mTOR as a central regulator of lifespan and aging

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Abstract

The mammalian/mechanistic target of rapamycin (mTOR) is a key component of cellular metabolism that integrates nutrient sensing with cellular processes that fuel cell growth and proliferation. Although the involvement of the mTOR pathway in regulating life span and aging has been studied extensively in the last decade, the underpinning mechanisms remain elusive. In this review, we highlight the emerging insights that link mTOR to various processes related to aging, such as nutrient sensing, maintenance of proteostasis, autophagy, mitochondrial dysfunction, cellular senescence, and decline in stem cell function.

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Most cited references 277

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The Hallmarks of Aging

Carlos López-Otín, Maria Blasco, Linda Partridge … (2014)

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.

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mTOR Signaling in Growth, Metabolism, and Disease.

Robert Saxton, David Sabatini (2017)

The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

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mTOR signaling in growth control and disease.

Mathieu Laplante, David M. Sabatini (2012)

The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation. Copyright © 2012 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

David Papadopoli: Role: VisualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

Karine Boulay: Role: Writing – Original Draft PreparationRole: Writing – Review & Editing

Lawrence Kazak: Role: Writing – Review & Editing

ORCID: https://orcid.org/0000-0002-7591-2544

Michael Pollak: Role: Writing – Original Draft Preparation

Frédérick Mallette: Role: Writing – Original Draft PreparationRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0001-7932-0338

Ivan Topisirovic: Role: ConceptualizationRole: SupervisionRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0002-5510-9762

Laura Hulea: Role: ConceptualizationRole: SupervisionRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

Journal

Journal ID (nlm-ta): F1000Res

Journal ID (iso-abbrev): F1000Res

Journal ID (pmc): F1000Research

Title: F1000Research

Publisher: F1000 Research Limited (London, UK )

ISSN (Electronic): 2046-1402

Publication date (Electronic): 2 July 2019

Publication date Collection: 2019

Volume: 8

Electronic Location Identifier: F1000 Faculty Rev-998

Affiliations

[1 ]Lady Davis Institute, SMBD JGH, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada

[2 ]Gerald Bronfman Department of Oncology, McGill University, 5100 de Maisonneuve Blvd. West, Suite 720, Montréal, QC, H4A 3T2, Canada

[3 ]Département de Biochimie et Médecine Moléculaire, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, Canada

[4 ]Maisonneuve-Rosemont Hospital Research Centre, 5415 Assumption Blvd, Montréal, QC, H1T 2M4, Canada

[5 ]Goodman Cancer Research Centre, 1160 Pine Avenue West, Montréal, QC, H3A 1A3, Canada

[6 ]Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, QC, H3G 1Y6, Canada

[7 ]Department of Experimental Medicine, McGill University, 845 Sherbrooke Street West, Montréal, QC, H3A 0G4, Canada

[8 ]Département de Médecine, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, Canada

Author notes

[a ] ivan.topisirovic@ 123456mcgill.ca

[b ] laura.hulea@ 123456mail.mcgill.ca

#These authors contributed equally to this work.

No competing interests were disclosed.

Author information

Lawrence Kazak https://orcid.org/0000-0002-7591-2544

Frédérick Mallette https://orcid.org/0000-0001-7932-0338

Ivan Topisirovic https://orcid.org/0000-0002-5510-9762

Article

DOI: 10.12688/f1000research.17196.1

PMC ID: 6611156

PubMed ID: 31316753

SO-VID: b73b2b4a-1366-4a52-8a8f-2205ee01d460

License:

This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date accepted : 20 June 2019

Funding

Funded by: Terry Fox Research Institute

Award ID: TFRI-242115

Funded by: CIHR/ISF/IDRC/Azrieli Foundation Joint Canada‐Israel Research Program

Funded by: Canadian Institutes of Health Research

Award ID: MOP-133442andPJT-159529

Funded by: Fonds de Recherche du Québec-Santé

Funded by: Cole Foundation

IT is a scholar of the Fonds de Recherche du Québec-Santé (FRQS; Junior 2). FAM holds the Canada Research Chair in Epigenetics of Aging and Cancer. KB is the recipient of a postdoctoral fellowship from the Cole Foundation. The work in our labs related to these problematics is funded in part by the Terry Fox Research Institute (TFRI-242115 to IT and MP), the CIHR/ISF/IDRC/Azrieli Foundation Joint Canada-Israel Research Program (to IT), and the Canadian Institutes of Health Research (MOP-133442 and PJT-159529 to FAM and LK, respectively).

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

mTOR as a central regulator of lifespan and aging

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Aging Pathobiology and Therapeutics

Most cited references 277

The Hallmarks of Aging

mTOR Signaling in Growth, Metabolism, and Disease.

mTOR signaling in growth control and disease.

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