Curcumin Inhibits TORC1 and Prolongs the Lifespan of Cells with Mitochondrial Dysfunction.

Aging is an inevitable biological process that contributes to the onset of age-related diseases, often as a result of mitochondrial dysfunction. Understanding the mechanisms behind aging is crucial for developing therapeutic interventions. This study investigates the effects of curcumin on postmitotic cellular lifespan (PoMiCL) during chronological aging in yeast, a widely used model for human postmitotic cellular aging. Our findings reveal that curcumin significantly prolongs the PoMiCL of wildtype yeast cells, with the most pronounced effects observed at lower concentrations, indicating a hormetic response. Importantly, curcumin also extends the lifespan of postmitotic cells with mitochondrial deficiencies, although the hormetic effect is absent in these defective cells. Mechanistically, curcumin inhibits TORC1 activity, enhances ATP levels, and induces oxidative stress. These results suggest that curcumin has the potential to modulate aging and offer therapeutic insights into age-related diseases, highlighting the importance of context in its effects.

Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanisms.

Uncovering the regulators of cellular aging will unravel the complexity of aging biology and identify potential therapeutic interventions to delay the onset and progress of chronic, aging-related diseases. In this work, we systematically compared genesets involved in regulating the lifespan of Saccharomyces cerevisiae (a powerful model organism to study the cellular aging of humans) and those with expression changes under rapamycin treatment. Among the functionally uncharacterized genes in the overlap set, YBR238C stood out as the only one downregulated by rapamycin and with an increased chronological and replicative lifespan upon deletion. We show that YBR238C and its paralog RMD9 oppositely affect mitochondria and aging. YBR238C deletion increases the cellular lifespan by enhancing mitochondrial function. Its overexpression accelerates cellular aging via mitochondrial dysfunction. We find that the phenotypic effect of YBR238C is largely explained by HAP4- and RMD9-dependent mechanisms. Furthermore, we find that genetic- or chemical-based induction of mitochondrial dysfunction increases TORC1 (Target of Rapamycin Complex 1) activity that, subsequently, accelerates cellular aging. Notably, TORC1 inhibition by rapamycin (or deletion of YBR238C) improves the shortened lifespan under these mitochondrial dysfunction conditions in yeast and human cells. The growth of mutant cells (a proxy of TORC1 activity) with enhanced mitochondrial function is sensitive to rapamycin whereas the growth of defective mitochondrial mutants is largely resistant to rapamycin compared to wild type. Our findings demonstrate a feedback loop between TORC1 and mitochondria (the TORC1-MItochondria-TORC1 (TOMITO) signaling process) that regulates cellular aging processes. Hereby, YBR238C is an effector of TORC1 modulating mitochondrial function.