Engineering ATP Import in Yeast Uncovers a Synthetic Route to Extend Cellular Lifespan

Aging results from the gradual accumulation of molecular damage as a result of cellular processes and is characterized by impaired functions, most notably an age-related decline in ATP production. However, the causal relationship between cellular ATP homeostasis and aging has not been established. In this study, we used a novel approach by harnessing a nucleotide transporter from a eukaryotic intracellular parasite to facilitate the direct import of extracellular ATP into budding yeast cells, enabling us to effectively manipulate their intracellular ATP levels. We found that depletion of ATP significantly reduces lifespan, while the supplementation of ATP in the growth medium fully restores it thereby extending lifespan. Moreover, gene expression analysis revealed that elevated ATP levels inhibit catabolic processes, indicating a suppression of glucose metabolism. Overall, our study revealed the direct impact of cellular ATP homeostasis on lifespan regulation that has never been directly tested before. This work offers new insights into the bioenergetic control of aging and positions energy metabolism as a promising target for longevity interventions. Overall design: Yeast strains expressing the Encephalitozoon cuniculi nucleotide transporter NTT1 or empty-vector controls were grown in complete synthetic medium to mid-log phase. Cells were either left untreated or treated with 5 mM extracellular ATP for 1 hour, and total RNA was extracted for RNA-seq analysis. Three independent biological replicates were collected per strain and treatment condition.