# Role of epigenetic decay in cell senescence and aging

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2022 · $457,821

## Abstract

PROJECT SUMMARY / ABSTRACT
There is a growing body of evidence that epigenetic changes may not simply be a symptom of aging but an
underlying cause (Brunet & Berger, 2014). In budding yeast, the reorganization of chromatin and resulting
alterations in gene expression are known contributors to aging. In mammals, similar processes appear to be
associated with aging but whether they truly cause aging is not yet known.
In the last round of this grant, we provided evidence that chromatin factors such as Sir2 in yeast and SIRT1 in
mammals, are key players in a process that suppresses epigenetic change and aging in eukaryotes. To
provide a direct test of whether epigenetic change can actually cause aging in a mammal, we have generated
a new mouse model called “ICE”, for inducible changes in the epigenome. This mouse carries a tamoxifen-
inducible endonuclease that induces non-mutagenic, site-specific DNA breaks (DSBs) at a few sites in the
mammalian genome, thereby stimulating epigenetic change. We can induce change in any tissue at any time
in a mouse's lifespan, then switch the system off, and monitor the effects on aging. Results to date are
consistent with alterations to the epigenome being a fundamental cause of aging in mammals.
This study is important, because it may explain long-standing questions about aging, such as why DNA repair
defects and nuclear Lamin mutations both result in diseases that resemble premature aging. It will also
address whether aging is uni-directional or reversible, and provide tools to screen for potent longevity
interventions and to “humanize” mouse models of disease.
In Aim 1, we utilize fibroblasts from ICE mice to elucidate the mechanisms that drive epigenetic changes and
the effects they have on the resilience of cells to DNA damage and senescence. Advanced genomic
technologies will allow us to map protein-binding, histone modifications, transcription profiles, DNA methylation
patterns, and the evolution of nuclear architectures in 3D during aging. In Aim 2, we test cause and effect in a
living mammal by inducing epigenetic change in young mice and observing the effects on nuclear organization
and the aging process. In Aim 3, we test if epigenetic decay can be prevented or reversed using the latest
genetic or pharmacological approaches. Together, this work will provide new information about whether
alterations in chromatin structure promote aging in eukaryotes and explore ways that this knowledge can be
exploited to improve the human condition.

## Key facts

- **NIH application ID:** 10343658
- **Project number:** 5R01AG019719-15
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** DAVID A. SINCLAIR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $457,821
- **Award type:** 5
- **Project period:** 2001-09-30 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10343658

## Citation

> US National Institutes of Health, RePORTER application 10343658, Role of epigenetic decay in cell senescence and aging (5R01AG019719-15). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10343658. Licensed CC0.

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