# Role of cellular senescence in cardiovascular aging

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2020 · $60,181

## Abstract

PROJECT SUMMARY
 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 toll on society. Despite significant gains in treating CVD over
the last few decades, 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, preventing development of cancer in the face of genotoxic insults; 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, including in 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: In vivo consequences of senescence in the CV system. 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: Role of senescent cells in modulating cardiac and arterial function.
This aim will determine the sensitivity of different cell types in the CV to senescence, including cardiomyocytes,
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: Translational validation of senescent markers identified in Aims 1-2. 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 potentially pr...

## Key facts

- **NIH application ID:** 10160622
- **Project number:** 3R01AG055822-03S1
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Simon Melov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $60,181
- **Award type:** 3
- **Project period:** 2018-06-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160622

## Citation

> US National Institutes of Health, RePORTER application 10160622, Role of cellular senescence in cardiovascular aging (3R01AG055822-03S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10160622. Licensed CC0.

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