# Project 2: Epigenetic Regulation of Aging Neural Stem Cells

> **NIH NIH P01** · STANFORD UNIVERSITY · 2020 · $581,499

## Abstract

SUMMARY
 The goal of this project is to identify the epigenomic changes in adult stem cells during aging and in
response to rejuvenating interventions, with the objective to restore youthful function to old stem cells. The
adult brain contains a reservoir of neural stem cells (NSCs) that can give rise to new neurons, astrocytes, and
oligodendrocytes throughout life. However, during aging, the ability of NSCs to give rise to new neurons
dramatically deteriorates. Exciting emerging data suggest that NSC decline can be reversed in part by blood
factors, exercise, and diet, indicating that specific molecular mechanisms could integrate these external stimuli
and reverse the decline of these cells. However, the molecular bases of the reversible age-dependent changes
in NSCs in response to environmental cues have been elusive.
 Our lab has embarked on a massive effort to identify changes in the epigenome and transcriptome of
NSCs during aging. Our results have uncovered a new chromatin signature – broad H3K4me3 domains – that
marks genes that are critical for NSC identity. Intriguingly, this signature also marks genes with increased
transcriptional levels and consistency (i.e. reduction of transcriptional noise). The central hypothesis of this
Project is that chromatin changes during aging reduces the robustness of transcriptional outputs, and that
restoring such epigenetic changes could rejuvenate the transcriptional output and function of old NSCs. As
such, the Specific Aims of this proposal are:
1. To understand how broad H3K4me3 domains and their transcriptional outputs are influenced by increasing
age and by rejuvenating strategies in old animals;
2. To specifically modulate broad H3K4me3 domains at critical functional genes in NSCs to reprogram
transcriptional outputs and function in old NSCs;
3. To generate systems-level aging models based on single cell gene expression changes in the aging
neurogenic niche.
 This study should provide unique mechanistic insights into the regulation of transcriptional outputs,
including transcriptional noise versus consistency, and how they are altered during aging in regenerative cells.
This study should also provide a fundamental understanding of aging in a complex system, comprising a
population of regenerative and more committed cells. Together, this knowledge should pave the way for
building new methods for `epigenetic reprogramming' of old cells to restore youthful function to old cells and
tissues.

## Key facts

- **NIH application ID:** 9934980
- **Project number:** 5P01AG036695-09
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** ANNE BRUNET
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $581,499
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934980

## Citation

> US National Institutes of Health, RePORTER application 9934980, Project 2: Epigenetic Regulation of Aging Neural Stem Cells (5P01AG036695-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934980. Licensed CC0.

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