mTOR signaling in aging and neurodegeneration: at the crossroad between metabolism dysfunction and impairment of autophagy
Open accessAbstract
Compelling evidence indicates that the mammalian target of rapamycin (mTOR) signaling pathway is involved in cellular senescence, organismal aging and age-dependent diseases. mTOR is a conserved serine/threonine kinase that is known to be part of two different protein complexes: mTORC1 and mTORC2, which differ in some components and in upstream and downstream signalling. In multicellular organisms, mTOR regulates cell growth and metabolism in response to nutrients, growth factors and cellular energy conditions. Growing studies highlight that disturbance in mTOR signalling in the brain affects multiple pathways including glucose metabolism, energy production, mitochondrial function, cell growth and autophagy. All these events are key players in age-related cognitive decline such as development of Alzheimer disease (AD). The current review discusses the main regulatory roles of mTOR signalling in the brain, in particular focusing on autophagy, glucose metabolism and mitochondrial functions. Targeting mTOR in the CNS can offer new prospective for drug discovery; however further studies are needed for a comprehensive understanding of mTOR, which lies at the crossroads of multiple signals involved in AD etiology and pathogenesis.
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Hyperactivation of mTORC1 is linked to dysregulation of autophagy, protein synthesis, and clearance of cellular debris.
“the hyperactivation of mTORC1 is linked to dysregulation of autophagy, protein synthesis, and clearance of cellular debris. 12”
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“12 Importantly, inhibition of autophagy is a mechanism by which mTORC1 hyperactivation may contribute to A β and phosphorylated tau (p-tau) aggregation in AD and DS-AD.”
- Authors
- Perluigi, M., Di Domenico, F., & Butterfield, D. A.
- Affiliations
- University of Kentucky (US)
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 84
- Pages
- 39-49
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2120435825
- Cited by
- 339
- References
- 18
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 38 · 2023: 30 · 2022: 27 · 2021: 41 · 2020: 28 · 2019: 27 · 2018: 40 · 2017: 20 · 2016: 28 · 2015: 12
- FWCI
- 26.29
- Type
- journal article
- Language
- en
- Open access
- green
- doaj.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- mTOR signaling, aging, neurodegeneration, autophagy, cellular senescence, mTORC1, mTORC2, glucose metabolism, mitochondrial function, age-related cognitive decline, Alzheimer's disease, brain energy metabolism, rapamycin
- MeSH terms
- Aging, Animals, Autophagy, Brain, Humans, Neurodegenerative Diseases, TOR Serine-Threonine Kinases
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