Abstract
A critical hallmark of aging is cellular senescence, a state of growth arrest and inflammatory cytokine release in cells, caused by a variety of stresses. Recent work has convincingly linked the accumulation of senescent cells in aged tissues to a decline in health and a limit of lifespan, primarily through "inflammaging". Importantly, interventions that clear senescent cells have achieved marked improvements in healthspan and lifespan in mice. A growing list of studies show that environmental stimuli can affect aging and longevity through conserved pathways which, in turn, modulate chromatin states. This review consolidates key findings of chromatin state changes in senescence including histone modifications, histone variants, DNA methylation and changes in three-dimensional genome organization. This information will facilitate the identification of mechanisms and discovery of potential epigenetic targets for therapeutic interventions in aging and age-related disease.
Highlights
Aging is accompanied by the accumulation of senescent cells in tissues
Cellular senescence was first discovered in cultured fibroblast cells, where prolonged passaging and replicative exhaustion led to growth arrest due to critically short telomeres [1, 2]
Senescence was eventually observed in cells subjected to a variety of stressors including oncogene induction, oxidative stress, acute DNA damage or mitochondrial dysfunction [3, 4]
Summary
Aging is accompanied by the accumulation of senescent cells in tissues. Cellular senescence was first discovered in cultured fibroblast cells, where prolonged passaging and replicative exhaustion led to growth arrest due to critically short telomeres [1, 2]. These upstream signals maintain the active metabolic state of senescent cells while promoting marked changes in the gene expression program such as downregulation of cell cycle genes and upregulation of SASP genes [13, 14]. In addition to the microscopic studies that identified SAHFs, genomics analysis of a panel of histone modifications in growing and OIS cells, showed altered occupancy of active (H3K4me3 and H3K36me3) and repressive (H3K9me3, H3K9me2, and H3K27me3) histone marks with all except H3K9me3 being correlated with alterations in transcription.
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