Calorie Restriction Suppresses Premature Ageing in Pro-Apoptotic Yeast Mutants Through an Autophagy-Independent Mechanism

The budding yeast Saccharomyces cerevisiae has long served as a valuable model for in- vestigating the molecular mechanisms underlying aging. Calorie restriction (CR) is a well-established intervention that extends lifespan across species, yet the underlying molec- ular mechanisms remain incompletely understood. In this study, we examined the effects of CR on the chronological lifespan, oxidative stress response, and autophagic activity of the Saccharomyces cerevisiae mutant Sclsm4∆1, which exhibits premature aging and elevated reac- tive oxygen species (ROS) levels due to defects in mRNA decapping and processing-bodies (PB) dynamics. We found that both moderate (0.1% glucose) and extreme (water incubation) CR significantly extended the lifespan of Sclsm4∆1 mutants and markedly reduced intra- cellular ROS accumulation without activating autophagy. These findings indicate that the beneficial effects of CR stem from improved redox homeostasis and metabolic adaptation, rather than from canonical autophagic pathways. Similar protective effects were observed in a chromosomal lsm4∆1 mutant generated via CRISPR–Cas9, confirming that CR rescues aging-related phenotypes in different genetic backgrounds. These insights reinforce the roles of nutrient signaling, RNA metabolism, and redox balance in lifespan regulation, offering new perspectives on the conserved anti-aging effects of calorie restriction.