# Systemic Mechanisms of Brain Rejuvenation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $559,152

## Abstract

PROJECT SUMMARY/ABSTRACT
The ability to enhance cognition by targeting circulating factors in the systemic milieu provides a unique and
underexplored therapeutic approach to brain aging. We and others have shown that systemic manipulations,
including exposure to young blood through heterochronic parabiosis (in which the circulatory system of a young
and old animal are joined) and young blood plasma administration, revitalize the aged hippocampus and
ameliorate cognitive decline in aged mice. The rejuvenating effects of young blood mirror those observed with
exercise, positing common bloodborne mechanisms of action by which broad systemic interventions exert their
beneficial effects. Preliminary data from our labs indicate that systemic administration of platelet factors derived
from either naïve young mice or exercised mice reverses age-related impairments in adult neurogenesis,
deceases neuroinflammation and restores cognitive function in aged mice. Moreover, using proteomics, our two
groups have independently identified CXCL4/platelet factor 4 (PF4)—a chemokine released from platelets,
involved in coagulation and a variety of immunomodulatory functions—as a potential young blood-derived and
exercise-induced anti-geronic circulating factor. The proposed study will investigate the rejuvenating and
therapeutic effects of platelet factors on the aged brain. Specifically, our hypothesis is that systemic exposure to
platelet factors rejuvenates adult neurogenesis, attenuates neuroinflammation and improves cognition, while
ameliorating neurodegenerative phenotypes. We will test this theory with three specific aims: 1: Determine
mechanisms downstream of PF4 underlying cognitive and regenerative rejuvenation in the aged hippocampus.
2: Examine the rejuvenating effects of PF4 on neuroinflammation in the aged hippocampus. 3: Investigate the
beneficial effects of PF4 in a mouse model of Alzheimer’s disease. Successful completion of these studies will
have significant translational potential, identifying platelet-derived circulating factors as candidate therapeutic
targets to restore age-related cognitive dysfunction and potentially treat dementia-related neurodegenerative
disorders such as Alzheimer’s disease.

## Key facts

- **NIH application ID:** 10467545
- **Project number:** 1R01AG077816-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** SAUL A VILLEDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $559,152
- **Award type:** 1
- **Project period:** 2022-06-15 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467545

## Citation

> US National Institutes of Health, RePORTER application 10467545, Systemic Mechanisms of Brain Rejuvenation (1R01AG077816-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10467545. Licensed CC0.

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