# Cerebral microhemorrhages and gait abnormalities in aging

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $433,015

## Abstract

Project Summary/ Abstract
The growing prevalence of multifocal cerebral microhemorrhages (CMHs), also known as "cerebral microbleeds," is
a significant and newly recognized problem in the aging population. These CMHs are major contributors to vascular
cognitive impairment (VCI) and gait and balance disorders, which are among the most common causes of falls in
older adults. Hypertension is the primary risk factor for CMHs in older adults, which are associated with the rupture
of small intracerebral vessels and progressive impairment of neuronal function. Despite affecting over 50% of older
individuals, the pathogenesis of CMHs remains obscure, and no therapeutic interventions are currently available for
their prevention. The objective of the present proposal is to elucidate the specific age-related mechanisms that lead
to increased cerebromicrovascular fragility and identify potential targets for prevention of CMHs using innovative
preclinical models. Results from recent studies provided insights into the cellular mechanisms by which aging may
increase cerebromicrovascular fragility and promote development of CMHs: increased presence of senescent
endothelial cells in the cerebral microcirculation. Our central hypothesis is that the accumulation of senescent
endothelial cells in the cerebral microcirculation, caused by aging, results in a microvascular phenotype that is prone
to fragility. Senescent cells release activated matrix metalloproteinases and other paracrine factors ("senescence-
associated secretory phenotype" or SASP), which promote structural maladaptation to high pressure, degradation of
collagen and remodeling of extracellular matrix, thus creating loci of least resistance that can easily burst upon induction
of hypertension. We will combine advanced imaging techniques and cutting-edge transcriptomics to investigate
microvascular structure and gene expression in senescent cells in the cerebral microcirculation of aged mice. Our
prediction, based on our working hypothesis, is that elimination of senescent cells, either through genetic manipulation
(p16-3MR mouse model) or by pharmacological means will protect the structural integrity of cerebral vessels
preventing the development of CMHs. Specific Aims: 1) Determine the causal link between increased presence of
senescent cells in the microcirculation and genesis of CMHs in aged mice. 2) Determine whether induction of
accelerated senescence exacerbates CMHs in young mice, mimicking the aging phenotype. 3) Determine how
senescence promotes a pro-fragility phenotype in cerebral microvessels. Together, the proposed studies will identify
a fundamental mechanism responsible for age-related exacerbation of CMHs, and the resulting vascular-induced
neurological deficits. The increased presence of senescent cells in the microcirculation and consequential
degradation of cerebrovascular structural integrity are key contributors to this phenomenon. By uncovering these
mechanisms, our research will...

## Key facts

- **NIH application ID:** 10826074
- **Project number:** 2R01AG055395-06A1
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Anna Csiszar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $433,015
- **Award type:** 2
- **Project period:** 2024-09-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10826074

## Citation

> US National Institutes of Health, RePORTER application 10826074, Cerebral microhemorrhages and gait abnormalities in aging (2R01AG055395-06A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10826074. Licensed CC0.

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