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Epigenetic Alteration

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Hallmarks of Aging Miniseries No. 3 Epigenetic Alteration

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As cells are exposed to environmental factors, they are subject to changes in their genome through epigenetic mechanisms. Such changes accumulate over time and have been correlated with the decline observed in aging cells.

Epigenetic changes in aging include decreased methylation of H3K9 and H3K27, together with increased trimethylation of H4K20 and H3K4. In general, these changes are correlated with decreases in the amount of heterochromatin and consequent increases in chromosome fragility and transcriptional noise.

Why do these molecular events occur? One theory is that age-associated DNA damage results in changes in the transcription of certain long noncoding RNAs (lncRNAs), such as KCNQ1OT1, PINT, and ANRIL, which then, in turn, regulate histone modifying enzymes. Whether this mechanism is directly relevant to aging remains to be proven.

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Epigenetic modulators in young versus old cells. In young cells, lncRNAs like ANRIL mediate association of polycomb repressive complexes with chromatin. In old cells, trithorax (MLL) derepressive complexes are associated instead, resulting in increased transcription. (Image adapted from O’Sullivan RJ, Karlseder J. The great unravelling: chromatin as a modulator of the aging process. Trends Biochem Sci. 2012; 37(11):466-76.)

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