# Does obesity exacerbate age-related cognitive decline via senescence?

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $397,500

## Abstract

PROJECT SUMMARY/ABSTRACT
This application investigates the relationship between obesity, 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. We have
found that senescent markers accumulated 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, restored neurogenesis and significantly decreased
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.
In order to test our hypothesis, we will use innovative mouse models which allow the elimination
of either p21Cip1 or p16Ink4a positive senescent cells (p21-ATTAC and INK-ATTAC), as well as a
novel transgenic model LOX-ATTAC (which we will cross with different Cre-expressing mice)
allowing us to clear p16Ink4a senescent cells specifically in neurons, microglia and astrocytes.
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 cell-types
(aim1). Additionally, we will examine the mechanisms mediating impaired lipid metabolism
during senescence in particular the role of lipid import, lipogenesis and β-oxidation to cellular
senescence by using a combination of genetic and imaging approaches as well as mass
spectrometry lipidomics studies. Finally, we will investigate if diet-induced obesity in mouse
models of AD exacerbates neurodegeneration via increased cellular senescence as well as the
impact of removal of senescent cells to the pathology of AD during obesity.
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:** 10259705
- **Project number:** 5R01AG068182-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Diana Jurk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2020-09-10 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259705

## Citation

> US National Institutes of Health, RePORTER application 10259705, Does obesity exacerbate age-related cognitive decline via senescence? (5R01AG068182-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10259705. Licensed CC0.

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