# Investigating the impact of peripheral senescent cells on the brain

> **NIH NIH R56** · MAYO CLINIC ROCHESTER · 2022 · $423,644

## Abstract

Abstract
Ever since the discovery of the senescence-associated secretory phenotype (SASP) having potent
autocrine and paracrine signaling effects, together with the demonstration of beneficial effects of
reducing senescent cell burden in progeroid and chronologically aged mice, the role of senescent cells
in the pathogenesis of many age-related chronic disorders has been extensively studied. As a result, it
has now been established that senescent cells accumulate in tissues by promoting local inflammation,
tissue aging and destruction, stem and progenitor cell dysfunction, and the spread of senescence to
non-senescent cells. More recently, the detrimental effects of senescent glial cells, senescent brain
ependymal cells, and senescent oligodendrocyte progenitor cells in various kinds of neurological
disorders have attracted significant interest. However, neither of these studies discerns the effects of
peripheral vs. central senescent cells. Indeed the impact of peripheral senescent cells on healthy brain
aging and age-related cognitive impairment remain unexplored yet. Existing evidence demonstrates
that a high burden of senescent cells in peripheral tissues plays a possible causal role in the
pathogenesis of multiple age-related chronic diseases, which is the leading predictive factor for
developing cognitive deficits later. We speculate that peripheral senescent cells link chronic diseases,
brain aging, and cognitive impairment. Thus, we hypothesize that high senescent cell burden in
peripheral tissues contributes to or accelerates age-related pathological changes in the
hippocampus, predisposing the brain to cognitive dysfunction. We will use three different
senescence-associated models to test our hypothesis. Aim1 is to test if increased peripheral senescent
cell burden contributes to age-dependent cognitive deficits in chronologically aged mice. Aim2 is to test
if obesity-driven peripheral senescent cells contribute to neuropsychiatric dysfunction and cognitive
deficits. Aim3 is to test if peripheral senescent cells accelerate age-dependent neuropathological
processes and cognitive deficits in Alzheimer’s disease model mice. We will apply our recently
developed cell transplantation model to test whether peripherally transplanted senescent cells directly
cause or exacerbate the cognitive decline in the context of aging, obesity, and Alzheimer’s diseases.
To further investigate the possible mechanisms of how peripheral senescent cells affect brain
microenvironments, we will examine cellular and molecular changes in the hippocampus resulting from
high periphery senescent cell burden using the newly developed mass cytometry (CyTOF) approach
and other complement methods. Overall, our studies will answer a critical question of whether reducing
peripheral senescent cell burden is necessary for treating age- and disease-related neurological
disorders and neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10670484
- **Project number:** 1R56AG068047-01A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Yi Zhu
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,644
- **Award type:** 1
- **Project period:** 2022-09-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10670484

## Citation

> US National Institutes of Health, RePORTER application 10670484, Investigating the impact of peripheral senescent cells on the brain (1R56AG068047-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10670484. Licensed CC0.

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