Intragenic repeat expansion in the cell wall protein gene HPF1 controls yeast chronological aging

Aging varies among individuals due to both genetics and environment but the underlying molecular mechanisms remain largely unknown. Using a highly recombined population, we found 30 distinct Quantitative Trait Loci (QTLs) that control chronological life span (CLS) in calorie rich and calorie restricted environments, and under rapamycin exposure. Calorie restriction and rapamycin extended life span in virtually all genotypes, but through different genetic variants. We tracked the two major QTLs to the cell wall glycoprotein genes and We found that massive expansion of intragenic tandem repeats within the N-terminal domain of was sufficient to cause pronounced life span shortening. Life span impairment by was buffered by rapamycin but not by calorie restriction. The repeat expansion shifted yeast cells from a sedentary to a buoyant state, thereby increasing their exposure to surrounding oxygen. The higher oxygenation altered methionine, lipid, and purine metabolism, and inhibited quiescence, which explains the life span shortening. We conclude that fast evolving intragenic repeat expansions can fundamentally change the relationship between cells and their environment with profound effects on cellular lifestyle and longevity.