TOR-Driven Aging: Speeding Car Without Brakes
Open accessAbstract
This article discusses that the traditional analogy of an aging organism with a rusting (albeit self-repairing) car is misleading. The true analogy is a speeding car that enters a low-speed zone and damages itself because it does not and cannot slow down. For such a car without brakes (and actually without a driver), aging from rusting never occurs. Using simple analogies (although turning gerontology upside down), this article discusses the origin of aging, how overactivation of the mTOR (Target of Rapamycin) pathway causes aging, why aging causes damage (organ damage) not damage causes aging, the link between aging and age-related diseases, slow aging versus aging tolerance and suppression of aging with rapamycin.
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The lifespan and healthspan of invertebrates are extended by mutations in pathways such as DAF-2, a gene that encodes for the IGF-1 pathway in C. elegans, or the mTOR signaling pathways that are linked to accelerating the aging process.
“The lifespan and healthspan of invertebrates are extended by mutations in pathways such as the DAF-2, a gene that encodes for the IGF-1 pathway in the nematode Caenorhabditis elegans (C. elegans), or the mTOR signaling pathways that are linked to accelerating the aging process (60, 62–65).”
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 [64]
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“Inhibition of the insulin/IGF-1/mTOR signaling pathway may be an essential mechanism through which pro-longevity interventions (e.g., rapamycin, calorie restriction) extend lifespan (Blagosklonny, 2009; Lamming, 2014; Lamming and Anderson, 2014).”
Mohammed, I., Hollenberg, M. D., Ding, H., & Triggle, C. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.718942 · Cited by 278 · see citing works
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“These hyper-functions lead to age-related diseases, such as atherosclerosis, hypertension, macular degeneration, increasing the probability of organismal death [32,33].”
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“May it decrease agingtolerance [127, 214]? This is a fascinating question to answer.”
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“Alternatively, mTORC1 signaling may be optimal during development, but inappropriately high for the maintenance of health later in life, and rapamycin acts to repress this overactive mTORC1 signaling (Blagosklonny, 2009).”
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“Specific characteristics of quasi-programs of aging and age-related diseases were discussed in detail.(41-45,49-52,86-90) The evolutionary theory predicts quasi-programs, like it predicts genes harmful later in life, if they are useful earlier in life.”
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“In a “TOR-centric” view of longevity regulation, TOR alone governs the life-extending and health-improving effects of CR/DR by: 1) integrating the flow of information on the organismal and intracellular nutrient and energy status from the protein kinases AMPK, PKA, PKB/AKT (the insulin/IGF-1 pathway) and ERK1/2 (the P…”
BackgroundTranscriptional regulation of the stress response by mTOR
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“And most detrimentally, mTOR is involved in diabetic complications and age-related diseases [2427, 51, 52-54].”
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“Aging in turn causes damage: not molecular damage but non-random organ damage (stroke, infarction, renal failure and so on) and death [13].”
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“AMPK signaling is a potent inhibitor of both the mTOR and the NF-jB-dependent pathways, the functions of which are associated with an enhanced aging process (Salminen et al. 2008; Blagosklonny 2009; Kapahi et al. 2010).”
From rapalogs to anti-aging formula
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“When developmental growth is completed, then mTOR (mammalian Target of Rapamycin) and some other signaling pathways) drives organismal aging [1, 15, 25, 26].”
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“In other words, aging is a quasi-program (not a program): an unintended and purposeless continuation of developmental programs, which are not switched off upon their completion [64-67], causing age-related diseases.”
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Hormesis does not make sense except in the light of TOR-driven aging
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“Furthermore, as it was already reviewed, “damage-induced aging” theory was ruled out by other evidence too [31-38].”
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“Both of these pathways regulate gene expression of several genes, are energy sensitive, and are involved in cellular aging [118, 119].”
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“This analogy is applicable not only to cellular senescence but also to organismal aging [30].”
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“During aging, oxidative stress and reactive oxygen species (ROS) lead to accumulated DNA damage and mitochondrial dysfunction.(1-10) As a consequence, dramatic reductions in oxygen consumption occur, shifting the entire body toward glycolytic metabolism or aerobic glycolysis(11-13) (Fig.”
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“As recently argued, aging is not driven by damage, but, in contrast, leads to damage (organ damage) [6-8].”
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Self-citationWhat is the Proximal Cause of Aging?
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“Soma is like a car without brakes and without a driver too [19].”
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Progeria, rapamycin and normal aging: recent breakthrough
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Self-citationBig mice die young but large animals live longer
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“Various applications and aspects of hyperfunction theory have been already extensively reviewed [19-35] (with references on other articles within), so here only a brief summary is needed in order to answer a particular question: “ Why big mice die young but large animals live longer”.”
BackgroundInfluentialSelf-citationNew biomarkers probing depth of cell senescence assessed by laser scanning cytometry
Zhao, H. L., Halicka, H. D., Traganos, F., Jorgensen, E. D., & Darżynkiewicz, Z. (2010) · Cytometry Part A · doi:10.1002/cyto.a.20983 · Cited by 47 · see citing works
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“Cellular hyperfunctions cause alterations in homeostasis, age-related diseases, and organismal damage.(19-25) In agreement, genetic, environmental (calorie restriction), or pharmacological inhibition of TOR extends life span in yeast, flies, worms, and mammals.”
BackgroundSelf-citationBlagosklonny, M. V. (2013) · Cell Cycle · doi:10.4161/cc.25062 · Cited by 44 · see citing works
“”(15) Or it can be damaged by an active process: myocardial infarction and stroke as a consequence of atherosclerosis, hypertension and thrombosis caused by MTOR-driven aging.(6,16) It is misleading to call any one theory “simply” disposable soma theory (DST), implying that other theories are not DSTs.”
BackgroundSelf-citationThe hyperfunction theory of aging: three common misconceptions
Blagosklonny, M. V. (2021) · Oncoscience · doi:10.18632/oncoscience.545 · Cited by 36 · see citing works
“stroke, infarction, cancer metastasis, broken hip) and death before molecular damage (rusting by free radicals) accumulates to deadly levels [2].”
BackgroundSelf-citationDisruptive chemicals, senescence and immortality
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“, AMP-activated protein kinase [AMPK], which antagonizes the gerogenic activity of mTOR) [13-29].”
BackgroundRejuvenating immunity: “anti-aging drug today” eight years later
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“In adults, its excessive activity leads to pathology (aging) [17-20].”
Self-citationThe Intricate Interplay between Mechanisms Underlying Aging and Cancer
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“Moreover, a significant enlargement of cells entering a state of senescence is caused by the AMPK/TOR signaling pathway, which promotes ribosome biogenesisand protein translation in the cytosol under the conditions of a senescence-associated irreversible cell cycle arrest (Figure 1) [9, 24, 80, 140, 191-195].”
BackgroundM(o)TOR of aging: MTOR as a universal molecular hypothalamus
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“The MTOR is the primary cause of cellular aging, or senescence, leading to the well recognized diseases of aging [47-50].”
BackgroundSelf-citationEnergy Metabolism and Metabolic Sensors in Stem Cells: The Metabostem Crossroads of Aging and Cancer
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“Also, mTOR, p53 and other genes are involved in age-related diseases and aging.(73-96) In replicative senescence of rodent cells the relationship between cell cycle arrest and geroconversion is more complex.”
BackgroundHypoxia and gerosuppression: The mTOR saga continues
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“This observation led to the argument that in order to receive the beneficial effects of mTOR inhibition in advanced age, mTOR signaling does not necessarily need to increase with aging (Baar et al., 2016; Blagosklonny, 2009).”
BackgroundFasting levels of hepatic p-S6 are increased in old mice
Leontieva, O. V., Paszkiewicz, G., & Blagosklonny, M. V. (2014) · Cell Cycle · doi:10.4161/15384101.2014.949150 · Cited by 22 · see citing works
“In theory the activity may even be decreased but still be inappropriately high for an aging organism.(22) In analogy, consider a car moving at 65 mph on highway.”
BackgroundSelf-citationWensink, M. J., & Cohen, A. A. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.671208 · Cited by 21 · see citing works
“Alternatives include hyperfunction, such as unchecked growth through hormonal pathways (Blagosklonny, 2009; Blagosklonny, 2012), or other malfunctioning that does not reduce to damage in its traditional sense.”
BackgroundVázquez‐Martín, A., Saurí, T., Menendez, O. J., Oliveras‐Ferraros, C., Cufí, S., Corominas-Faja, B., López‐Bonet, E., & Menéndez, J. A. (2012) · Cell Cycle · doi:10.4161/cc.22551 · Cited by 22 · see citing works
“However, the fact that M phase-associated upregulation of phospho-mTOR occurs in human cancers in vivo,(17) together with the confirmatory finding that prolonged but not acute treatment with rapamycin drastically reduces the amount of mTOR-associated Ser2481 autophosphorylation, may open a new avenue to better underst…”
BackgroundAging biology: a new frontier for drug discovery
Verdaguer, E., Junyent, F., Folch, J., Beas‐Zárate, C., Auladell, C., Pallàs, M., & Camins, A. (2012) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2012.660144 · Cited by 22 · see citing works
“To date, effective antiaging treatments have been limited to CR [99].”
BackgroundInfluentialConstitutive and induced functions of the p53 gene
Zheltukhin, A. O., & Chumakov, P. M. (2010) · Biochemistry (Moscow) · doi:10.1134/s0006297910130110 · Cited by 22 · see citing works
The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases
McClements, L., Annett, S., Yakkundi, A., & Robson, T. (2015) · Current Molecular Pharmacology · doi:10.2174/1874467208666150519115729 · Cited by 22 · see citing works
Modulation of Autophagy: A Novel “Rejuvenation” Strategy for the Aging Liver
Xu, F., Tautenhahn, H., Dirsch, O., & Dahmen, U. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6611126 · Cited by 20 · see citing works
“The age-related impairment of AMPK activation impedes autophagosome formation, affects cellular homeostasis, and further promotes the aging process via weakening its inhibitory effect on mTOR [17, 18, 88].”
BackgroundContemporary views on human aging and longevity
Chmielewski, P. P., Borysławski, K., & Strzelec, B. (2016) · Anthropological Review · doi:10.1515/anre-2016-0010 · Cited by 16 · see citing works
Blagosklonny, M. V. (2018) · Aging · doi:10.18632/aging.101750 · Cited by 15 · see citing works
“The theory of hyperfunctional aging [25-32] addresses this paradox.”
BackgroundSelf-citationBlagosklonny, M. V. (2019) · Aging · doi:10.18632/aging.102664 · Cited by 13 · see citing works
“Just as in vitro geroconversion is a continuation of growth, organismal aging is an unintended and harmful continuation of developmental growth post-development [1, 32].”
BackgroundSelf-citationInvolvement of Autophagy in Ageing and Chronic Cholestatic Diseases
Pinto, C., Ninfole, E., Benedetti, A., Marzioni, M., & Maroni, L. (2021) · Cells · doi:10.3390/cells10102772 · Cited by 13 · see citing works
Baliou, S., Apetroaei, M.-M., Hatzidaki, E., Kuzmin, S. V., Tzatzarakis, M. N., Arsene, A. L., Tsatsakis, A. M., & Ιωάννου, Π. (2025) · Life · doi:10.3390/life15060873 · Cited by 14 · see citing works
“According to the World Health Organization (WHO), a value of less than 25 kg/m 2 is encountered in overweight individuals, whereas a value greater than 30 is observed in obese patients [16].”
Potential Geroprotectors – From Bench to Clinic
Moskalev, A. (2023) · Biochemistry (Moscow) · doi:10.1134/s0006297923110056 · Cited by 10 · see citing works
Correlative imaging of ionic transport and electronic structure in nano Li 0.5 FePO 4 electrodes
Lu, M., Yu, F., Hu, Y., Zaghib, K., Schougaard, S. B., Wang, Z., Zhou, J., Wang, J., Goodenough, J. B., & Sham, T. (2019) · Chemical Communications · doi:10.1039/c9cc09116e · Cited by 9 · see citing works
Aging control with resveratrol
Pallàs, M., Junyent, F., Verdaguer, E., Beas‐Zárate, C., & Camins, A. (2010) · Drug Discovery Today Therapeutic Strategies · doi:10.1016/j.ddstr.2011.01.001 · Cited by 9 · see citing works
Chen, H., & Maklakov, A. A. (2013) · Worm · doi:10.4161/worm.23704 · Cited by 9 · see citing works
mTORC1 Deficiency Modifies Volume Homeostatic Responses to Dietary Sodium in a Sex-Specific Manner
Brooks, D. L. P., Garza, A., Guzelce, E. C., Gholami, K., Treesaranuwattana, T., Maris, S. A., Ranjit, S., Tay, C. S., Lee, J. M., Romero, J. R., et al. (2020) · Endocrinology · doi:10.1210/endocr/bqaa041 · Cited by 7 · see citing works
Carrera‐Bastos, P., Muskiet, M. H. A., Ordóñez, F. M., Pruimboom, L., Lucía, A., Luque, R. M., & Muskiet, F. A. J. (2025) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-025-09996-z · Cited by 5 · see citing works
Barzilai, D. A. (2025) · Aging · doi:10.18632/aging.206189 · Cited by 4 · see citing works
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“Rapamycin is an antifungal agent produced by soil bacteria that inhibits mTOR and prolongs life in animal models.(25,26) Thus, inhibition of mTOR may slow down aging and have benefits in preventing chronic diseases such as cancer, diabetes, neurodegenerative diseases, heart disease, and metabolic syndrome.”
BackgroundThe Interaction between Metabolic Disease and Ageing
Rana, K. S., Griffiths, H. R., Placido, N., & Brown, J. E. P. (2014) · Global Journal of Obesity Diabetes and Metabolic Syndrome · doi:10.17352/2455-8583.000002 · Cited by 4 · see citing works
“Alongside this emerging role in nutrient sensing and metabolism, mTor has a well-defined role in cell growth and ageing [41-43].”
BackgroundA brief history of the hyperfunction theory of aging and future directions
de Magalhães, J. P. (2026) · Aging · doi:10.18632/aging.206403 · Cited by 2 · see citing works
“From his first publication in 2006, he argued that TOR activation promotes hyperfunction, aging, and age-related diseases – a concept he expanded upon in later work [36].”
Behavioral evaluation of aging in experimental animals
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“The endogenous levels of ROS, 67 such as superoxide anions and hydrogen peroxide, are often low and play important roles in 68 signaling transduction, defense, and other normal cell functions (Blagosklonny 2008; Rahman 69 2007; Weinberger et al. 2010).”
InfluentialSlade, L., Etheridge, T., & Szewczyk, N. J. (2024) · Preprints.org · doi:10.20944/preprints202403.1866.v1 · Cited by 1 · see citing works
Mechanisms Linking Lipid Metabolism and Longevity in Yeast
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Disruptive chemicals, senescence and immortality
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Ontology (3): The Case for Programs: Altruistic Suicide, Quasi-Programs and Smurfs
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Potential geroprotectors - from the banch to the clinic
Moskalev, A. (2023) · Biochemistry (Moscow) · doi:10.31857/s0320972523110064
Theories of Ageing across Ages
Kirkwood, T. B. L. (2024) · Cambridge University Press eBooks · doi:10.1017/9781009007245.003
A review of rapamycin in companion dogs
Ryave, J., & Coleman, A. E. (2025) · Journal of Veterinary Science · doi:10.4142/jvs.25219 · Cited by 1 · see citing works
“This, along with the measurable benefits of mTOR inhibition on lifespan, has led some authors to conclude that “even normal” mTORC1 activity levels might be too high to maintain health in aging tissues [13,29].”
Senescence in Oncogenesis: From Molecular Mechanisms to Therapeutic Opportunities
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- Authors
- Blagosklonny, M. V.
- Affiliations
- Roswell Park Comprehensive Cancer Center (US)
- Corresponding author
- Blagosklonny, Mikhail V
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2009-12-15
- Volume
- 8
- Issue
- 24
- Pages
- 4055-4059
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W2086669723
- Cited by
- 95
- References
- 0
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 7 · 2015: 6 · 2014: 9 · 2013: 8 · 2012: 17
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mTOR signaling, aging, rapamycin, age-related diseases, slow aging, organ damage
- MeSH terms
- Aging, Animals, Humans, Immunosuppressive Agents, Longevity, Protein Serine-Threonine Kinases, Sirolimus, Intracellular Signaling Peptides and Proteins, TOR Serine-Threonine Kinases
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