# Targeting Cellular Senescence to Extend Healthspan

> **NIH NIH P01** · MAYO CLINIC ROCHESTER · 2020 · $397,500

## Abstract

PROJECT SUMMARY/ABSTRACT
This project aims to investigate the relationship between metabolic dysfunction, senescence,
brain aging and the development of Alzheimer’s disease (AD).
Cellular senescence is a well-established driver of tissue and organismal aging, a process
thought to be partly mediated via the induction of a chronic Senescence-associated secretory
phenotype (SASP). Consequently, there is great interest in selectively targeting senescent cells
as a strategy to promote healthy aging. My laboratory has found that senescent cells
accumulate in glia cells and neurons in different brain regions of obese and aged mice.
Importantly, we showed that clearance of senescent cells, using both genetic and
pharmacological approaches, restores neurogenesis and significantly decreases obesity-
induced anxiety-like behavior. Additionally, we found that senescent cells were a contributor to
the accumulation of fat deposits in the brain, a phenotype common between aging, obesity and
AD. This led us to hypothesize that obesity, by inducing senescence in the brain, exacerbates
age-related cognitive decline and contributes to neurodegenerative diseases such as AD.
This project will be a supplement to Project 1 led by Dr. Kirkland on: “Cellular Senescence and
Metabolic Dysfunction”, part of the Mayo/UMN P01 AG 62413, which aims to investigate the
impact of senotherapies in the context of obesity and age-related diseases. Thus, investigating
the mechanistic links between obesity and senescence in the context of brain aging and AD is a
natural and logical extension of this project.
In order to test our hypothesis, we will use innovative mouse models developed as part of the
P01 which allow the elimination of either p21Cip1 or p16Ink4a positive senescent cells (p21 ATTAC
and INK-ATTAC). Using these models, we will be able to elucidate the functional impact of
senescent cell clearance during aging and obesity, in particular, the relative contribution of
different senescent sub-types (aim1). Additionally, we will be able to evaluate the efficacy of
newly identified senotherapeutic compounds in a mouse model of AD (aim 2). These novel
candidate drugs (which include several FDA approved compounds and natural products) have
been identified as part of the Drug Discovery and Development Core led by Dr. Paul Robbins
(University of Minnesota) as part of the P01.
Our ultimate goal is to identify new interventions that target senescent cells to alleviate cognitive
decline during aging and AD.

## Key facts

- **NIH application ID:** 10117964
- **Project number:** 3P01AG062413-02S1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** JAMES L. KIRKLAND
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,500
- **Award type:** 3
- **Project period:** 2019-06-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117964

## Citation

> US National Institutes of Health, RePORTER application 10117964, Targeting Cellular Senescence to Extend Healthspan (3P01AG062413-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10117964. Licensed CC0.

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