ORGANISING THE SENESCENCE ASSOCIATED SECRETORY PHENOTYPE AND ELUCIDATING HMGB1’S ROLE IN ITS FORMATION

Abstract

Senescent cells have detrimental effects on their tissue micro-environment and contribute to various diseases through the secretion of a the senescent-associated secretory phenotype (SASP). The composition of SASP varies based on cell types, senescence induction methods, and senescence types, complicating the understanding of its formation. Nevertheless, the SASP can be organized into a Core SASP, an NFkB- and P21-arm, a mitochondrion disfunction associated SASP (MIDAS) and P-21 associated secretory phenotype (PASP). The most common and consistently found SASP factors form a Core SASP. SASP has a distinct pro-inflammatory NFkB arm and a P21 regulated arm. MIDAS results from mitochondrial dysfunction during senescence, characterized by the conditional absence of an IL-1 cytokine arm and the presence of CCL27. PASP, activated through p21, is marked by the presence of CXCL14 and IL34. Post-translational modifications to high mobility group box 1 (HMGB1), particularly acetylation and oxidation, play a crucial role in regulating different SASP phenotypes. Acetylation is necessary for HMGB1 to interact with NF-kB and p53 leading secretion of the broad/core SASP. Oxidation induces PASP, and excessive acetylation leads to a pro-inflammatory MIDAS containing IL1. Focusing on Core SASP factors and differentiating between SASP phenotypes can expedite the identification of these phenotypes and uncover the underlying mechanisms, potentially aiding in the development of new therapeutic solutions for many diseases.