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Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging
Matthew P. Baier, Rojina Ranjit, Daniel B. Owen, Jenna L. Wilson, Megan A. Stiles, Anthony M. Masingale, Zachary Thomas, Anne Bredegaard et al.. Aging Cell, 2025-03-12
Topic: Risk, prevention and care in population studies
ABSTRACT Cognitive function in aging is heterogeneous: while some older individuals develop significant impairments and dementia, others remain resilient and retain cognitive function throughout their lifespan. The molecular mechanisms that underlie these divergent cognitive trajectories, however, remain largely unresolved. Here, we utilized a high‐resolution home‐cage‐based cognitive testing paradigm to delineate mechanisms that contribute to age‐related cognitive heterogeneity. We cognitively stratified aged C57Bl/6N male mice by cognitive performance into intact (resilient) or impaired subgroups based on young performance benchmarks. Cognitively impaired males exhibited marked reactive gliosis in the hippocampus, characterized by microglial activation, increased astrocyte arborization, and elevated transcriptional expression of reactivity markers. These changes were accompanied by increased markers of cellular senescence and the associated senescence‐associated secretory phenotype (SASP) in impaired animals, including p16 INK4a , SASP factors (e.g., Il‐6 , Il‐1b , Mmp3 ), and SA‐β‐gal staining in the hippocampus. Notably, clearance of senescent cells using senolytic agents dasatinib and quercetin ameliorated the heterogeneity in cognitive performance observed with age and attenuated impairment‐associated gliosis, senescence markers, and mitochondrial dysfunction. Aged female mice could not be stratified into subgroups yet showed increased neuroinflammation with age that was not resolved with senolytics. Collectively, our findings implicate cellular senescence as a central driver of sex‐specific neuroinflammation that drives divergent cognitive trajectories in aging. Thus, we demonstrate that senolytic treatment is an effective therapeutic strategy to mitigate cognitive impairment by reducing neuroinflammation and associated metabolic disturbances.
Key findings
- ABSTRACT Cognitive function in aging is heterogeneous: while some older individuals develop significant impairments and dementia, others remain resilient and retain cognitive function throughout their lifespan.
- Collectively, our findings implicate cellular senescence as a central driver of sex‐specific neuroinflammation that drives divergent cognitive trajectories in aging.
Why it matters
In aged male mice, cognitive impairment was accompanied by markers of cellular senescence and inflammation in the hippocampus, and clearing senescent cells with dasatinib and quercetin reduced these markers and the cognitive differences. This is early animal research, so it does not yet show that senolytic drugs can treat or prevent Alzheimer's disease in people.
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Study details
- Evidence strengthLow
How this study scored 44/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Aging Cell) |
| Journal's citation record | 2 / 4 | Aging Cell: journal h-index 216 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 23 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 7.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 12.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 2 / 4 | Cited 23 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Sreemathi Logan: h-index 21 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Oklahoma: institution h-index 716 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40077862) |
| Free to read | 2 / 2 | Free to read |
| Total | 44 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Baier, M. P., Ranjit, R., Owen, D. B., Wilson, J. L., Stiles, M. A., Masingale, A. M., et al. (2025). Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging. Aging Cell. https://doi.org/10.1111/acel.70041
Vancouver
Baier MP, Ranjit R, Owen DB, Wilson JL, Stiles MA, Masingale AM, et al. Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging. Aging Cell. 2025. doi:10.1111/acel.70041. PMID: 40077862.
BibTeX
@article{baier2025-40077862,
author = {Baier, Matthew P. and Ranjit, Rojina and Owen, Daniel B. and Wilson, Jenna L. and Stiles, Megan A. and Masingale, Anthony M. and Thomas, Zachary and Bredegaard, Anne and others},
title = {{Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging}},
journal = {Aging Cell},
year = {2025},
doi = {10.1111/acel.70041},
pmid = {40077862},
url = {https://doi.org/10.1111/acel.70041}
}
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