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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.
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“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.
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“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]
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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]
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“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]
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Citations
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“Longevity has also been linked to immune function, with many critical signaling networks that regulate longevity such as insulin-IGF like (IIL) and TOR pathways (Grewal, 2009; Johnson et al., 2013; Kapahi et al., 2017; Partridge et al., 2011) shown to communicate with the central immune pathways for robust regulation…”
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“…drug rapamycin is a specific and potent inhibitor of the mechanistic target of rapamycin (mTOR) that has been shown to increase life span and delay or reverse age-associated functional decline and pathology in numerous tissues and organs in laboratory animals, including mice (Johnson et al. 2013).”
BackgroundGoncharov, N. V., Popova, P. I., Kudryavtsev, I. V., Головкин, А. С., Savitskaya, I. V., Авдонин, П. П., Korf, E. A., Voitenko, N. G., Belinskaia, D. A., Serebryakova, M. K., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031888 · Cited by 27
“…illnesses such as cancer, cardiovascular disorders, and NDDs. Aging results from the progressive dysregulation of several molecular pathways, and mTOR and AMPK signaling have been suggested to play a role in the complex changes of key biological networks involved in cellular senescence [93,94].”
BackgroundRapamycin induces pluripotent genes associated with avoidance of replicative senescence
Pospelova, T. V., Bykova, T. V., Zubova, S. G., Katolikova, N. V., Yartzeva, N. M., & Pospelov, V. A. (2013) · Cell Cycle · doi:10.4161/cc.27396 · Cited by 26
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Inverse correlation between longevity and developmental rate among wild C. elegans strains
Lee, Y., Hwang, W., Jung, J., Park, S., Cabatbat, J. J. T., Kim, P., & Lee, S. (2016) · Aging · doi:10.18632/aging.100960 · Cited by 25
Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency
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“…lifespan, mitochondrial disease INTRODUCTION Reduced nutrient signaling, accomplished either by dietary restriction (DR) or genetic inhibition of the mTOR pathway, can robustly extend lifespan in many different species and protect against multiple age-related disorders (Johnson et al., 2013a).”
InfluentialGant, J. C., Blalock, E. M., Chen, K.-C., Kadish, I., Thibault, O., Porter, N. M., & Landfield, P. W. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.2234-17.2017 · Cited by 25
“Twenty-four mTOR pathway genes were identified by searching the GO database and the literature (Johnson et al., 2013).”
BackgroundSeryl tRNA synthetase cooperates with POT1 to regulate telomere length and cellular senescence
Li, Y., Li, X., Cao, M., Jiang, Y., Yan, J., Liu, Z., Yang, R., Chen, X., Sun, P., Xiang, R., et al. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0078-1 · Cited by 27
Direct physical interaction of active Ras with mSIN1 regulates mTORC2 signaling
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A Common Pathway for a Rare Disease?
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Longevity pathways are associated with human ovarian ageing
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“These interventions include, for example, a caloric restriction diet and inhibition of the mechanistic target of rapamycin (mTOR) pathway, which are commonly believed to optimize longevity (Fontana et al., 2010; Johnson et al., 2013).”
BackgroundCirculating microRNA profile in humans and mice with congenital GH deficiency
Saccon, T. D., Schneider, A., Marinho, C. G., Nunes, A., Noureddine, S. A., Dhahbi, J. M., López, Y. O. N., LeMunyan, G., Salvatori, R., Oliveira, C. R. P., et al. (2021) · Aging Cell · doi:10.1111/acel.13420 · Cited by 24
“Several interventions that successfully slow down aging target the mTOR pathway (Johnson et al., 2013).”
BackgroundMcIntyre, R. L., Denis, S. W., Kamble, R., Molenaars, M., Petr, M. A., Schomakers, B. V., Rahman, M., Gupta, S. D., Tóth, M. L., Vanapalli, S. A., et al. (2021) · Aging Cell · doi:10.1111/acel.13381 · Cited by 23
“Because mTOR and PI3Kinase inhibitors are both known to increase lifespan, and act within the FOXO longevity pathway (Babar et al., 1999; Hay, 2011), we con - cluded that our approach could indeed identify compounds that are known to extend lifespan through the FOXO signaling pathway.”
BackgroundThe tumor suppression theory of aging
Wolf, A. M. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111583 · Cited by 27
“fects (Johnson and Kaeberlein, 2016; Laplante and Sabatini, 2012; Salmon, 2015), be efficient in retarding aging mediated by mutation and clonal expansion (Johnson et al., 2013; Martinet et al., 2014).”
BackgroundAlfatah, M., & Eisenhaber, F. (2022) · GeroScience · doi:10.1007/s11357-022-00598-0 · Cited by 23
“TORC1 and AMPK are the glucose-sensing complexes involved in aging process [32, 43].”
BackgroundInnate immunity dysregulation in aging eye and therapeutic interventions
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Exploring the Prospective Role of Propolis in Modifying Aging Hallmarks
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“The mTOR plays a crucial role in regulating aging and age-related diseases through its involvement in two separate complexes, known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [238].”
BackgroundMechanisms of Senescence and Anti-Senescence Strategies in the Skin
Konstantinou, E. K., Longange, E., & Kaya, G. (2024) · Biology · doi:10.3390/biology13090647 · Cited by 26
“It is evolutionary conserved and consists of two different complexes, mTORC1 and mTORC2, which differ functionally and structurally [183,184].”
BackgroundComputational Systems Biology for Aging Research
Auley, M. T. M., & Mooney, K. M. (2014) · Interdisciplinary topics in gerontology and geriatrics · doi:10.1159/000364928 · Cited by 24
Randhawa, R., Sehgal, M., Singh, T. R., Duseja, A. K., & Changotra, H. (2015) · Gene · doi:10.1016/j.gene.2015.02.056 · Cited by 25
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“Nitrogen availability is monitored by the TOR pathway in many organisms, which is known to affect CLS (Otsubo and Yamamato, 2008; Johnson et al., 2013); a correlation between nitrogen intake and aging has been reported in humans (Fontana et al., 2008).”
BackgroundBasisty, N., Liu, Y., Reynolds, J., Karunadharma, P. P., Dai, D., Fredrickson, J., Beyer, R. P., MacCoss, M. J., & Rabinovitch, P. S. (2017) · The Journals of Gerontology Series A · doi:10.1093/gerona/glx047 · Cited by 25
Chadwick, S. R., Fazio, E. N., Etedali‐Zadeh, P., Genereaux, J. L., Duennwald, M. L., & Lajoie, P. (2019) · Current Genetics · doi:10.1007/s00294-019-01019-0 · Cited by 25
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“…and memory functions, reduce tau pathology (Caccamo et al., 2010), increase autophagy and decrease the amyloid β level in animal models of AD (Spilman et al., 2010). mTOR inhibition can also increase lifespan and delay age-related cognitive impairments (Johnson et al., 2013; Maiese et al., 2013).”
BackgroundeIF4E phosphorylation modulates pain and neuroinflammation in the aged
Mody, P. H., Santos, N. L. D., Barron, L. R., Price, T. J., & Burton, M. D. (2020) · GeroScience · doi:10.1007/s11357-020-00220-1 · Cited by 25
Tulipano, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313068 · Cited by 26
Genes and Pathways That Influence Longevity in Caenorhabditis elegans
Lee, Y., An, S. W. A., Artan, M., Seo, M., Hwang, A. B., Jeong, D., Son, H. G., Hwang, W., Lee, D.-Y., Seo, K., et al. (2015) · Springer eBooks · doi:10.1007/978-4-431-55763-0_8 · Cited by 24
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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
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