While much of the focus on cellular senescence in aging remains to find ways to selectively destroy these problem cells, there are also efforts to instead change their behavior. The reason why a growing burden of senescent cells in aged tissues is harmful, even when these cells make up only a tiny fraction of the overall cell population, is that they energetically secrete pro-inflammatory factors. This activity is disruptive to tissue structure and function when sustained over time. If senescent cells could be blocked from producing inflammatory secretions, their harms would be much reduced.
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.
Link: https://doi.org/10.18632/aging.206224
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