# Role of cellular senescence in cardiovascular aging

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2020 · $784,023

## Abstract

Aging is the primary risk factor for cardiovascular disease (CVD), and by 2030, 40% of Americans will
have some form of CVD incurring a huge economic and human toll on society. Much remains unknown about
why cardiovascular dysfunction increases with age. One potential cause of cardiovascular aging is cellular
senescence. This complex stress response can be beneficial or detrimental, depending on the physiological
context. Two hallmarks of the response are: 1) a permanent arrest of cell proliferation; and 2) development of
a senescence-associated secretory phenotype (SASP) -- the transcriptional upregulation and secretion of
numerous inflammatory cytokines, chemokines, growth factors and proteases. Senescent cells increase with
age in many tissues, including the cardiovascular (CV) system, and the SASP is associated with a variety of
age-related pathologies, including cardiac and vascular dysfunction. Senescent cells accumulate with age in
the hearts and vasculature of mice and humans, but it is not known if cellular senescence is a cause or
consequence of cardiovascular aging. We developed a novel mouse model that permits the visualization
and elimination of senescent cells in vivo and their isolation from tissues, making it possible to study the
function of integrated systems -- such as the heart and vasculature -- with and without senescent cells. We
propose to test the novel hypothesis that senescent cells, and particularly the SASP, are an important
mechanistic process driving CV aging. To test this hypothesis, we will develop three specific aims.
 Aim 1: Determine the extent to which senescent cells cause CV system dysfunction in settings
of both experimental senescence and natural aging. This aim will determine when and where senescent
cells arise in the cardiovasculature, using an acute model, as well as naturally aged mice. We will employ our
novel mouse model, the 3MR mouse in which we can eliminate cells to contrast CV function with and without
senescent cells; Aim 2: Determine the cellular and molecular mechanisms by which senescent cells
negatively impact cardiovascular tissue. This aim will determine the sensitivity of critical cell types in the CV
to senescence, including fibroblasts, endothelial cells, and vascular smooth muscle cells isolated from both
arteries and intact hearts. We will determine how secreted factors from senescent cells influence function of
other cell types using co-cultures and genetic strategies; Aim 3: To identify novel therapeutic targets for
age-related CV dysfunction in humans. Having established specific protein and gene expression signatures
for different cell types as a result of senescence in aims 1 and 2, in this final aim we will use a novel
translational model – biopsies of endothelial cells from humans to validate our predictions about senescence in
different aged humans.
 Overall our program will provide novel insights into the role of senescence as a major mediator of age-
related CVD, and poten...

## Key facts

- **NIH application ID:** 9849153
- **Project number:** 5R01AG055822-03
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Judith Campisi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $784,023
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849153

## Citation

> US National Institutes of Health, RePORTER application 9849153, Role of cellular senescence in cardiovascular aging (5R01AG055822-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9849153. Licensed CC0.

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