Inhibition of the metalloprotease ADAM19 as a novel senomorphic strategy to ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP)

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