# Targeting cellular senescence to prevent accelerated vascular aging induced by the common chemotherapeutic agent doxorubicin

> **NIH NIH R21** · UNIVERSITY OF COLORADO · 2022 · $195,625

## Abstract

PROJECT SUMMARY/ABSTRACT
Advancing age is the primary risk factor for cardiovascular diseases (CVD). Increased CVD risk with aging is
mediated primarily by vascular dysfunction, including impaired vascular endothelial function and
increased large elastic artery (primarily aortic) stiffening. These changes in vascular function are largely
due to excessive reactive oxygen species (ROS) as a result of increased mitochondrial superoxide production,
which reduce bioavailability of the vasodilatory molecule nitric oxide (NO) and induce structural changes in the
arterial wall. However, the upstream events regulating these processes are incompletely understood. Cellular
senescence, a physiological state of largely-permanent cell cycle arrest coupled with the secretion of pro-
inflammatory factors (i.e., the senescence-associated secretory phenotype [SASP]), has recently been
established by us and others to be a key mechanism of age-related vascular dysfunction.
Interestingly, young adults who have undergone cancer treatment with doxorubicin (DOXO) chemotherapy
have vascular dysfunction (e.g., lower endothelial function and greater aortic stiffness), similar to or even
worse than what is observed in older adults without disease. Moreover, the mechanisms underlying DOXO-
induced vascular dysfunction are similar to those with advancing age, including greater mitochondrial ROS and
lower NO bioavailability. As such, DOXO chemotherapy is viewed as a model of accelerated vascular aging,
but like with naturally aging, the upstream mechanistic events governing these cellular processes have not
been established. We hypothesize that cellular senescence is a novel therapeutic target for the prevention
and/or treatment of accelerated vascular aging following DOXO chemotherapy treatment.
The purpose of this NIH Exploratory/Development grant (R21) application in response to NOT-CA-21-031
(Understanding the effects of cancer treatment on aging trajectories) is to investigate the role of cellular
senescence in mediating accelerated vascular aging induced by the common chemotherapeutic agent
doxorubicin (DOXO).
Hypothesis 1: Clearance of senescent cells (senolysis) in vivo following DOXO treatment in young adult
animals will prevent vascular dysfunction via suppression of mitochondrial ROS bioactivity and consequent
preservation of NO bioavailability. DOXO-treated mice administered a “senolytic” intervention will have
vascular function similar what is observed in young adult mice that received vehicle treatment.
Hypothesis 2: DOXO-induced activation of the SASP will reduce vascular (endothelial) cell function and these
effects will be mediated by activation of cellular senescence.
Deliverables: The results of these studies will advance our understanding of the effects of cancer
treatment on aging outcomes and provide new insight into cellular senescence as a novel therapeutic target
to reduce vascular dysfunction and CVD risk in DOXO-treated cancer survivors.

## Key facts

- **NIH application ID:** 10505896
- **Project number:** 1R21AG078408-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** DOUGLAS R SEALS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $195,625
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10505896

## Citation

> US National Institutes of Health, RePORTER application 10505896, Targeting cellular senescence to prevent accelerated vascular aging induced by the common chemotherapeutic agent doxorubicin (1R21AG078408-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10505896. Licensed CC0.

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