Negative effect of gst-35 on the health span of Caenorhabditis elegans through lysosomal dysfunction via the pmk-1 and skr genes

As global life expectancy continues to increase, shifting our focus from solely extending lifespans to actively pursuing healthy ageing is crucial. GSTA1-3 members of the alpha class of glutathione S-transferase are involved in diverse biological processes, including metabolism and immune regulation, indicating their influence on human health and lifespan. We used Caenorhabditis elegans as a model organism to examine the impact of gst-35, an orthologous gene of mammalian GSTA1, GSTA2, and GSTA3, on healthy ageing. Our findings indicated that gst-35 overexpression had deleterious effects on various physiological aspects of nematodes. The overexpression specifically caused a significant reduction in nematode lifespan, inhibited nematode development and growth, and substantially diminished reproduction, physical fitness, and stress resistance. Conversely, gst-35 knockout in nematodes showed a partial improvement in physical fitness and stress resistance. Comprehensive RNA-sequencing transcriptome analysis revealed that gst-35 overexpression perturbed metabolic homeostasis. Additionally, gst-35 overexpression induceds lysosomal dysfunction via pmk-1 and skr, affecting the process of healthy ageing. These findings unravel the intricate role of gst-35 in the ageing process, contributing to the expanding knowledge in the field of healthy ageing research. Overall design: To investigate the specific mechanism by which gst-35 affects the health cycle of nematodes, we used N2, PHX6971 (knockout), and PHX7528 (overexpression) nematode strains to detect changes in gene transcription levels on the fifth day of adult nematodes.