# Mechanisms of brain rejuvenation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $396,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Cognitive decline continues to be one of greatest health threats affecting the elderly. In fact, aging remains the
single most dominant risk factor for dementia-related neurodegenerative diseases, including Alzheimer's
disease. When considering, the rate at which the human population is aging, it becomes imperative to identify
means by which to maintain cognitive integrity by protecting against, or even counteracting, the effects of
aging. Presupposed dogma holds that the old brain is unable to combat the effects of aging due to a lack of
inherent plasticity that facilitates permanent age-related functional impairments. We, and others, have begun to
challenge such dogma by showing that systemic manipulations such as heterochronic parabiosis (in which the
circulatory systems of young and old animals are connected) can enhance adult stem cell function in the aged
brain. Moreover, my lab recently demonstrated that neuronal and cognitive rejuvenation is possible in the aged
brain by systemic administration of young blood plasma, and identified the transcription factor Creb as a critical
mediator of brain rejuvenation. While the burgeoning field of rejuvenation research is fast growing, the current
focus thus far has been placed on identifying individual blood-borne factors in young blood. However, this
approach has left fundamental questions unexplored: 1. How long lasting are the rejuvenating effects of young
blood on the old brain? 2. What mechanistic changes does young blood elicit in the old brain to promote
rejuvenation? 3. Do the beneficial effects of young blood on the aged brain extend to dementia-related
neurodegenerative diseases such as Alzheimer's disease? The purpose of the proposed study is thus to
investigate the rejuvenating and therapeutic effects of young blood on the aged brain. Specifically, our
hypothesis is that systemic exposure to young blood elicits long lasting rejuvenation of synaptic and cognitive
functions, while ameliorating neurodegenerative phenotypes. We will test this theory with three Specific Aims:
1. Characterize the kinetics of brain rejuvenation following systemic exposure to young blood. 2. Identify
molecular mechanisms downstream of Creb underlying brain rejuvenation by young blood. 3. Distinguish
rejuvenating versus therapeutic effects of young blood in a model of accelerated aging and Alzheimer's
disease. Ultimately, these studies will challenge traditional views of brain aging by using the rejuvenating
effects of young blood to obtain a mechanistic understanding of the cellular events required for unleashing the
latent plasticity within the old brain. The results will also have significant translational potential, revealing
pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative
diseases such as Alzheimer's disease.

## Key facts

- **NIH application ID:** 9924450
- **Project number:** 5R01AG053382-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** SAUL A VILLEDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2016-08-15 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924450

## Citation

> US National Institutes of Health, RePORTER application 9924450, Mechanisms of brain rejuvenation (5R01AG053382-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9924450. Licensed CC0.

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