Slowing down aging-associated accumulation of molecular damage or its prevention represents a promising therapeutic paradigm to combat aging-related disease and death. While several chemical compounds extend lifespan in model organisms, their mechanism of action is often unknown, reducing their therapeutic potential. Using a systematic approach, here we characterize the impact of the GMP pathway on yeast lifespan and elucidate GMP synthesis inhibition as a lifespan extension mechanism. We further discover that proteasome activation extends lifespan in part through the GMP pathway. GMP synthesis inhibition exerts its lifespan extension effect independently of the canonical nutrient-sensing pathway regulating lifespan. Exposing longitudinally aging yeast cells to GMP pathway inhibition in an age-dependent manner, we demonstrate that the lifespan extension is facilitated by slowing, rather than reversing, the aging process in cells. Using a GUK1 mutant with lower GMP-to-GDP conversion activity, we observe lifespan extension, suggesting that reduced GDP level by itself can also extend yeast lifespan. These findings elucidate the involvement of nucleotide metabolism in the aging process. The existence of clinically-approved GMP pathway inhibitors elicits the potential of a new class of therapeutics for aging-related disorders.
Keywords: Aging; GDP; GMP; Mycophenolic acid; Proteasome; Replicative lifespan; Yeast.