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.