The DOI matches its Crossref record; 100 of the 100 references it cites were found in a registry or an index.
mTOR is a key modulator of ageing and age-related disease
Open accessAbstract
Many experts in the biology of ageing believe that pharmacological interventions to slow ageing are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the mammalian target of rapamycin (mTOR) pathway, which is induced by amino acids, growth factors, and RT, is often inhibited during CR, and mediates CR-induced health benefits in model organisms [37].”
From Resistance Training Prevents Muscle Loss Induced by Caloric Restriction in Obese Elderly Individuals: A Systematic Review and Meta-Analysis (2018) · cites this paper as [37]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [121]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [121]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Genetic down-regulation of mTORC1 activity in yeast, worms and flies extends longevity and attenuates further longevity benefits from DR, suggesting that mTOR inhibition phenocopies DR”
From The Hallmarks of Aging (2013) · cites this paper as Johnson et al., 2013
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Inhibition of mTOR has been shown to extend lifespan and to improve the function of ageing organ systems, including the immune system, in multiple preclinical species.18, 19”
From Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials (2021) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“One of the best validated mechanisms underlying ageing biology is the activity of the protein kinase mTOR.”
From Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials (2021) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“More importantly, these pathways have been evaluated in mammalian models, in which health span and lifespan have been extended by genetic manipulation or drugs (Johnson et al., 2013).”
From Metformin as a tool to target aging (2016) · cites this paper as Johnson et al., 2013
In the citing paper
“Of significance is that metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster (fruit fly) (221–225).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [224]
In the citing paper
“Of significance is that metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster (fruit fly) (221–225).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [224]
In the citing paper
“Based on previous studies in the aging field, it is believed that Nrf2 is repressed by mTOR pathway (downstream target); therefore, an inhibition of mTOR by rapamycin would increase the activity of Nrf2 (Johnson et al., 2013).”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Johnson et al., 2013
In the citing paper
“The benefits of nicotinamide riboside can be suppressed by treatment of mice with inhibitors of either SIRT1 or mTOR complex 1 (mTORC1), which is paradoxical as inhibition of mTORC1 signalling normally extends healthspan and lifespan220.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [220]
In the citing paper
“The benefits of nicotinamide riboside can be suppressed by treatment of mice with inhibitors of either SIRT1 or mTOR complex 1 (mTORC1), which is paradoxical as inhibition of mTORC1 signalling normally extends healthspan and lifespan220.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [220]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
Autophagy fights disease through cellular self-digestion
Mizushima, N., Levine, B., Cuervo, A. M., & Klionsky, D. J. (2008) · Nature · doi:10.1038/nature06639 · Cited by 6,452
TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
Inoki, K., Zhu, T., & Guan, K.-L. (2003) · Cell · doi:10.1016/s0092-8674(03)00929-2 · Cited by 3,914
AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint
Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E., & Shaw, R. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.003 · Cited by 3,849
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
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., et al. (2009) · Nature · doi:10.1038/nature08221 · Cited by 3,766
Aging, natural death, and the compression of morbidity
Fries, J. F. (1980) · New England Journal of Medicine · doi:10.1056/nejm198007173030304 · Cited by 3,356
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
Kenyon, C. J. (2010) · Nature · doi:10.1038/nature08980 · Cited by 2,739
Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys
Colman, R. J., Anderson, R. M., Johnson, S. C., Kastman, E. K., Kosmatka, K. J., Beasley, T. M., Allison, D. B., Cruzen, C., Simmons, H. A., Kemnitz, J. W., et al. (2009) · Science · doi:10.1126/science.1173635 · Cited by 2,277
Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
Um, S. H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P. R., Kozma, S. C., Auwerx, J., et al. (2004) · Nature · doi:10.1038/nature02866 · Cited by 1,677
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
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
Geroscience: Linking Aging to Chronic Disease
Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., Franceschi, C., Lithgow, G. J., Morimoto, R. I., Pessin, J. E., et al. (2014) · Cell · doi:10.1016/j.cell.2014.10.039 · Cited by 2,764
The PI3K Pathway in Human Disease
Fruman, D. A., Chiu, H., Hopkins, B. D., Bagrodia, S., Cantley, L. C., & Abraham, R. T. (2017) · Cell · doi:10.1016/j.cell.2017.07.029 · Cited by 2,749
“The evolutionarily conserved role of PI3K and mTOR in organismal aging also provides new opportunities to extend lifespan and, more importantly, healthspan through partial pathway inhibition (Johnson et al., 2013; Pan and Finkel, 2017; Selman et al., 2009; Wu et al., 2013).”
Facing up to the global challenges of ageing
Partridge, L., Deelen, J., & Slagboom, P. E. (2018) · Nature · doi:10.1038/s41586-018-0457-8 · Cited by 1,475
Ageing and the pathogenesis of osteoarthritis
Loeser, R. F., Collins, J. A., & Diekman, B. O. (2016) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2016.65 · Cited by 1,344
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
Promoting Health and Longevity through Diet: From Model Organisms to Humans
Fontana, L., & Partridge, L. (2015) · Cell · doi:10.1016/j.cell.2015.02.020 · Cited by 1,245
SIRT1 and other sirtuins in metabolism
Chang, H.-C., & Guarente, L. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.12.001 · Cited by 1,157
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
The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates
Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., Monti, D., Capri, M., & Salvioli, S. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00061 · Cited by 945
“In fact, an inhibition of this pathway extends the lifespan of many species (84).”
BackgroundIn Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.
Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., Li, M., Lam, D., Kurita, M., Beyret, E., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.052 · Cited by 988
β-Hydroxybutyrate: A Signaling Metabolite
Newman, J. C., & Verdin, E. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064916 · Cited by 872
“This is one of several examples of intersections between BHB, its signaling effects, and mTOR/rapamycin, a canonical longevity-regulating pathway (55).”
Regulated cell death (RCD) in cancer: key pathways and targeted therapies
Peng, F., Liao, M., Qin, R., Zhu, S., Peng, C. Y., Fu, L., Chen, Y., & Han, B. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01110-y · Cited by 895
Metabolic 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
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
Lipton, J. O., & Şahin, M. (2014) · Neuron · doi:10.1016/j.neuron.2014.09.034 · Cited by 767
Human Ageing Genomic Resources: new and updated databases
Tacutu, R., Thornton, D., Johnson, E., Budovsky, A., Barardo, D., Craig, T., Diana, E., Lehmann, G., Toren, D., Wang, J., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gkx1042 · Cited by 738
“Examples of these include MYC, an oncogene mainly studied in the context of cancer (8), MTOR, a regulator of several cellular processes which was found to play a role in ageing in various model organisms (9), and TP53, a well-known tumour suppressor (10) (Figure 1).”
BackgroundSKN-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
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 702
“Recent studies have found that rapamycin can inhibit the mechanistic target of rapamycin (mTOR) protein kinase and extend the average lifespan of yeast, C. elegans, and fruit flies, but the role in mammals needs to be explored further (Johnson et al. 2013).”
BackgroundmTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review
Weichhart, T. (2018) · Gerontology · doi:10.1159/000484629 · Cited by 596
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
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
“Loss of S6 kinase promotes longevity in yeast, flies, worms, and mice (Johnson et al., 2013), and increased 4E-BP1 activity promotes longevity at least in flies.”
InfluentialMarçais, A., Cherfils‐Vicini, J., Viant, C., Degouve, S., Viel, S., Fenis, A., Rabilloud, J., Mayol, K., Tavares, A., Bienvenu, J., et al. (2014) · Nature Immunology · doi:10.1038/ni.2936 · Cited by 643
Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases
Barnes, P. J., Baker, J. R., & Donnelly, L. (2019) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201810-1975tr · Cited by 571
Metabolic Regulation of T Cell Longevity and Function in Tumor Immunotherapy
Kishton, R. J., Sukumar, M., & Restifo, N. P. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.016 · Cited by 548
“At a cellular level, CR (and pharmacological or genetic mimetics) acts through the regulation of cellular signaling pathways that are key players in modulating the activities of cell intrinsic metabolic pathways (Figure 3) (Johnson et al., 2013).”
mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse Model of Leigh Syndrome
Johnson, S. C., Yanos, M. E., Kayser, E.-B., Quintana, A., Sangesland, M., Castanza, A., Uhde, L., Hui, J., Wall, V. Z., Gagnidze, A., et al. (2013) · Science · doi:10.1126/science.1244360 · Cited by 512
AMPK at the Nexus of Energetics and Aging
Burkewitz, K., Zhang, Y., & Mair, W. B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.002 · Cited by 483
mTOR as a key regulator in maintaining skeletal muscle mass
Yoon, M.-S. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00788 · Cited by 495
“Inhibition of mTOR signaling in aged muscle may have similar beneficial effects on multiple age related pathologies (Johnson et al., 2013b).”
BackgroundTORC1 inhibition enhances immune function and reduces infections in the elderly
Mannick, J. B., Morris, M., Hockey, H.-U. P., Roma, G., Beibel, M., Kulmatycki, K., Watkins, M., Shavlakadze, T., Zhou, W., Quinn, D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aaq1564 · Cited by 496
Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice
Bitto, A., Ito, T. K., Pineda, V. V., LeTexier, N. J., Huang, H. Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K., et al. (2016) · eLife · doi:10.7554/elife.16351 · Cited by 474
New Insights Into the Role of mTOR Signaling in the Cardiovascular System
Sciarretta, S., Forte, M., Frati, G., & Sadoshima, J. (2018) · Circulation Research · doi:10.1161/circresaha.117.311147 · Cited by 497
Sirtuins, a promising target in slowing down the ageing process
Grabowska, W., Sikora, E., & Bielak-Zmijewska, A. (2017) · Biogerontology · doi:10.1007/s10522-017-9685-9 · Cited by 470
Calorie restriction and sirtuins revisited
Guarente, L. (2013) · Genes & Development · doi:10.1101/gad.227439.113 · Cited by 464
Control of satellite cell function in muscle regeneration and its disruption in ageing
Sousa-Victor, P., García-Prat, L., & Muñoz-Cánoves, P. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00421-2 · Cited by 476
Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases
Giorgi, C., Marchi, S., Simões, I. C. M., Ren, Z., Morciano, G., Perrone, M., Patalas‐Krawczyk, P., Borchard, S., Jędrak, P., Pierzynowska, K., et al. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.05.006 · Cited by 484
Mammalian Target of Rapamycin Signaling in Cardiac Physiology and Disease
Sciarretta, S., Volpe, M., & Sadoshima, J. (2014) · Circulation Research · doi:10.1161/circresaha.114.302022 · Cited by 458
Aging Hallmarks and the Role of Oxidative Stress
Maldonado, E., Morales, S., Urbina, F., & Solari, A. (2023) · Antioxidants · doi:10.3390/antiox12030651 · Cited by 491
“The inhibition of this pathway confers protection against several age-associated diseases and extends the lifespan in several organisms [260].”
BackgroundAutophagy and the cell biology of age-related disease
Leidal, A. M., Levine, B., & Debnath, J. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0235-8 · Cited by 424
The Mitochondrial Basis of Aging and Age-Related Disorders
Srivastava, S. (2017) · Genes · doi:10.3390/genes8120398 · Cited by 446
“Finally, pharmacological drugs such as rapamycin (mTOR inhibitor) and metformin (AMPK activator) also extend lifespan in model organisms and confer protection against several age-related pathologies [217,218].”
BackgroundCai, Y., Song, W., Li, J., Jing, Y., Liang, C., Zhang, L., Zhang, X., Zhang, W., Liu, B., An, Y., et al. (2022) · Science China Life Sciences · doi:10.1007/s11427-022-2161-3 · Cited by 450
Metformin: Mechanisms in Human Obesity and Weight Loss
Yerevanian, A., & Soukas, A. A. (2019) · Current Obesity Reports · doi:10.1007/s13679-019-00335-3 · Cited by 414
Ageing and rejuvenation of tissue stem cells and their niches
Brunet, A., Goodell, M. A., & Rando, T. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00510-w · Cited by 407
Asymmetric organocatalysis: an enabling technology for medicinal chemistry
Han, B., He, X., Liu, Y., He, G., Peng, C. Y., & Li, J. (2021) · Chemical Society Reviews · doi:10.1039/d0cs00196a · Cited by 409
Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism
Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., Caples, K., Bradley, L., Beaver, L. M., Ho, E., et al. (2017) · Aging Cell · doi:10.1111/acel.12587 · Cited by 360
Inflammaging decreases adaptive and innate immune responses in mice and humans
Frasca, D., & Blomberg, B. B. (2016) · Biogerontology · doi:10.1007/s10522-015-9578-8 · Cited by 357
Meiners, S., Eickelberg, O., & Königshoff, M. (2015) · European Respiratory Journal · doi:10.1183/09031936.00186914 · Cited by 340
Healthy aging: The ultimate preventative medicine
Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015) · Science · doi:10.1126/science.aad3267 · Cited by 341
Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity
Ewald, C. Y., Landis, J. N., Abate, J. P., Murphy, C. T., & Blackwell, T. K. (2014) · Nature · doi:10.1038/nature14021 · Cited by 331
Accelerated ageing of the lung in COPD: new concepts
Mercado, N., Ito, K., & Barnes, P. J. (2015) · Thorax · doi:10.1136/thoraxjnl-2014-206084 · Cited by 350
Hu, J., Ma, L., Nie, Y., Chen, J., Zheng, W., Wang, X., Xie, C., Zheng, Z., Wang, Z., Yang, T., et al. (2018) · Cell Host & Microbe · doi:10.1016/j.chom.2018.11.006 · Cited by 339
“Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that regulates cellular metabolism by its phosphorylation function (Johnson et al., 2013).”
BackgroundThe metabolic regulation of aging
Finkel, T. (2015) · Nature Medicine · doi:10.1038/nm.3998 · Cited by 325
Restoring function after spinal cord injury: towards clinical translation of experimental strategies
Ramer, L. M., Ramer, M. S., & Bradbury, E. J. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70144-9 · Cited by 335
Molecular logic of mTORC1 signalling as a metabolic rheostat
Valvezan, A. J., & Manning, B. D. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0038-7 · Cited by 310
Effect of rapamycin on aging and age-related diseases—past and future
Selvarani, R., Mohammed, S., & Richardson, A. (2021) · GeroScience · doi:10.1007/s11357-020-00274-1 · Cited by 290
A review of inflammatory mechanism in airway diseases
Aghasafari, P., George, U. Z., & Pidaparti, R. M. V. (2018) · Inflammation Research · doi:10.1007/s00011-018-1191-2 · Cited by 325
“Sirtuins (SIRT1 and SIRT6) upregulate FOXO3A and promotes autophagy [124, 128, 129].”
BackgroundA sestrin-dependent Erk–Jnk–p38 MAPK activation complex inhibits immunity during aging
Lanna, A., Gomes, D. C. O., Muller-Durovic, B., McDonnell, T., Escors, D., Gilroy, D. W., Lee, J. H., Karin, M., & Akbar, A. N. (2017) · Nature Immunology · doi:10.1038/ni.3665 · Cited by 284
Reduced Expression of MYC Increases Longevity and Enhances Healthspan
Hofmann, J. W., Zhao, X., De Cecco, M., Peterson, A. L., Pagliaroli, L., Manivannan, J., Hubbard, G. B., Ikeno, Y., Zhang, Y., Feng, B., et al. (2015) · Cell · doi:10.1016/j.cell.2014.12.016 · Cited by 293
Autophagy and the hallmarks of aging
Kaushik, S., Tasset, I., Arias, E., Pampliega, O., Wong, E., Martinez-Vicente, M., & Cuervo, A. M. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101468 · Cited by 285
The Genetics of Aging: A Vertebrate Perspective
Singh, P. P., Demmitt, B. A., Nath, R. D., & Brunet, A. (2019) · Cell · doi:10.1016/j.cell.2019.02.038 · Cited by 259
“In fact, interventions in humans are already being developed as a result of understanding the genetic regulation of aging, including rapamycin and related compounds (Johnson et al., 2013; Mannick et al., 2014) and metformin (Barzilai et al.”
BackgroundKetogenic diets, mitochondria, and neurological diseases
Gano, L. B., Patel, M., & Rho, J. M. (2014) · Journal of Lipid Research · doi:10.1194/jlr.r048975 · Cited by 291
Mohammed, I., Hollenberg, M. D., Ding, H., & Triggle, C. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.718942 · Cited by 278
Metformin: Is it a drug for all reasons and diseases?
Triggle, C. R., Mohammed, I., Bshesh, K., Marei, I., Ye, K., Ding, H., MacDonald, R. S., Hollenberg, M. D., & Hill, M. A. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155223 · Cited by 300
Discovery of piperlongumine as a potential novel lead for the development of senolytic agents
Wang, Y., Chang, J., Liu, X., Zhang, X., Zhang, S., Zhang, X., Zhou, D., & Zheng, G. (2016) · Aging · doi:10.18632/aging.101100 · Cited by 274
Regulation of Stem Cell Aging by Metabolism and Epigenetics
Ren, R., Ocampo, A., Liu, G., & Belmonte, J. C. I. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.019 · Cited by 286
Skeletal Aging and Osteoporosis: Mechanisms and Therapeutics
Chandra, A., & Rajawat, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073553 · Cited by 281
Senescence in COPD and Its Comorbidities
Barnes, P. J. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034314 · Cited by 278
Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics
Yu, B., Ma, J., Li, J., Wang, D., Wang, Z., & Wang, S. (2020) · Nature Communications · doi:10.1038/s41467-020-16312-7 · Cited by 275
Therapeutic Targeting of Autophagy in Disease: Biology and Pharmacology
Cheng, Y., Ren, X., Hait, W. N., & Yang, J. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.007120 · Cited by 262
Aging of the T Cell Compartment in Mice and Humans: From No Naive Expectations to Foggy Memories
Nikolich-Žugich, J. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401174 · Cited by 259
Horizons in the evolution of aging
Flatt, T., & Partridge, L. (2018) · BMC Biology · doi:10.1186/s12915-018-0562-z · Cited by 273
Importance of circadian timing for aging and longevity
Acosta-Rodríguez, V. A., Rijo‐Ferreira, F., Green, C. B., & Takahashi, J. S. (2021) · Nature Communications · doi:10.1038/s41467-021-22922-6 · Cited by 258
McCormick, M. A., Delaney, J. R., Tsuchiya, M., Tsuchiyama, S. K., Shemorry, A., Sim, S., Chou, A., Ahmed, U., Carr, D. T., Murakami, C. J., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.09.008 · Cited by 242
Valenzano, D. R., Benayoun, B. A., Singh, P. P., Zhang, E., Etter, P. D., Hu, C., Clément‐Ziza, M., Willemsen, D., Cui, R., Harel, I., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.008 · Cited by 245
H3K36 methylation promotes longevity by enhancing transcriptional fidelity
Sen, P., Dang, W., Donahue, G., Dai, J., Dorsey, J., Cao, X., Liu, W., Cao, K., Perry, R., Lee, J. Y., et al. (2015) · Genes & Development · doi:10.1101/gad.263707.115 · Cited by 233
Self-citationAutophagy in Cardiovascular Aging
Abdellatif, M., Sedej, S., Carmona-Gutierrez, D., Madeo, F., & Kroemer, G. (2018) · Circulation Research · doi:10.1161/circresaha.118.312208 · Cited by 239
“Downregulation or inhibition of mTOR promotes longevity of different model organisms.(57) In mice, reduced expression of mTOR(58) or its inhibition by rapamycin early(59) or even late in life(60) is sufficient to extend lifespan.”
BackgroundWang, S., Li, H., Yuan, M., Fan, H., & Cai, Z. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.1015500 · Cited by 236
“Second, inhibition of mTORC1 by AMPK is brought about by direct phosphorylation of the Ser722 and Ser792 residues in RAPTOR (Regulatory-associated protein of mTOR) (Johnson et al., 2013).”
BackgroundEvolution of sex differences in lifespan and aging: causes and constraints
Maklakov, A. A., & Lummaa, V. (2013) · BioEssays · doi:10.1002/bies.201300021 · Cited by 227
Ganguly, P., El‐Jawhari, J. J., Giannoudis, P. V., Burska, A. N., Ponchel, F., & Jones, E. (2017) · Cell Transplantation · doi:10.1177/0963689717721201 · Cited by 236
“This pathway has been the target of wide interest ever since it was discovered, and it has been suggested that inhibition of this pathway could extend the life span of rodents.(89) The role of rapamycin in the differentiation of MSCs or their progenitors has also been studied, but to date, the results are controversia…”
BackgroundTargeting immune dysfunction in aging
Borgoni, S., Kudryashova, K. S., Burka, K., & de Magalhães, J. P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101410 · Cited by 232
“Rapamycin, a specific mTORC1 inhibitor and CR mimicker, is able to increase longevity in various model organisms (Blagosklonny, 2019; Johnson et al., 2013).”
Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans
Heintz, C., Doktor, T. K., Lanjuin, A., Escoubas, C. C., Zhang, Y., Weir, H. J. M., Dutta, S., Silva-García, C. G., Bruun, G. H., Morantte, I. G., et al. (2016) · Nature · doi:10.1038/nature20789 · Cited by 217
Vitamin D cell signalling in health and disease
Berridge, M. J. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.01.008 · Cited by 215
Sierra, F. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025163 · Cited by 226
Roles of mTOR complexes in the kidney: implications for renal disease and transplantation
Fantus, D., Rogers, N. M., Grahammer, F., Huber, T. B., & Thomson, A. W. (2016) · Nature Reviews Nephrology · doi:10.1038/nrneph.2016.108 · Cited by 208
PI3K/AKT/mTOR signaling pathway as a therapeutic target for ovarian cancer
Li, H., Zeng, J., & Shen, K. (2014) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-014-3377-3 · Cited by 206
Wang, S., Xia, P., Ye, B., Huang, G., Liu, J., & Fan, Z. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.10.005 · Cited by 209
Sharples, A. P., Hughes, D. C., Deane, C. S., Saini, A. S., Selman, C., & Stewart, C. E. (2015) · Aging Cell · doi:10.1111/acel.12342 · Cited by 204
Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo
Omori, S., Wang, T.-W., Johmura, Y., Kanai, T., Nakano, Y., Kido, T., Susaki, E. A., Nakajima, T., Shichino, S., Ueha, S., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.09.006 · Cited by 194
The Effects of Intermittent Fasting on Brain and Cognitive Function
Gudden, J., Vásquez, A. A., & Bloemendaal, M. (2021) · Nutrients · doi:10.3390/nu13093166 · Cited by 212
“Neurons are able to regulate the synthesis of proteins in response to fluctuations in the availability of nutrition, namely through the mTOR pathway [29].”
BackgroundGut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway
He, D. N., Wu, H., Xiang, J., Ruan, X., Peng, P., Ruan, Y., Chen, Y., Wang, Y., Yu, Q., Zhang, H., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13911-x · Cited by 198
Mechanisms of development of multimorbidity in the elderly
Barnes, P. J. (2015) · European Respiratory Journal · doi:10.1183/09031936.00229714 · Cited by 204
Tubastatin A/ACY-1215 Improves Cognition in Alzheimer's Disease Transgenic Mice
Zhang, L., Liu, C., Wu, J., Tao, J.-J., Sui, X., Yao, Z., Xu, Y., Huang, L., Zhu, H., Sheng, S., et al. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140066 · Cited by 193
Characterization of the direct targets of FOXO transcription factors throughout evolution
Webb, A. E., Kundaje, A., & Brunet, A. (2016) · Aging Cell · doi:10.1111/acel.12479 · Cited by 182
Protein biogenesis machinery is a driver of replicative aging in yeast
Janssens, G. E., Meinema, A. C., González, J., Wolters, J. C., Schmidt, A., Guryev, V., Bischoff, R., Wit, E. C., Veenhoff, L. M., & Heinemann, M. (2015) · eLife · doi:10.7554/elife.08527 · Cited by 199
Romero, Y., Bueno, M., Ramírez, R., Álvarez, D., Sembrat, J., Goncharova, E. A., Rojas, M. M., Selman, M., Mora, A. L., & Pardo, A. (2016) · Aging Cell · doi:10.1111/acel.12514 · Cited by 193
Arriola Apelo, S. I., Neuman, J. C., Baar, E. L., Syed, F. A., Cummings, N. E., Brar, H. K., Pumper, C. P., Kimple, M. E., & Lamming, D. W. (2016) · Aging Cell · doi:10.1111/acel.12405 · Cited by 182
“Rapamycin is an FDA-approved compound that robustly extends lifespan in yeast, worms, flies, and mice (Johnson et al., 2013).”
BackgroundMethionine Restriction Extends Lifespan in Progeroid Mice and Alters Lipid and Bile Acid Metabolism
Bárcena, C., Quirós, P. M., Durand, S., Mayoral, P., Rodríguez, F., Caravia, X. M., Mariño, G., Garabaya, C., Fernández-García, M. T., Kroemer, G., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.089 · Cited by 185
Molecular and phenotypic biomarkers of aging
Xia, X., Chen, W., McDermott, J., & Han, J.-D. J. (2017) · F1000Research · doi:10.12688/f1000research.10692.1 · Cited by 188
Kulkarni, A. S., Brutsaert, E. F., Anghel, V., Zhang, K., Bloomgarden, N., Pollak, M., Mar, J. C., Hawkins, M., Crandall, J. P., & Barzilai, N. (2018) · Aging Cell · doi:10.1111/acel.12723 · Cited by 183
Exercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction
Pandey, A., Shah, S. J., Butler, J., Kellogg, D. L., Lewis, G. D., Forman, D. E., Mentz, R. J., Borlaug, B. A., Simon, M. A., Chirinos, J. A., et al. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.07.014 · Cited by 184
Metadata
- Authors
- Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M.
- Affiliations
- University of Washington (US)
- Guangdong Medical College (CN)
- Corresponding author
- Kaeberlein, Matt
- Venue
- Nature
- Published
- 2013-01-16
- Volume
- 493
- Issue
- 7432
- Pages
- 338-345
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3687363
- OpenAlex
- W2010583480
- Cited by
- 1,676
- References
- 100
- Citations by year
- 2026: 87 · 2025: 82 · 2024: 117 · 2023: 121 · 2022: 113 · 2021: 164 · 2020: 136 · 2019: 140 · 2018: 125 · 2017: 133 · 2016: 136 · 2015: 119 · 2014: 131 · 2013: 72
- FWCI
- 9.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG031108, T32AG000057, P01AG001751, R01AG039390, R01AG038550, P30AG013280)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- mTOR, aging, age-related diseases, lifespan extension, rapamycin, mTOR inhibitors, pharmacological interventions
- MeSH terms
- Aging, Animals, Humans, Insulin, Insulin-Like Growth Factor I, Longevity, Signal Transduction, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
