Abstract
Cellular senescence is a tumor suppressive response that has become recognized as a major contributor of tissue aging. Senescent cells undergo a stable proliferative arrest that protects against neoplastic transformation, but acquire a secretory phenotype that has long-term deleterious effects. Studies are still unraveling the effector mechanisms that underlie these senescence responses with the goal to identify therapeutic interventions. Such effector mechanisms have been linked to the dramatic remodeling in the epigenetic and chromatin landscape that accompany cellular senescence. We discuss these senescence-associated epigenetic changes and their impact on the senescence phenotypes, notably the proliferative arrest and senescence associated secretory phenotype (SASP). We also explore possible epigenetic targets to suppress the deleterious effects of senescent cells that contribute towards aging.
Highlights
Cellular senescence is a tumor suppressive response that has become recognized as a major contributor of tissue aging
Inhibition of HMGB2 limits the senescence associated secretory phenotype (SASP) without affecting the senescence proliferative arrest. These results indicate that the deleterious, pro-tumorigenic, SASP can be uncoupled from the senescence-associated heterochromatic foci (SAHF), which is associated with the beneficial tumor suppressive proliferative arrest of the senescent cells [73]
Senescent cells undergo distinct epigenetic changes that serve several effector functions, which are summarized in Figure 1 and Table 1
Summary
Cellular senescence was originally identified as a cellular aging phenomenon, but is recognized as an intrinsic tumor suppressive mechanism that is accompanied by distinct phenotypic changes, such as epigenetic and chromatin remodeling of nuclear architecture. Studies showed that selectively eliminating senescent cells improved the healthspan and suppressed the pathologic features of progeriod and naturally-aged mice [15,28] The success of these studies led many to research pharmacological drugs that induce apoptosis of senescent cells, which has been termed senolytic compounds [16]. Senescent cells undergo nuclear phenotypic changes wherein the epigenetic and chromatin landscape undergo widespread alterations Such changes have been linked to the altered gene expression and effector mechanisms that play a role in the proliferative arrest and acquisition of the SASP during cellular senescence. We will review these possibilities and the impact of chromatin and epigenetic changes in regulating cellular senescence and susceptibility for aging
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