Boosting Cellular Longevity Through Intracellular ATP Modulation

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. SignificanceCellular energy homeostasis is a crucial factor in determining the health and longevity of organisms. While intracellular ATP levels are tightly regulated, the idea that cells can directly take in extracellular ATP to influence metabolism has not been thoroughly explored. In this study, we engineered yeast cells to import external ATP and demonstrated that this approach significantly alters mitochondrial function, metabolic flow, and aging processes. Our findings show that ATP uptake inhibits catabolic pathways and enhances mitochondrial maintenance, thereby extending cellular lifespan through a novel and non-traditional mechanism. This research reveals an unexpected degree of metabolic flexibility and introduces a synthetic biology-based method to reprogram energy metabolism and longevity. The principles established in this study provide a new framework for understanding the role of cellular bioenergetics in aging, highlighting how the modulation of ATP availability can impact metabolic states and lifespan regulation.