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Aging and epigenetic drift: a vicious cycle
Jean-Pierre Issa
Jean-Pierre Issa
Published January 2, 2014
Citation Information: J Clin Invest. 2014;124(1):24-29. https://doi.org/10.1172/JCI69735.
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Review Series

Aging and epigenetic drift: a vicious cycle

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Abstract

The term epigenetics refers to stable patterns of gene expression that are seen during differentiation or X chromosome inactivation and are not dependent on dynamic changes in coding DNA. These gene expression states are encoded in the epigenome — a collection of marks on DNA or on histone tails that are established during embryogenesis. Genome-wide studies in aging cells and tissues have uncovered stochastic DNA methylation drift (gradual increases or decreases at specific loci) that reflects imperfect maintenance of epigenetic marks. Drift creates epigenetic mosaicism in aging stem cells that could potentially restrict their plasticity and worsen phenotypes such as stem cell exhaustion and focal proliferative defects that can lead to cancer.

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Jean-Pierre Issa

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Figure 2

A model of the effects of the aging epigenome on stem cell function.

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A model of the effects of the aging epigenome on stem cell function.
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Young stem cells have relatively uniform epigenomes. During aging, stem cells replicate and stochastic errors in DNA methylation maintenance introduce epigenetic mosaicism. Exposures and/or chronic inflammation accelerate this process by promoting stem cell replication (e.g., for tissue repair) or by working directly on the epigenome. Continued epigenetic mosaicism results in restricted differentiation in some stem cells, leading to stem cell exhaustion and a selective growth advantage in other stem cells, which then leads to clonal expansion and local hyperproliferation. The combination of stem cell exhaustion and clonal expansion contributes to phenotypes and diseases of aging. In turn, these proliferative and restricted differentiation phenotypes promote epigenetic drift, creating a vicious cycle that exponentially increases the rate of some diseases such as cancer.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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