelson, J. F., et al. (2013) · Aging Cell · doi:10.1111/acel.12194 · Cited by 624 · see citing works
Self-citationSIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation
Barber, M. F., Michishita-Kioi, E., Xi, Y., Tasselli, L., Kioi, M., Moqtaderi, Z., Tennen, R. I., Paredes, S., Young, N. L., Chen, K., et al. (2012) · Nature · doi:10.1038/nature11043 · Cited by 621 · see citing works
Morselli, E., Maiuri, M. C., Markaki, M., Megalou, E., Pasparaki, A., Palikaras, K., Criollo, A., Galluzzi, L., Malik, S. A., Vitale, I., et al. (2010) · Cell Death & Disease · doi:10.1038/cddis.2009.8 · Cited by 613 · see citing works
Interventions to slow aging in humans: are we ready?
Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., Curiel, T. J., Cabo, R., Franceschi, C., Gems, D., et al. (2015) · Aging Cell · doi:10.1111/acel.12338 · Cited by 592 · see citing works
FOXO transcription factors: key regulators of cellular quality control
Webb, A. E., & Brunet, A. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.02.003 · Cited by 620 · see citing works
- Authors
- Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., Pahor, M., Javors, M. A., Fernandez, E., & Miller, R. A.
- Affiliations
- Jackson Laboratory (US)
- The University of Texas at San Antonio Health Science Center (US)
- National Institutes of Health (US)
- University of Michigan (US)
- NYU Langone Health (US)
- University of Florida (US)
- Corresponding author
- Harrison, David E.
- ORCID
- Venue
- Nature
- Published
- 2009-07
- Volume
- 460
- Issue
- 7253
- Pages
- 392-395
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2786175
- OpenAlex
- W2048376025
- Cited by
- 3,766
- References
- 32
- Citations by year
- 2026: 185 · 2025: 208 · 2024: 182 · 2023: 199 · 2022: 211 · 2021: 225 · 2020: 194 · 2019: 252 · 2018: 202 · 2017: 219 · 2016: 232 · 2015: 249 · 2014: 254 · 2013: 228 · 2012: 262
- FWCI
- 74.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institute on Aging (AG 022308, AG13319, P30AG025707, AG022307, AG022303, AG025707, P30AG013319, U01AG022307, P30AG028740, U01AG022308, U01AG022303)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- rapamycin, mTOR signaling, TOR signaling, lifespan extension, aging, genetically heterogeneous mice, sex differences in longevity, age-related diseases, PI3K/AKT/mTOR pathway, cancer mortality, dietary restriction, autophagy, translational regulation, survival analysis
- MeSH terms
- Administration, Oral, Aging, Animals, Carrier Proteins, Diet, Disease Susceptibility, Female, Longevity, Male, Specific Pathogen-Free Organisms, Time Factors, Survival Analysis, Phosphotransferases (Alcohol Group Acceptor), Sirolimus, Mice, TOR Serine-Threonine Kinases
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