# Molecular mechanisms underlying the preservation of neural stem cell quiescence during aging

> **NIH NIH RF1** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2022 · $1,120,249

## Abstract

PROJECT SUMMARY – ORIGINAL APPLICATION
Cognitive decline is a major feature of aging and neurodegenerative diseases such as Alzheimer’s disease.
Neurogenesis, the formation of new neurons, supports learning, memory, mood regulation, and sensory
functions in the healthy mammalian brain. During aging, neurogenesis is dramatically reduced due to
impairments in neural stem cell (NSC) pools. The mechanisms responsible for dysfunction of the NSC reservoir
are not fully understood, but significant evidence implicates changes to the quiescent NSCs, which are the source
of the neurogenic lineage. This work investigates the mechanisms responsible for failed activation of quiescent
NSCs with age. This project is significant because identification of the mechanisms underlying dysfunction of
quiescent NSCs with age will reveal strategies to restore new neuron formation in aging and neurodegeneration.
Published and preliminary work shows that quiescent NSCs, though relatively dormant, are defective at the
chromatin, gene expression, and metabolic levels with age. This study takes an integrated approach to reveal
the specific target genes and processes responsible for defects in NSC quiescence with age. Specific Aim 1 will
investigate how mitophagy regulates metabolic health of NSCs during aging. Aim 2 employs an integrated multi-
omics strategy to fully elucidate the epigenomic and metabolic changes that occur the neurogenic lineage with
age. Finally, Aim 3 will address the mechanisms by which NSCs return to quiescence, and the extent to which
failure in this process results in depletion of the functional NSC pool with age. Collectively, this work will result
in a comprehensive understanding of how dormant NSCs are affected by aging in the mammalian brain. In the
long term, these studies have the potential to lead to the development of interventions to improve healthy aging
and restore cognition in the context of neurodegeneration.

## Key facts

- **NIH application ID:** 10939293
- **Project number:** 7RF1AG053268-07
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Ashley E Webb
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,120,249
- **Award type:** 7
- **Project period:** 2017-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939293

## Citation

> US National Institutes of Health, RePORTER application 10939293, Molecular mechanisms underlying the preservation of neural stem cell quiescence during aging (7RF1AG053268-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10939293. Licensed CC0.

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