# Age-related vascular cognitive impairment: role of endothelial senescence

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $362,500

## Abstract

PROJECT SUMMARY/ ABSTRACT
 More than 50 million people over the age of 65 are currently affected by vascular
cognitive impairment and dementia (VCID). Although the specific mechanisms for aging-
induced VCID are not yet known, there is increasing evidence that alterations of the
neurovascular unit play a crucial role. The objective of this proposal is to elucidate the
mechanistic role of senescence-related endothelial dysfunction in cognitive impairment. The
central hypothesis is that aging primarily promotes endothelial senescence in the brain and
subsequent dysfunction, altering the production of vasodilator mediators, impairing
neurovascular coupling responses, promoting blood-brain barrier (BBB) disruption and
microvascular rarefaction. The resulting decline in cerebral blood flow (CBF) and increased
neuroinflammation contribute to cognitive impairment. The proposed work is novel as it will be
the first to demonstrate that aging-induced endothelial senescence is a critical contributing
factor to the pathogenesis of VCID. The results will likely identify specific mechanisms and
reveal potential therapies that are capable of improving CBF and restoring learning and
memory. The following aims are proposed: 1) Determine how endothelial senescence alters
neurovascular coupling responses, CBF and cognition in aging. The working hypothesis is that
aging-induced activation of p16-dependent cellular senescence program in endothelial cells
impairs vasodilator function. It is predicted that elimination of senescent endothelial
cells, through genetic manipulation or through senolytic therapies will restore neurovascular
function and improve CBF and cognition in aged mice. 2) Determine how senescence alters
microvascular density and BBB integrity in aging. The working hypothesis is that activation of
p16-dependent cellular senescence program in endothelial cells impairs endothelial barrier
function and compromise the maintenance of the microcirculatory network. It is predicted that
elimination of senescent cells will restore BBB, attenuating neuroinflammation and increase
cerebromicrovascular density in aged mice. 3) Determine cellular heterogeneity among
senescent endothelial cells in conjunction with their morphological and functional
characteristics. Together, the proposed studies will identify a fundamental mechanism
governing aging-induced cerebrovascular changes eventually leading to cognitive impairment.

## Key facts

- **NIH application ID:** 10044293
- **Project number:** 1R01AG068295-01
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Anna Csiszar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,500
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044293

## Citation

> US National Institutes of Health, RePORTER application 10044293, Age-related vascular cognitive impairment: role of endothelial senescence (1R01AG068295-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10044293. Licensed CC0.

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