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.

Public Health Relevance

The increasing health burden of the world's aging population underscores the need to understand the biological mechanisms of aging and develop therapies to prolong our healthspan. There is emerging evidence that aging is due, in part, to a progressive disruption in how our DNA is packaged within the nucleus as a result of having to repair broken DNA. To test this hypothesis, we have generated a mouse called ?ICE? (for inducible changes in epigenetics) that allows us to disrupt DNA packaging and study its effects on cell senescence and aging, providing clues to why we age and a tool to discover interventions that may extend healthspan in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG019719-11A1
Application #
9383896
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2001-09-30
Project End
2022-05-31
Budget Start
2017-07-01
Budget End
2018-05-31
Support Year
11
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Pathology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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Sinclair, David A; Guarente, Leonard (2014) Small-molecule allosteric activators of sirtuins. Annu Rev Pharmacol Toxicol 54:363-80

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