Document Type

Article

Publication Date

3-20-2025

Publication Title

Aging (Albany NY)

Keywords

JGM, Animals, Humans, Mice, Cellular Senescence, ADAM Proteins, Senescence-Associated Secretory Phenotype, Drosophila Proteins, Permeability, DNA Damage, Genome-Wide Association Study, Aging

JAX Source

Aging (Albany NY).

Volume

17

Issue

3

First Page

757

Last Page

777

ISSN

1945-4589

PMID

40117561

DOI

https://doi.org/10.18632/aging.206224

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.

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