# Molecular Regulation of Stem Cell Aging

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $661,325

## Abstract

SUMMARY
 The loss of tissue homeostasis and regenerative capacity is an almost ubiquitous aspect of mammalian
aging. Underlying this age-related change is a decline in the potential of tissue-specific stem cells to participate
in tissue maintenance and repair. In skeletal muscle, this has been amply demonstrated for the resident
muscle stem cells (MuSCs), whose response to injury has been shown to decline with age in. Nevertheless,
the molecular basis of the cellular changes that integrate cell-intrinsic and cell-extrinsic influences to render
MuSCs less responsive with age is not well understood. Likewise, the molecular basis for the restoration of
youthful function to aged stem cells by rejuvenating interventions remain to be elucidated. Understanding these
fundamental mechanisms of MuSC aging and rejuvenation will provide the potential for being able to intervene
to restore youthful characteristics to aged stem cells, thus enhancing aged tissue repair and regeneration.
 Toward these goals, this Project focuses on key themes of the Overall Program of epigenetics in stem cell
aging. In Aim 1, focusing on the intersection of metabolism and epigenetics in collaboration with Project 2,
we will focus on the mechanisms of loss of heterochromatin in MuSCs with age, focusing on the role of the
metabolite s-adenosylmethionine (SAM) and its role in histone methylation reactions are relevant to
heterochromatin formation and maintenance. This Aim will rely heavily on the bioinformatic resources of
Core C. In Aim 2, we will expand our studies for “rejuvenating interventions” (specifically, diet (in the form of
fasting) and exercise, in collaboration with Projects 2 and 3) pursued during the previous grant cycle to
examine. We will examine the downstream mediators of the beneficial effects of these interventions, studying
them both in terms of the metabolic and epigenetic pathways explored in Aim 1 and also in terms of unbiased
assessments. In Aim 3, we will examine age-related heterogeneities of MuSCs at the single cell and spatial
levels, focusing on our recent findings of the bimodality of aged MuSCs in terms of glutathione levels. In close
collaboration with Core B, we will use MIBI-TOF technology to test for regional variations as correlates and
determinants of specific subsets of MuSCs that we have identified in aged muscle. In close collaboration
with Core C, we will continue to develop spatial transcriptomic analysis of MuSC niche heterogeneity in a
broader, unbiased fashion, taking advantage of the architecture of muscle and rarity of MuSCs to be able to
expand our targeted proteomic analyses to genome-wide transcriptomic analyses. Together, these studies will
advance our understanding of stem cell aging and approaches to restore youthful function to aged stem cells
as a way to enhance tissue homeostasis and repair in older individuals.

## Key facts

- **NIH application ID:** 10768510
- **Project number:** 2P01AG036695-12A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** THOMAS A. RANDO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $661,325
- **Award type:** 2
- **Project period:** 2011-07-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768510

## Citation

> US National Institutes of Health, RePORTER application 10768510, Molecular Regulation of Stem Cell Aging (2P01AG036695-12A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10768510. Licensed CC0.

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