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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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“Impaired insulin or TOR signaling extend lifespan in multiple organisms and delays the age-dependent functional decline and the onset of age-related diseases such as cancer, diabetes, and cardiovascular diseases (39,40).”
BackgroundThe Interconnections Between Somatic and Ovarian Aging in Murine Models
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“At the cellular level, the life-extending effects of CR are dependent on FOXO3 and decrease mTOR activation (33,34).”
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“Treatment with the drug rapamycin, a caloric restriction mimetic that prolongs life span in animal models, functions at least in part by reducing protein translation [1,2].”
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“In general, those biochemical pathways that promote longevity act by inhibiting the translation through downregulation of eEF2 [30, 31].”
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“elegans and mammalian systems, rather than numerous consecutive publications that have been already covered by many outstanding previous reviews (Carmona and Michan, 2016; Fontana and Partridge, 2015; Gems and Partridge, 2013; Johnson et al., 2013; Kenyon, 2010; López-Otín et al., 2013; Pitt and Kaeberlein, 2015; Taor…”
BackgroundMTBP and MYC: A Dynamic Duo in Proliferation, Cancer, and Aging
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“In wt cells, the mTOR kinase and substrates were dephosphorylated with similar dynamics (amplitude, kinetics) after LD and HD, possibly to counteract the inhibition of autophagy or the induction of senescence [103,104].”
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Vidović, T., Dakhovnik, A., Hrabovskyi, O., MacArthur, M. R., & Ewald, C. Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24097850 · Cited by 16
“Despite mTOR being the prime target against many age-related and chronic pathologies [30], relatively few mTOR inhibitors have been developed to slow the aging process.”
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“AMPK is a key activator of autophagy that inhibits mTOR, an important negative regulator of autophagy.(38,39) As an autophagy initiating kinase, ULK1 is a downstream signaling molecule in the AMPK/mTOR signaling pathway.”
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HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice
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“27 Furthermore, ranked 4 th and 5 th included other molecules that extend lifespan in Caenorhabditis elegans , including digoxin, 28 taxifolin, 29 genistein, 30 and catechin.”
BackgroundmTOR and SGLT-2 Inhibitors: Their Synergistic Effect on Age-Related Processes
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“Later, multiple studies demonstrated that the inhibition of mTOR can also prolong lifespan in humans and numerous disease models [41].”
BackgroundSomvanshi, V. S., Gahoi, S., Banakar, P., Thakur, P. K., Kumar, M., Sajnani, M. R., Pandey, P., & Rao, U. (2016) · BMC Genomics · doi:10.1186/s12864-016-2510-z · Cited by 16
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“There has been evidence of the metabolic effects of diet on aging and age-related diseases (Mattison et al., 2000; Speakman and Mitchell, 2011; Johnson et al., 2013; Solon-Biet et al., 2014; Finkel, 2015).”
BackgroundRashid, M. M., Lee, H., & Jung, B. H. (2017) · Journal of Chromatography B · doi:10.1016/j.jchromb.2017.11.027 · Cited by 16
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Redd1 protects against post‑infarction cardiac dysfunction by targeting apoptosis and autophagy
Huang, P., Fu, J. F., Chen, L., Ju, C., Wu, K., Liu, H., Liu, Y., Qi, B., Qi, B., & Liu, L. (2019) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2019.4366 · Cited by 16
“mTOR is recognized as a highly conserved serine/threonine kinase that controls cellular metabolism and growth in response to diverse stimuli (11,57,58).”
BackgroundCardiovascular Disease and Aging
Chiao, Y. A., Lakatta, E. G., Ungvari, Z. I., Dai, D., & Rabinovitch, P. S. (2015) · Springer eBooks · doi:10.1007/978-3-319-23246-1_5 · Cited by 16
Rapamycin-induced hyperglycemia is associated with exacerbated age-related osteoarthritis
Minton, D. M., Elliehausen, C. J., Javors, M. A., Santangelo, K. S., & Konopka, A. R. (2021) · Arthritis Research & Therapy · doi:10.1186/s13075-021-02637-1 · Cited by 16
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“Long-term activation, instead, leads to stem cell exhaustion, and its inhibition preserves adult stem cell function (Johnson et al., 2013).”
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Age exacerbates abnormal protein expression in a mouse model of Down syndrome
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“…in gene expression occur in normal brain aging; such changes have been reported in levels of components of the MTOR pathway, glutamate receptor subunits, and multiple other proteins involved in synaptic plasticity (reviewed in Yankner et al 2008; Bishop et al 2010; Johnson et al 2013).”
BackgroundRole of autophagy and its molecular mechanisms in mice intestinal tract after severe burn
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“(38) Now, the mTOR is deemed to be a key modulator and a pharmacologic target of health, disease, aging and and age-related disease.(39-41) AMPK and mTOR are key cellular nutrient indicators and cell growth regulators.”
BackgroundPotential Application of Ixeris dentata in the Prevention and Treatment of Aging-Induced Dry Mouth
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“Inhibiting mTOR signaling via small molecules like rapamycin is currently the gold standard for pharmacological longevity interventions [50, 62]. mTOR inhibition improves healthy survival across vast evolutionary distances and in every model system in which it has been tested [14, 44, 55, 120].”
BackgroundHe, B., Shao, B., Cheng, C., Ye, Z., Yang, Y., Fan, B., Xia, H., Wu, H., Liu, Q., & Zhang, J. (2024) · Toxics · doi:10.3390/toxics12060396 · Cited by 15
“…is also involved in mediating cellular senescence, and blocking of this pathway, at various points, extends lifespans from yeast to mammals [30]. mTOR overactivity for mice lead to elevated lung-cell senescence, remodeling of small pulmonary arterioles, and an increase in pulmonary…”
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“mTOR is recognized as a highly conserved serine/ threonine kinase that regulates cellular metabolism and growth in response to diverse stimuli.(6-9) mTOR is the catalytic subunit of two functionally and structurally distinct complexes (mTORC1 and mTORC2).”
BackgroundInfluentialLeow, S.-S., LUU, A., Shrestha, S., Hayes, K. C., & Sambanthamurthi, R. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.03.013 · Cited by 15
“, 2016), effects on multiple molecular pathways which regulate lifespan (Granado-Serrano et al., 2010; Johnson et al., 2013; Meng et al., 2015; Seo et al., 2013)and stimulating stress resistance as a result of hormesis (Proshkina et al.”
Cестрины – шлагбаумы на путях от стресса к старению и болезням
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Neuronal Mechanisms that Drive Organismal Aging Through the Lens of Perception
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“Briefly, TOR and GCN2 are both serine-threonine kinases that function as amino acid sensors and regulate a wide range of downstream biological processes that modulate growth, metabolism, and life span (59, 60).”
BackgroundA patent review of mTOR inhibitors for cancer therapy (2011–2020)
Qiu, H., Wang, P., & Zhang, M. (2021) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2021.1940137 · Cited by 15
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Role of fruits in aging and age-related disorders
Arif, M. U., Khan, M. K. I., Riaz, S., Nazir, A., Maan, A. A., Amin, U., Saeed, F., & Afzaal, M. (2022) · Experimental Gerontology · doi:10.1016/j.exger.2022.111763 · Cited by 17
The sooner, the better: ROS, kinases and nutrients at the onset of the damage response in Drosophila
Serras, F. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1047823 · Cited by 13
“The decreased activity of these pathways can improve health and delay aging (Johnson et al., 2013; Flatt and Partridge, 2018).”
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“Recently it is found that mTORC1 is also has an important role in aging and age-related diseases [68].”
BackgroundA high-fiber diet mimics aging-related signatures of caloric restriction in mammals
Hu, F., Yu, L., Tu, X., Huang, R., Yan, X., Wang, L., Wei, X., Wei, X., & Wu, Z. (2025) · Nature Communications · doi:10.1038/s41467-025-61046-z · Cited by 15
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“The mTOR pathway promotes anabolic processes and cellular growth, whereas AMPK supports catabolic pathways and adaptation to stress [28,29].”
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“Autophagy induction has been widely reported to extend lifespan [62, 101].”
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Age-associated molecular changes are deleterious and may modulate life span through diet
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Pharmaceutical Intervention of Aging
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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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