LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity

Abstract Cellular senescence is associated with pleiotropic essential physiopathological processes including aging and age-related diseases. The persistent DNA damage response (DDR) is a major stress leading to senescence, but the underlying molecular link remains elusive. Here, we identified La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as a novel aging antagonist. DDR-mediated Ataxia Telangiectasia Mutated (ATM) activation triggered the extracellular shuttling and down regulation of LARP7, which dampened SIRT1 deacetylase activity, enhanced p53 and NF-κB transcriptional activity by augmenting their acetylation, and thereby accelerated cellular senescence. Deletion of LARP7 led to senescent cell accumulation and premature aging in rodent model. Furthermore, we show that this ATM-LARP7-SIRT1-p53/NF-κB senescence axis was active in vascular aging and atherogenesis, and preventing its activation substantially alleviated aging and atherogenesis. Together, this study identifies LARP7 as a gatekeeper for senescence, and the altered ATM-LARP7-SIRT1-p53/NF-κB pathway plays an important role in DDR-mediated cellular senescence and aging-related atherosclerosis.