Negative Effect of Gst-35 on the Health Span of Caenorhabditis elegans Through Lysosomal Dysfunction via the Pmk-1 and Skr Genes

Abstract

As global life expectancy increases, the focus has shifted from merely extending lifespan to promoting healthy aging. GSTA1, GSTA2, and GSTA3 (GSTA1-3), members of the alpha class of glutathione S-transferases, are involved in diverse biological processes, including metabolism and immune regulation, highlighting their potential influence on human health span and lifespan. In this study, we employed Caenorhabditis elegans as a model organism to investigate the role of gst-35, an ortholog of mammalian GSTA1-3, in healthy aging. Our results demonstrated that gst-35 overexpression has detrimental effects on multiple physiological functions in nematodes. Specifically, gst-35 overexpression significantly reduced lifespan, impaired development and growth, and substantially diminished reproductive capacity, physical fitness, and stress resistance. In contrast, gst-35 knockout partially enhanced physical fitness and stress resistance. Comprehensive RNA-sequencing transcriptome analysis revealed that gst-35 overexpression disrupted metabolic homeostasis and induced lysosomal dysfunction. These effects were mediated through the activation of the pmk-1 signaling pathway and suppression of skr genes, which collectively impaired healthy aging processes. These findings illuminate the complex role of gst-35 in aging and provide valuable insights into the molecular mechanisms underlying healthy aging, offering potential targets for interventions aimed at promoting health span.