Cellular senescence is a hallmark of the aging process and contributes to chronic disease vulnerability. Although senescence acts acutely as a tumor suppressor mechanism, chronically it also contributes to inflammation in aged tissue through the senescence-associated secretory phenotype (SASP). Hence, removal of senescent cells in vivo improves healthspan and lifespan, although pharmacological ?senolytic? approaches tend to have toxic side effects, likely limiting the utility of senolytics as tools to promote healthy aging. As proof-of-concept for an alternative approach, suppression of SASP in vivo reduces chronic liver inflammation and delays onset of hepatocellular carcinoma. Recently, we have shown that SASP is dependent on expulsion of cytosolic chromatin fragments (CCF) from the nucleus into the cytoplasm of senescent cells. We have recently linked mitochondrial dysfunction to CCF production through a retrograde mitonuclear signaling pathway. This pathway is blocked by histone deacetylase inhibitors through an unknown mechanism. Unexpectedly, we recently discovered the histone deacetylase HDAC7 localizes in the nucleus of senescent cells, is required for CCF formation, and is sensitive to mitochondrial status. We hypothesize that HDAC7 is a novel component of mitochondria-nucleus retrograde signaling in senescent cells. This proposal has two Aims, to: 1) Determine the mitonuclear signaling role of HDAC7, 2) Determine the nuclear role of HDAC7 in CCF formation. Elucidation of the mechanism of this signaling pathway is of interest to all biologists but can also identify therapeutic targets for reduction of SASP. This approach can uncover alternatives to senolytic drugs for treatment of age-associated disease and promote healthy aging.
Senescent cells accumulate with age and contribute to many age-associated diseases by promoting inflammation. This proposal investigates causes of senescence-associated inflammation at the cellular and molecular level, which can provide new therapeutic targets for treatment of age-associated diseases and promote healthy aging.
