# Systemic Cell Senescence as a Mediator of Brain Aging Through Circulation

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $476,576

## Abstract

PROJECT SUMMARY
Aging is the strongest risk factor for cognitive decline and dementia. Targeting fundamental aging mechanisms
offers promising new strategies to counter brain dysfunction. Recent breakthroughs have demonstrated that
proteins in aged blood circulation mechanistically contribute to accelerated brain aging, and senescent cells
(SCs) accumulate in aging and may drive tissue deterioration, in part, through the proinflammatory senescence
associated secretory phenotype (SASP). This research is designed to test whether progeronic SASP
proteins produced by systemic SCs mechanistically contribute to accelerated brain aging through
blood circulation. This premise is based on published findings establishing that aged blood circulation and/or
direct administration of progeronic plasma proteins that are putative SASP factors are sufficient to transfer an
accelerated aging phenotype to young mouse brain and our research demonstrating that systemic SC
clearance attenuates the SASP in circulation, which is associated with improvements in brain inflammatory
parameters and cognitive decline. To test our central hypothesis, we will combine circulatory exchange
methods with mouse models in which SCs can be eliminated or production of the SC proteome can be
precisely monitored, which will enable us to study whether reducing the circulating SASP is sufficient
to ameliorate the adverse influence of aged blood on brain homeostasis. We will develop an innovative
transgenic mouse model that will enable bioorthogonal labeling of the nascent p16+ SC proteome. This will
empower our discovery of the age- and tissue-specific p16+SC-proteome, its contribution to the
circulating progeronic proteome, and its responsivity to SC clearance. Administration of bioorthogonally
labeled aged plasma +/- SC clearance to young mice will facilitate discovery of candidate SASP proteins
responsible for accelerated aging brain phenotypes for further mechanistic interrogation. Modifying aged blood
composition and targeting SCs are therapeutics actively being pursued for ameliorating age-related decline.
This project is designed to mechanistically synergize and advance these two promising concepts. Our research
may preclinically implicate systemic SC clearance as an option to deplete the progeronic influence of aged
blood, ultimately revealing a novel approach for treatment or prevention of age-dependent cognitive decline
and dementia.

## Key facts

- **NIH application ID:** 10191895
- **Project number:** 1R01AG071686-01
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Marissa Joy Schafer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $476,576
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191895

## Citation

> US National Institutes of Health, RePORTER application 10191895, Systemic Cell Senescence as a Mediator of Brain Aging Through Circulation (1R01AG071686-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10191895. Licensed CC0.

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