# Molecular Regulation of Stem Cell Aging

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $680,096

## Abstract

SUMMARY
The overall goal of this project is to identify functional metabolic changes in adult neural stem cells during aging,
with the objective of `reprogramming' chromatin and transcriptional states in old stem cells and rejuvenate their
function. The adult brain contains regenerative neurogenic niches that comprise neural stem cells (NSCs). NSCs
can give rise to new neurons, astrocytes, and oligodendrocytes and contribute to aspects of learning and memory
as well as injury repair. During aging, the ability of NSCs to generate new neurons decline dramatically.
Interestingly, neurogenic decline can be reversed at least in part by `rejuvenating interventions' (e.g. diet and
exercise), raising the exciting possibility that specific mechanisms can boost regenerative niches to counter
aging. While some mechanisms underlying NSC decline have been identified, a systematic characterization of
the program that regulate regenerative neurogenic regions during aging has been elusive. Identifying how
metabolic changes impacts neurogenic niche aging and how metabolic interventions `reprogram' chromatin and
transcriptional states will be critical to design efficient molecular strategies to slow the functional deterioration of
regenerative niches and enhance the repair potential of the nervous system during aging.
We have recently performed large scale CRISPR-Cas9 functional screens in vitro and in vivo in old NSCs, which
unbiasedly identified glucose metabolism as a critical way to boost old NSC function during aging. In parallel,
our lab has embarked on a systematic effort to identify the reversible changes in the epigenome, transcriptome
and metabolome in neurogenic regions during aging, at both single cell and spatial resolution. Our central
hypothesis is that boosting the metabolic states of old NSCs could reprogram chromatin and transcriptional
states to rejuvenate the function of old neurogenic region. We propose the following experiments:
1. To identify the mechanisms by which manipulating glucose metabolism boosts old neural stem cells by
 impacting their chromatin and transcriptional states in collaboration with Project 1, Core B, and Core C;
2. To use `aging clocks' based on single cell RNA-seq to test in a scalable manner the impact of metabolic
 interventions on specific cell types in old stem cell niches in synergy with Projects 1 and 3 and Core C;
3. To examine the spatial relationship between metabolic and chromatin/transcription states in cells from the
 neurogenic niche in young, old, and rejuvenated individuals in collaboration with Core B.
This project has major implications for countering brain aging and diseases such as Alzheimer's disease.

## Key facts

- **NIH application ID:** 10768511
- **Project number:** 2P01AG036695-12A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ANNE BRUNET
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $680,096
- **Award type:** 2
- **Project period:** 2011-07-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768511

## Citation

> US National Institutes of Health, RePORTER application 10768511, Molecular Regulation of Stem Cell Aging (2P01AG036695-12A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10768511. Licensed CC0.

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