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

## TL;DR

This study explores how inhibiting ADAM19, a metalloprotease, can reduce gut damage and aging markers by affecting the secretory phenotype of senescent cells.

## Contribution

The study identifies ADAM19 inhibition as a novel senomorphic strategy to reduce gut permeability and senescence markers.

## Key findings

- Knockdown of meltrin in Drosophila reduced gut permeability and DNA damage after irradiation.
- ADAM19 inhibition in mice decreased gut permeability and inflammation.
- ADAM19 inhibition in human fibroblasts reduced SASP factors and senescence markers.

## Abstract

Accumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a Drosophila 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 meltrin (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP). Knockdown of meltrin 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 ADAM19 in mice using batimastat-94 reduced gut permeability and inflammation in the gut. Our findings extend to human primary fibroblasts, where ADAM19 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 ADAM19 cleavage site. These data suggest that ADAM19 inhibition could represent a novel senomorphic strategy.