Abstract 13273: Late Senolytic Therapy Improves Cerebrovascular Endothelial Function but Not Cognition in Middle-Aged Severely Atherosclerotic Mice
Bibliographic record
Abstract
Introduction: Age-related and atherosclerosis-related vascular dysfunction contributes to neuro-vascular uncoupling, which induces neuronal damage and leads to precocious cognitive loss. This dysfunction could be partially explained by the accumulation of senescent cells (SnC) that remain metabolically active and release many pro-inflammatory factors. Hypothesis: Targeted elimination of SnC with a senolytic restores cerebrovascular function, maintains neuro-vascular coupling and slows cognitive decline. Methods and Results: Nine-month old male atherosclerotic mice (ATX, LDLR -/- ;hApoB +/+ ) were treated (n=13), or not (n=11), for 3 months with navitoclax (50mg/kg), a Bcl2 inhibitor that stimulates global elimination of SnC overexpressing this antiapoptotic pathway. Twelve-month old vehicle-treated ATX mice developed atheroma plaques up to the upper neck portion of the carotid arteries, but not in the cerebral circulation. Three months treatment with navitoclax reduced aortic plaques size (-32%, p<0.001) from 40±2% in vehicle-treated mice to 27±2% in navitoclax mice. At 12 months, endothelial dysfunction was severe in vehicle-treated ATX mice, as evidenced by a strong reduction in flow-mediated dilation (FMD) of pressurized posterior cerebral arteries ex vivo ; navitoclax improved endothelium-dependent dilatation by 50% (for example, FMD at 20 dyn/cm 2 : 58±10%) compared to vehicle-treated mice (FMD: 29±7%; p<0.05). Two cognitive tests were performed: the Y-maze and the novel object recognition tests, to assess exploratory behavior and executive function, respectively. A gradual decline of both exploratory and executive memory was observed from 3 to 6, 9 and 12 months in vehicle-treated ATX mice; navitoclax, however, did not prevent this cognitive decline. Conclusion: Global elimination of SnC slowed atherosclerotic plaque development and restored cerebral endothelial function, demonstrating that senescence contributes to vascular dysfunction. The absence of cognitive improvement with navitoclax suggests an irreversible state of neuronal damage that could not be affected by the late senolytic treatment. To demonstrate the role of SnC in cognitive impairment, an earlier senolytic therapy will be needed.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".