Proteostasis failure and cellular senescence in long‐term cultured postmitotic rat neurons
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Cellular senescence, a stress‐induced irreversible cell cycle arrest, has been defined for mitotic cells and is implicated in aging of replicative tissues. Age‐related functional decline in the brain is often attributed to a failure of protein homeostasis (proteostasis), largely in postmitotic neurons, which accordingly is a process distinct by definition from senescence. It is nevertheless possible that proteostasis failure and cellular senescence have overlapping molecular mechanisms. Here, we identify postmitotic cellular senescence as an adaptive stress response to proteostasis failure. Primary rat hippocampal neurons in long‐term cultures show molecular changes indicative of both senescence (senescence‐associated β‐galactosidase, p16, and loss of lamin B1) and proteostasis failure relevant to Alzheimer's disease. In addition, we demonstrate that the senescent neurons exhibit resistance to stress. Importantly, treatment of the cultures with an mTOR antagonist, protein synthesis inhibitor, or chemical compound that reduces the amount of protein aggregates relieved the proteotoxic stresses as well as the appearance of senescence markers. Our data propose mechanistic insights into the pathophysiological brain aging by establishing senescence as a primary cell‐autonomous neuroprotective response.
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Blockage of autophagy during cell senescence has been consistently observed in cultured neurons.
“Indeed, the blockage of autophagy during cell senescence has been consistently observed in cultured neurons [56, 80].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [56]
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- Authors
- Ishikawa, S., & Ishikawa, F.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Ishikawa, Fuyuki
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2019-11-25
- Volume
- 19
- Issue
- 1
- Pages
- e13071-e13071
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC6974705
- OpenAlex
- W2990274291
- Cited by
- 67
- References
- 45
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 7 · 2023: 9 · 2022: 14 · 2021: 15 · 2020: 5 · 2019: 1
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, other-oa)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
- Funders
- Japan Society for the Promotion of Science (15K14449)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- cellular senescence, proteostasis, postmitotic neurons, hippocampal neurons, long-term neuronal culture, brain aging, Alzheimer's disease, senescence-associated β-galactosidase, p16, lamin B1, mTOR inhibition, protein synthesis inhibition, protein aggregates, neuroprotection, stress tolerance
- MeSH terms
- Proteostasis, Aging, Animals, Cells, Cultured, Humans, Neurons, Cellular Senescence, Rats
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