# Cellular senescence as a potential sex-specific driver of small vessel disease and post-stroke cognitive impairment in late adulthood

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $234,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Stroke is the leading cause of long-term disability in the United States and is the third leading cause of death in
women, and the fifth in men. Through improvements in acute ischemic stroke management with increased use
of thrombolytics and thrombectomy, there are a growing number of patients surviving ischemic stroke. Recent
findings suggest that ~65% of stroke survivors live with some degree of cognitive impairment that negatively
impacts their quality of life. Compared with men, women experience worse post-stroke functional and quality-
of-life outcomes. Reasons for this disproportionate stroke burden are not clear. Cerebral small vessel disease
(SVD), such as cerebral amyloid angiopathy (CAA), is highly prevalent in older adulthood and a common
cause of stroke, mild cognitive impairment, and dementia. The female sex is associated with more severe
vascular brain lesions secondary to SVD, and long-term cognitive deterioration after acute lacunar stroke.
Indeed, the underlying pathological mechanisms and relationship between SVD and ischemic stroke have
remained elusive, in part, because animal models rarely examine stroke pathophysiology in the setting of SVD.
The long-term sequelae and how they differ between sexes have been largely ignored. Our proposal aims to
understand the chronicity of events, secondary injury mechanisms, and disease phenotypes underlying the
chronic phase of stroke. We hypothesize that stroke causes accelerated brain aging in a sex-specific manner,
with postmenopausal females having worse neurological outcomes. We further hypothesize that brain injury-
induced senescence is a key driver of inflammatory neurodegeneration. Our preliminary data suggest that
ischemic stroke is a chronic neurodegenerative disease with non-resolving inflammation and cognitive deficits
that continue to worsen over time. We identified senescent microglia as potential culprits. To explore this
further, Aim 1 will examine the chronic and evolving neurological consequences of SVD following stroke. Male
and female Tg-SwDI and wildtype C57Bl/6 control mice (12-months-old) will undergo middle cerebral artery
occlusion or sham surgery and be evaluated longitudinally using magnetic resonance imaging and a battery of
behavioral tests at 1-, 3-, and 6-months post-stroke. Biomarkers of aging/disease will be examined to generate
a temporal map of chronic pathologies. In Aim 2, we propose that delayed treatment strategies targeting the
elimination of senescent cells will reduce chronic inflammation, vascular amyloidosis, white matter loss,
neurodegeneration, and cognitive decline. Using the same paradigm outlined above, we will administer a
senolytic combinatorial therapy, dasatinib plus quercetin, starting at 1-month post-stroke, to determine whether
mitigating secondary injury can improve CAA disease course and functional outcomes. In summary, the
proposed aims will determine if injury-induced senescence is responsible for acceler...

## Key facts

- **NIH application ID:** 10985912
- **Project number:** 1R21AG089655-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Rodney Ritzel
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985912

## Citation

> US National Institutes of Health, RePORTER application 10985912, Cellular senescence as a potential sex-specific driver of small vessel disease and post-stroke cognitive impairment in late adulthood (1R21AG089655-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10985912. Licensed CC0.

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