# Epigenetic Reprogramming of Cellular Age

> **NIH NIH R01** · PALO ALTO VETERANS INSTIT FOR RESEARCH · 2021 · $426,000

## Abstract

PROJECT SUMMARY
 Current ideas that systemic factors regulate the aging of cells and tissues, in terms of both promoting and
reversing the aging process, have emerged from studies of heterochronic parabiosis (HP) and heterochronic
blood exchange (HBE) protocols. Our lab performed the first HP studies in order to assess cellular aging and
rejuvenation as it relates to tissue homeostasis and repair and in terms of molecular determinants of cellular age.
Initially, we focused changes in muscle stem cells (MuSCs), but we and others later explored these phenotypic
changes in many different cell populations. Since then, we have explored the molecular mechanisms by which
systemic factors might influence the aging process. Based on numerous lines of evidence, we have hypothesized
that the alteration in cellular aging features is due to a form of epigenetic reprogramming that is akin to that which
occurs during induced pluripotent stem cell generation but without the loss of cellular differentiation.
 A general feature of cellular aging is the loss of heterochromatin and subsequent dysregulation of
transcriptional stability. Heterochromatin is prominently associated with specific histone modifications, most
notably by di- and tri-methylation of lysine 9 on histone 3 (H3K9me2 and H3K9me3, respectively). In Preliminary
Studies, we have shown the H3K9me3 and heterochromatin can be regulated in MuSCs, with loss of both leading
to features seen in aging cells. Based on these data and related published findings, the primary hypothesis of
this proposal is that a primary mediator of HP and HBE transposition of aging phenotypes to young and old cells
is the regulation of the cellular epigenome, and with a specific focus on H3K9 methylation and heterochromatin
formation.
 To test this hypothesis, this proposal is divided into three Specific Aims. Aim 1: To assess the transcriptional
and epigenetic signature of MuSCs in response to HP. We will establish HP and control pairs, and we will assess
the MuSC molecular signatures compared to control mice in assays of the transcriptome and the epigenome.
Aim 2: To examine the epigenetic mechanisms underlying the transposition of aging phenotypes in MuSCs.
Using genetic and pharmacologic tools, we will modulate H3K9 methylation in young and old MuSCs exposed
to young or old serum in vitro. We will test for the effect of changes in H3K9 methylation on the phenotypic
changes of MuSCs previously described in response to heterochronic serum exposure. Aim 3: To test in vivo
for the essential roles of H3K9 methyltransferase and demethylase activities in mediating the effects of HP on
MuSCs. We will use genetic and pharmacologic tools to modulate H3K9 methylation in MuSCs in vivo. We will
assess epigenetic and heterochromatin status, as well as the functional changes in MuSCs in response to HP.
Together, these studies will elucidate molecular mechanisms of epigenetic programming of age in response to
HP and HBE.

## Key facts

- **NIH application ID:** 10195469
- **Project number:** 1R01AG071783-01
- **Recipient organization:** PALO ALTO VETERANS INSTIT FOR RESEARCH
- **Principal Investigator:** THOMAS A. RANDO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $426,000
- **Award type:** 1
- **Project period:** 2021-05-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10195469

## Citation

> US National Institutes of Health, RePORTER application 10195469, Epigenetic Reprogramming of Cellular Age (1R01AG071783-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10195469. Licensed CC0.

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