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
Items 301–400 of 1,006
Zhang, H., Xu, J., Long, Y., Maimaitijiang, A., Su, Z., Li, W., & Li, J. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312928 · Cited by 97
“…regulator, where the extents of phosphorylation and accumulation of the protein are also considered important markers of cellular senescence [80,86–90]; (c) cellular responses involving the DDR, metabolic reprogramming and chromatin remodeling via the senescence-associated secretory phenotype…”
Hekimi, S., Wang, Y., & Noë, A. (2016) · Frontiers in Genetics · doi:10.3389/fgene.2016.00161 · Cited by 83
Zhang, N., & Cao, L. (2017) · Current Genetics · doi:10.1007/s00294-017-0697-4 · Cited by 86
Metabolic Communication and Healthy Aging: Where Should We Focus Our Energy?
Smith, H. J., Sharma, A., & Mair, W. B. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.06.011 · Cited by 83
A distinct astrocyte subtype in the aging mouse brain characterized by impaired protein homeostasis
Lee, E., Jung, Y., Park, Y. R., Lim, S., Choi, Y.-J., Lee, S. Y., Kim, C. H., Mun, J. Y., & Chung, W. (2022) · Nature Aging · doi:10.1038/s43587-022-00257-1 · Cited by 85
“4a) 26,27 .”
Influence of the Mediterranean Diet on Healthy Aging
Andreo-López, M. C., Contreras-Bolívar, V., Muñoz‐Torres, M., García-Fontana, B., & García‐Fontana, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054491 · Cited by 94
“Specifically, mTOR is a kinase that is formed by two protein complexes: mTORC1 and mTORC2 [171].”
BackgroundGenetic evidence for common pathways in human age‐related diseases
Johnson, S. C., Dong, X., Vijg, J., & Suh, Y. (2015) · Aging Cell · doi:10.1111/acel.12362 · Cited by 78
Cellular senescence: Implications for metabolic disease
Schafer, M. J., Miller, J. D., & LeBrasseur, N. K. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.08.047 · Cited by 87
Host Resistance and Immune Aging
Bandaranayake, T., & Shaw, A. C. (2016) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2016.02.007 · Cited by 88
Mammalian target of rapamycin (mTOR) as a potential therapeutic target in various diseases
Kaur, A., & Sharma, S. (2017) · Inflammopharmacology · doi:10.1007/s10787-017-0336-1 · Cited by 85
Hall, H., Medina, P., Cooper, D. A., Escobedo, S. E., Rounds, J., Brennan, K., Vincent, C., Miura, P., Doerge, R. W., & Weake, V. M. (2017) · BMC Genomics · doi:10.1186/s12864-017-4304-3 · Cited by 80
“Thus, decreased Rheb levels during aging could decrease mTOR pathway activity, which extends lifespan and is protective against age-related pathology [58].”
BackgroundChang, K., Kang, P., Liu, Y., Huang, K., Miao, T., Sagona, A. P., Nezis, I. P., Bodmer, R., Ocorr, K., & Bai, H. (2020) · Autophagy · doi:10.1080/15548627.2019.1704117 · Cited by 73
“[15,33] and attenuates stress-induced cardiomyopathies [11,34–36].”
Recent advances in the field of caloric restriction mimetics and anti-aging molecules
Martel, J., Chang, S.-H., Wu, C.-Y., Peng, H., Hwang, T., Ko, Y., Young, J. D., & Ojcius, D. M. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101240 · Cited by 83
Hypothalamic miR-103 Protects from Hyperphagic Obesity in Mice
Vinnikov, I. A., Hajdukiewicz, K., Reymann, J., Beneke, J., Czajkowski, R., Roth, L. C., Novak, M., Roller, A., Dörner, N., Starkuviene, V., et al. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.4251-13.2014 · Cited by 81
Parikh, I. J., Guo, J., Chuang, K., Zhong, Y., Rempe, R. G., Hoffman, J. D., Armstrong, R., Bauer, B., Hartz, A. M. S., & Lin, A. (2016) · Aging · doi:10.18632/aging.101094 · Cited by 84
Rapamycin extends life- and health span because it slows aging
Blagosklonny, M. V. (2013) · Aging · doi:10.18632/aging.100591 · Cited by 82
Yue, F., Bi, P., Wang, C., Li, J., Liu, X., & Kuang, S. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.11.002 · Cited by 81
Insulin signaling in the long-lived reproductive caste of ants
Yan, H., Opachaloemphan, C., Carmona-Aldana, F., Mancini, G., Mlejnek, J., Descostes, N., Sieriebriennikov, B., Leibholz, A., Zhou, X., Ding, L., et al. (2022) · Science · doi:10.1126/science.abm8767 · Cited by 88
Jung, H., Kim, D. O., Byun, J.-E., Kim, W. S., Kim, M. J., Song, H. Y., Kim, Y. K., Kang, D.-K., Park, Y.-J., Kim, T.-D., et al. (2016) · Nature Communications · doi:10.1038/ncomms13674 · Cited by 81
Rapamycin improves healthspan but not inflammaging in nfκb1−/− mice
Correia‐Melo, C., Birch, J., Fielder, E., Rahmatika, D., Taylor, J., Chapman, J., Lagnado, A., Carroll, B. M., Miwa, S., Richardson, G., et al. (2019) · Aging Cell · doi:10.1111/acel.12882 · Cited by 77
Napoli, M., & Flores, E. R. (2016) · British Journal of Cancer · doi:10.1038/bjc.2016.384 · Cited by 80
Karunadharma, P. P., Basisty, N., Dai, D., Chiao, Y. A., Quarles, E. K., Hsieh, E. J., Crispin, D. A., Bielas, J. H., Ericson, N. G., Beyer, R. P., et al. (2015) · Aging Cell · doi:10.1111/acel.12317 · Cited by 81
Circadian clock: linking epigenetics to aging
Orozco-Solís, R., & Sassone‐Corsi, P. (2014) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2014.06.003 · Cited by 83
Leontieva, O. V., Paszkiewicz, G., & Blagosklonny, M. V. (2014) · Aging Cell · doi:10.1111/acel.12211 · Cited by 80
Antiaging effects of bioactive molecules isolated from plants and fungi
Martel, J., Ojcius, D. M., Ko, Y., Chang, C., & Young, J. D. (2019) · Medicinal Research Reviews · doi:10.1002/med.21559 · Cited by 79
“Autophagy can be activated by rapamycin, an immunosuppressive drug used to prevent organ transplant rejection in humans but which also increases lifespan in various organisms ranging from worms to mice.(125,127) Rapamycin extends lifespan by 9% to 14% in aged mice(128) and by 10% to 15% in young mice.”
BackgroundSIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B
Ye, Y., Yang, K., Liu, H., Yu, Y., Song, M., Huang, D., Lei, J., Zhang, Y., Liu, Z., Chu, Q., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00486-y · Cited by 81
“Additionally, pioneering works based on rodent models have identified a panel of molecular mechanisms involved in cardiac aging or associated phenotypes, such as mTOR, AMPK and PPARα/PGC-1α signaling pathways 7,10–13 .”
BackgroundEvidence for the hallmarks of human aging in replicatively aging yeast
Janssens, G. E., & Veenhoff, L. M. (2016) · Microbial Cell · doi:10.15698/mic2016.07.510 · Cited by 80
Rapamycin treatment attenuates age-associated periodontitis in mice
An, J. Y., Quarles, E. K., Mekvanich, S., Kang, A., Liu, A., Santos, D., Miller, R. A., Rabinovitch, P. S., Cox, T. C., & Kaeberlein, M. R. (2017) · GeroScience · doi:10.1007/s11357-017-9994-6 · Cited by 79
Hwang, A. B., & Brack, A. S. (2017) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2017.08.008 · Cited by 83
Mitochondrial function and mitochondrial DNA maintenance with advancing age
Gaziev, A. I., Abdullaev, S., & Podlutsky, A. (2014) · Biogerontology · doi:10.1007/s10522-014-9515-2 · Cited by 77
Lu, Y.-X., Regan, J. C., Eßer, J., Drews, L. F., Weinseis, T., Stinn, J., Hahn, O., Miller, R. A., Grönke, S., & Partridge, L. (2021) · eLife · doi:10.7554/elife.62233 · Cited by 76
“…players in organismal ageing are alteration of the epigenetic machinery and dysregulation of the insulin/Igf (IIS)/mechanistic target of rapamycin (mTOR) nutrient-sensing network (Alic and Partridge, 2011; Benayoun et al., 2015; Johnson et al., 2013; López-Otı́n et al., 2013; Pal and Tyler, 2016).”
BackgroundWhy Is Aging Conserved and What Can We Do about It?
Pitt, J. N., & Kaeberlein, M. R. (2015) · PLoS Biology · doi:10.1371/journal.pbio.1002131 · Cited by 81
Waldera-Lupa, D. M., Kalfalah, F. M., Florea, A., Sass, S., Kruse, F., Rieder, V., Tigges, J., Fritsche, E., Krutmann, J., Busch, H. S., et al. (2014) · Aging · doi:10.18632/aging.100698 · Cited by 79
Cau, P., Navarro, C. L., Harhouri, K., Roll, P., Sigaudy, S., Kaspi, É., Perrin, S., Sandre‐Giovannoli, A. D., & Lévy, N. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.03.021 · Cited by 80
Bayliss, J. A., Lemus, M. B., dos Santos, V. V., Deo, M., Davies, J. S., Kemp, B. E., Elsworth, J. D., & Andrews, Z. B. (2016) · PLoS ONE · doi:10.1371/journal.pone.0159381 · Cited by 78
Targeting metabolism in cellular senescence, a role for intervention
Nacarelli, T., & Sell, C. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.08.049 · Cited by 79
“Beneficial effects of rapamycin on metabolism have also been observed in the mitochondrial disease mouse model of Leigh Syndrome (Johnson et al., 2013a).”
BackgroundInfluentialZhang, Z., Wang, X., Zhang, D., Liu, Y., & Lin, L. (2019) · Aging · doi:10.18632/aging.101759 · Cited by 76
Sorrenti, V., Benedetti, F., Buriani, A., Fortinguerra, S., Caudullo, G., Davinelli, S., Zella, D., & Scapagnini, G. (2022) · Pharmaceuticals · doi:10.3390/ph15080912 · Cited by 82
Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms
Grotta, R. L., Frigé, C., Matacchione, G., Olivieri, F., de Candia, P., Ceriello, A., & Prattichizzo, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012325 · Cited by 75
“Insulin and growth factors stimulate mTORC1 through PI(3)K and protein kinase B (AKT) kinase signalling, whereas AMPK has an inhibitory effect [35,36].”
BackgroundThe role of the TOR pathway in mediating the link between nutrition and longevity
Lushchak, O., Strilbytska, O., Piskovatska, V., Storey, K. B., Koliada, A., & Vaiserman, A. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.03.005 · Cited by 73
The mTOR pathway is necessary for survival of mice with short telomeres
Ferrara‐Romeo, I., Martínez, P., Saraswati, S., Whittemore, K., Graña‐Castro, O., Poluha, L. T., Serrano, R., Hernández-Encinas, E., Blanco‐Aparicio, C., Flores, J. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14962-1 · Cited by 76
Effect of young exosomes injected in aged mice
Lee, B.-R., Kim, J.-H., Choi, E.-S., Cho, J. H., & Kim, E. (2018) · International Journal of Nanomedicine · doi:10.2147/ijn.s170680 · Cited by 72
“23,24 In our study, p16 Ink4A and MTOR were downregulated in the lungs and liver (except for MTOR in the lungs) after injection of young exosomes.”
Functional Role of Calstabin2 in Age-related Cardiac Alterations
Yuan, Q., Chen, Z., Santulli, G., Gu, L., Yang, Z.-G., Yuan, Z.-Q., Zhao, Y.-T., Xin, H., Deng, K.-Y., Wang, S., et al. (2014) · Scientific Reports · doi:10.1038/srep07425 · Cited by 72
Yap/Taz mediates mTORC2-stimulated fibroblast activation and kidney fibrosis
Gui, Y., Li, J., Lu, Q., Ye, F., Wang, M., He, W., Yang, J., & Dai, C. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.004073 · Cited by 72
“As a core component, mTOR participates in forming two distinct complexes, named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (17, 18).”
BackgroundMagnesium and the Hallmarks of Aging
Dominguez, L. J., Veronese, N., & Barbagallo, M. (2024) · Nutrients · doi:10.3390/nu16040496 · Cited by 78
“Experimental studies in yeast, worms, flies, and mice have found that the genetic downregulation of mTOR-Complex1 (mTORC1) activity promotes healthy aging [131].”
BackgroundLuo, X.-Y., Qu, S.-L., Tang, Z., Zhang, Y. E., Liu, M., Peng, J., Tang, H. R., Yu, K., Zhang, C., Ren, Z., et al. (2014) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.07.019 · Cited by 73
Resveratrol vs. calorie restriction: Data from rodents to humans
Lam, Y. Y., Peterson, C. M., & Ravussin, É. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2013.04.005 · Cited by 75
Targeting Mitochondria in Alzheimer Disease: Rationale and Perspectives
Lanzillotta, C., Domenico, F. D., Marzia Perluigi, A., & Butterfield, D. A. (2019) · CNS Drugs · doi:10.1007/s40263-019-00658-8 · Cited by 75
“Further, inhibition of mTOR is known to occur via activation of AMP activated protein kinase (AMPK) [60], as indexed by increased phosphorylation of Thr172 on the α-subunit, lowering activity of some ATP-consuming pathways while promoting ATP synthesis through others such as fatty acid oxidation.”
Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum
Lu, A. T.-H., Hannon, E. J., Levine, M. E., Hao, K., Crimmins, E. M., Lunnon, K., Kozlenkov, A., Mill, J. S., Dracheva, S. M., & Horvath, S. (2016) · Nature Communications · doi:10.1038/ncomms10561 · Cited by 72
ATF 4 activity: a common feature shared by many kinds of slow‐aging mice
Li, W., Li, X., & Miller, R. A. (2014) · Aging Cell · doi:10.1111/acel.12264 · Cited by 74
García‐Velázquez, L., & Arias, C. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.06.001 · Cited by 70
Aging and cardiovascular diseases: the role of gene-diet interactions
Corella, D., & Ordovás, J. M. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.08.002 · Cited by 83
The GID ubiquitin ligase complex is a regulator of AMPK activity and organismal lifespan
Liu, H., Ding, J., Köhnlein, K., Urban, N., Ori, A., Villavicencio‐Lorini, P., Walentek, P., Klotz, L., Hollemann, T., & Pfirrmann, T. (2019) · Autophagy · doi:10.1080/15548627.2019.1695399 · Cited by 69
“Thus we like to suggest that inhibition of the GID-complex is a promising strategy for pharmacological manipulation of the AMPK-MTOR signaling axis to treat chronic conditions like polycystic kidney diseases [39], type 2 diabetes [40,41] or to alter organismal longevity [42].”
BackgroundModeration of mitochondrial respiration mitigates metabolic syndrome of aging
Tavallaie, M., Voshtani, R., Deng, X., Qiao, Y., Jiang, F., Collman, J. P., & Fu, L. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1917948117 · Cited by 71
Rajpal, A., & Ismail‐Beigi, F. (2020) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14080 · Cited by 74
Cell senescence, rapamycin and hyperfunction theory of aging
Blagosklonny, M. V. (2022) · Cell Cycle · doi:10.1080/15384101.2022.2054636 · Cited by 74
Singh, K. P., Bennett, J. A., Casado, F. L., Walrath, J. L., Welle, S. L., & Gasiewicz, T. A. (2013) · Stem Cells and Development · doi:10.1089/scd.2013.0346 · Cited by 71
Linking pathways in the developing and aging brain with neurodegeneration
Kovács, G. G., Adle‐Biassette, H., Milenković, I., Cipriani, S., van Scheppingen, J., & Aronica, E. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.03.045 · Cited by 69
GH and ageing: Pitfalls and new insights
Bartke, A., & Darcy, J. (2017) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2017.02.005 · Cited by 74
Vazirpanah, N., Ottria, A., van der Linden, M., Wichers, C. G. K., Schuiveling, M., van Lochem, E. G., Phipps‐Green, A. J., Merriman, T. R., Zimmermann, M., Jansen, M., et al. (2019) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2018-214656 · Cited by 70
“16–18 These comorbidities are a heavy concomitant disease burden in gout, for which contemporary urate-lowering treatments have not been effective.”
The Roles of H19 in Regulating Inflammation and Aging
Wang, B., Suen, C.-W. W., Ma, H., Wang, Y., Kong, L. D., Qin, D., Lee, W., & Li, G. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.579687 · Cited by 76
“Inflammation and hyperactivated mTOR are often associated (47), and thus H19 could be a potential suppressor of aging-related inflammation by suppressing mTOR activity.”
BackgroundLiu, D., Zhang, Y., Gharavi, R., Park, H. R., Lee, J., Siddiqui, S., Telljohann, R., Nassar, M. R., Cutler, R. G., Becker, K. G., et al. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13176 · Cited by 68
“…mTOR-related signaling networks mTOR signaling plays key roles in regulating energy metabolism, cell growth, adaptive stress responses and autophagy, and abnormalities in mTOR signaling are implicated in cancers, obesity, and age-related diseases (Laplante and Sabatini 2012; Johnson et al. 2013).”
BackgroundTargeting mTOR signaling by polyphenols: A new therapeutic target for ageing
Pazoki–Toroudi, H., Amani, H., Ajami, M., Nabavi, S. F., Braidy, N., Kasi, P. D., & Nabavi, S. M. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.07.004 · Cited by 70
Spatial and functional separation of mTORC1 signalling in response to different amino acid sources
Fernandes, S., Angelidaki, D.-D., Nüchel, J., Pan, J., Gollwitzer, P., Elkis, Y., Artoni, F., Wilhelm, S., Kovacevic-Sarmiento, M., & Demetriades, C. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01523-7 · Cited by 69
“As AAs are the building blocks to make proteins and mTORC1 controls Article https://doi.org/10.1038/s41556-024-01523-7 mTORC1—caused mainly by mutations in its upstream regulators—is of clinical relevance and a common feature of most cancer types and several metabolic disorders 5,14–16 .”
InfluentialmTOR and autophagy in regulation of acute lung injury: a review and perspective
Hu, Y., Liu, J., Wu, Y., Lou, J., Mao, Y., Shen, H., & Chen, Z. (2014) · Microbes and Infection · doi:10.1016/j.micinf.2014.07.005 · Cited by 69
miR-17 extends mouse lifespan by inhibiting senescence signaling mediated by MKP7
Du, W. W., Yang, W., Fang, L., Xuan, J. W., Li, H., Khorshidi, A., Gupta, S., Li, X., & Yang, B. B. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.305 · Cited by 69
Connecting the Dots: From DNA Damage and Repair to Aging
Pan, M., Li, K., Lin, S., & Hung, W.-C. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17050685 · Cited by 73
Николаевна, П. Е., Lashmanova, E., Dobrovolskaya, E., Zemskaya, N. V., Kudryavtseva, A. V., Shaposhnikov, M. V., & Moskalev, A. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2016.00505 · Cited by 71
Uddin, M. S., Rahman, M. A., Kabir, M. T., Behl, T., Mathew, B., Perveen, A., Barreto, G. E., Bin-Jumah, M. N., Abdel‐Daim, M. M., & Ashraf, G. M. (2020) · IUBMB Life · doi:10.1002/iub.2324 · Cited by 66
Zhang, Y., He, X., Wu, X., Lei, M., Wei, Z., Zhang, X., Wen, L., Xu, P., Li, S., & Qu, S. (2017) · Cell Death & Disease · doi:10.1038/cddis.2016.491 · Cited by 66
Proteostasis failure and cellular senescence in long‐term cultured postmitotic rat neurons
Ishikawa, S., & Ishikawa, F. (2020) · Aging Cell · doi:10.1111/acel.13071 · Cited by 67
“The mTOR pathway plays pivotal roles in the maintenance of proteostasis via its regulation of autophagy and protein synthesis (Laplante & Sabatini, 2012). mTOR dysregulation contributes to age-dependent tissue dysfunctions, including cognitive impairment (Johnson et al., 2013; Yang et al., 2014).”
BackgroundKumar, R., Sharma, A., Gupta, M., Padwad, Y. S., & Sharma, R. (2019) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-019-09576-z · Cited by 72
“Although in vivo experiments have shown that inhibition of Akt/mTOR signaling prolongs lifespan [13], however, causes and consequences of persistent mTOR signaling during senescence are still not clear [44].”
BackgroundThe cellular mechanobiology of aging: from biology to mechanics
Bajpai, A., Li, R., & Chen, W. (2020) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14529 · Cited by 71
Lemoine, M. (2020) · Biology & Philosophy · doi:10.1007/s10539-020-09765-z · Cited by 80
Evaluation of off-label rapamycin use to promote healthspan in 333 adults
Kaeberlein, T. L., Green, A. S., Haddad, G., Hudson, J., Isman, A., Nyquist, A., Rosen, B. S., Suh, Y., Zalzala, S., Zhang, X., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00818-1 · Cited by 66
“Off-label use of rapamycin has been gaining increasing attention, however, due to its efficacy and reproducibility for longevity and healthspan extension in preclinical studies [12, 13].”
BackgroundThe mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer’s disease
Talboom, J. S., Velázquez, R., & Oddo, S. (2015) · npj Aging and Mechanisms of Disease · doi:10.1038/npjamd.2015.8 · Cited by 67
Cellular aging towards osteoarthritis
Li, Y., Xiao, W., & Luo, W. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.12.012 · Cited by 67
Novel strategies for anti-aging drug discovery
Saraswat, K., & Rizvi, S. I. (2017) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2017.1349750 · Cited by 66
Kovács, Z., Brunner, B., & Ari, C. (2021) · Nutrients · doi:10.3390/nu13072197 · Cited by 68
“Indeed, for xample, mTORC1 sup orts protein synthesis by phosphorylation of S6K1 (ribosomal protein S6 kinase 1) and 4EBP1 (eukaryotic translation initiation factor 4E binding protein 1) molecules, which processes may be activated by Akt kinase (protein kinase B) [6,75,76] (Figure 1).”
BackgroundJayatunga, D. P. W., Hone, E., Khaira, H., Lunelli, T., Singh, H., Guillemin, G. J., Fernando, B., Garg, M. L., Verdile, G., & Martins, R. N. (2021) · Nutrients · doi:10.3390/nu13113744 · Cited by 67
Mesenchymal Stem Cell Senescence during Aging:From Mechanisms to Rejuvenation Strategies
Jiang, X., Li, W., Ge, L., & Lü, M. (2023) · Aging and Disease · doi:10.14336/ad.2023.0208 · Cited by 70
“rapamycin delays aging-related diseases, as well as prevents the development of MSC senescence by increasing cloning frequency and proliferation via the Akt/mTOR pathway [102, 143].”
BackgroundThe metabolic sensor AMPK: Twelve enzymes in one
Smiles, W. J., Ovens, A. J., Oakhill, J. S., & Kofler, B. (2024) · Molecular Metabolism · doi:10.1016/j.molmet.2024.102042 · Cited by 69
“For this reason, mTORC1 has been pinned as one of the foremost pro-aging factors in mammalian systems and AMPK a promising therapeutic counterbalance [254,255].”
Gerosuppression by pan-mTOR inhibitors
Leontieva, O. V., & Blagosklonny, M. V. (2016) · Aging · doi:10.18632/aging.101155 · Cited by 67
Sirt6 deficiency results in progression of glomerular injury in the kidney
Huang, W., Liu, H., Zhu, S., Woodson, M., Liu, R., Tilton, R. G., Miller, J. D., & Zhang, W. (2017) · Aging · doi:10.18632/aging.101214 · Cited by 66
Rapamycin Increases Mortality in db/db Mice, a Mouse Model of Type 2 Diabetes
Sataranatarajan, K., Ikeno, Y., Bokov, A., Feliers, D., Yalamanchili, H., Lee, H. J., Mariappan, M. M., Tabatabai-Mir, H., Diaz, V., Prasad, S., et al. (2016) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glv170 · Cited by 65
Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program)
Leontieva, O. V., Demidenko, Z. N., & Blagosklonny, M. V. (2015) · Oncotarget · doi:10.18632/oncotarget.4836 · Cited by 65
Mechanisms underlying the neuroprotective effect of brain reserve against late life depression
Fréret, T., Gaudreau, P., Schumann‐Bard, P., Billard, J., & Popa‐Wagner, A. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-013-1154-2 · Cited by 70
Baker, J. R., Donnelly, L., & Barnes, P. J. (2020) · CHEST Journal · doi:10.1016/j.chest.2020.01.027 · Cited by 65
Nutrients and Pathways that Regulate Health Span and Life Span
Pignatti, C., D’Adamo, S., Stefanelli, C., Flamigni, F., & Cetrullo, S. (2020) · Geriatrics · doi:10.3390/geriatrics5040095 · Cited by 68
Yeast replicative aging: a paradigm for defining conserved longevity interventions
Wasko, B. M., & Kaeberlein, M. R. (2013) · FEMS Yeast Research · doi:10.1111/1567-1364.12104 · Cited by 67
Rapamycin suppresses brain aging in senescence-accelerated OXYS rats
Kolosova, N. G., Vitovtov, A. O., Muraleva, N. A., Евгеньевич, А. А., Stefanova, N. A., & Blagosklonny, M. V. (2013) · Aging · doi:10.18632/aging.100573 · Cited by 65
SCAN1-TDP1 trapping on mitochondrial DNA promotes mitochondrial dysfunction and mitophagy
Ghosh, A., Bhattacharjee, S., Chowdhuri, S. P., Mallick, A., Rehman, I., Basu, S., & Das, B. B. (2019) · Science Advances · doi:10.1126/sciadv.aax9778 · Cited by 64
Ocular Disease Therapeutics: Design and Delivery of Drugs for Diseases of the Eye
Cheng, K., Hsieh, C., Nepali, K., & Liou, J. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01033 · Cited by 69
Leucine-sensing mechanism of leucyl-tRNA synthetase 1 for mTORC1 activation
Kim, S., Yoon, I., Son, J., Park, J., Kim, K., Lee, J.-H., Park, S., Kang, B. S., Han, J. M., Hwang, K. Y., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109031 · Cited by 66
Targeting mitochondrial dysfunction as in aging and glaucoma
Osborne, N. N., Núñez‐Álvarez, C., & del Olmo‐Aguado, S. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.05.010 · Cited by 64
Exploiting mTOR Signaling: A Novel Translatable Treatment Strategy for Traumatic Optic Neuropathy?
Morgan-Warren, P. J., Berry, M., Ahmed, Z., Scott, R. A. H., & Logan, A. (2013) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.13-12803 · Cited by 63
Hu, J. P., Nie, Y., Chen, S., Xie, C., Fan, Q., Wang, Z., Long, B., Yan, G., Zhong, Q., & Yan, X. (2017) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2017.05.026 · Cited by 64
Maintenance of Homeostasis in the Aging Hypothalamus: The Central and Peripheral Roles of Succinate
Chen, T. T., Maevsky, E. I., & Uchitel, M. L. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00007 · Cited by 62
de Cavanagh, E. M. V., Inserra, F., & Ferder, L. (2015) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00459.2014 · Cited by 66
Misra, J., Mohanty, S. T., Madan, S. S., Fernandes, J. A., Ebetino, F. H., Russell, R. G. G., & Bellantuono, I. (2015) · Stem Cells · doi:10.1002/stem.2255 · Cited by 60
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
