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Cited by 47Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsStress Responses and Cortisol

Cellular senescence as a driver of cognitive decline triggered by chronic unpredictable stress

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Lin, Yu-Fen, Wang, Li-Yun, Chen, Chi-Sheng, Li, Chia-Chun, Hsiao, Ya-Hsin·2021·Neurobiology of Stress
DOI 10.1016/j.ynstr.2021.100341PMC PMC8163993
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Abstract

When an individual is under stress, the undesired effect on the brain often exceeds expectations. Additionally, when stress persists for a long time, it can trigger serious health problems, particularly depression. Recent studies have revealed that depressed patients have a higher rate of brain aging than healthy subjects and that depression increases dementia risk later in life. However, it remains unknown which factors are involved in brain aging triggered by chronic stress. The most critical change during brain aging is the decline in cognitive function. In addition, cellular senescence is a stable state of cell cycle arrest that occurs because of damage and/or stress and is considered a sign of aging. We used the chronic unpredictable stress (CUS) model to mimic stressful life situations and found that, compared with nonstressed control mice, CUS-treated C57BL/6 mice exhibited depression-like behaviors and cognitive decline. Additionally, the protein expression of the senescence marker p16INK4a was increased in the hippocampus, and senescence-associated β-galactosidase (SA-β-gal)-positive cells were found in the hippocampal dentate gyrus (DG) in CUS-treated mice. Furthermore, the levels of SA-β-gal or p16INK4a were strongly correlated with the severity of memory impairment in CUS-treated mice, whereas clearing senescent cells using the pharmacological senolytic cocktail dasatinib plus quercetin (D + Q) alleviated CUS-induced cognitive deficits, suggesting that targeting senescent cells may be a promising candidate approach to study chronic stress-induced cognitive decline. Our findings open new avenues for stress-related research and provide new insight into the association of chronic stress-induced cellular senescence with cognitive deficits.

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Authors
Lin, Y.-F., Wang, L.-Y., Chen, C.-S., Li, C.-C., & Hsiao, Y.-H.
Affiliations
National Cheng Kung University (TW)
Corresponding author
Hsiao, Ya-Hsin
ORCID
Venue
Neurobiology of Stress
Publisher
Elsevier BV
Published
2021-11
Volume
15
Pages
100341
ISSN
2352-2895 (ISSN-L)
DOI
10.1016/j.ynstr.2021.100341
PMC
PMC8163993
OpenAlex
W3160438235
Cited by
47
References
105
Citations by year
2026: 7 · 2025: 14 · 2024: 5 · 2023: 11 · 2022: 8 · 2021: 2
FWCI
4.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Stress (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministry of Science and Technology, Taiwan (MOST 109, 061-MY3, MOST 107?, MOST109-2628-B006-020, 2314-B-006, MOST107-2314-B006-061-MY3)
  • National Cheng Kung University
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
cellular senescence, chronic unpredictable mild stress, cognitive decline, depression, brain aging, p16INK4a, senescence-associated β-galactosidase, hippocampus, dentate gyrus, memory impairment, senolytics, dasatinib, quercetin, senolytic therapy

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