Inhibition of the metalloprotease ADAM19 as a Novel Senomorphic Strategy to Ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP)

• DOI: 10.1101/2024.12.16.628718
• Publication Date: 2025-01-01T17:37:11Z
• Authors: Sudipta Bar; Tyler A.U Hilsabeck; Baline Pattavina; Jose Alberto Lope...; Nathan Basisty; Joanna Bons; Mark Watson; Birgit Schilling; Judith Campisi; Pankaj Kapahi; Amit Sharma
• Keywords: Senescence

Accumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a Drosophila model to investigate the effects radiation-induced on intestine. In this model, examined irradiation-responsive senescence in fly Through an unbiased genome-wide association study (GWAS) utilizing 156 strains from Genetic Reference Panel (DGRP), identified meltrin β (the drosophila orthologue mammalian ADAM19) as potential modulator senescence-associated secretory phenotype (SASP). Knockdown resulted reduced gut permeability, damage, and expression marker β-galactosidase (SA-β-gal) following irradiation. Additionally, inhibition ADAM19 mice using batimastat-94 permeability inflammation gut. Our findings extend human primary fibroblasts, where knockdown or pharmacological decreased specific SASP factors SA-β-gal. Furthermore, proteomics analysis factor senescent cells revealed significant decrease associated with cleavage site. These data suggest that could represent novel senomorphic strategy.