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.

减缓与衰老相关的分子损伤积累或其预防代表了对抗衰老相关疾病和死亡的有希望的治疗范式。虽然几种化合物可以延长模型生物的寿命，但它们的作用机制通常是未知的，从而降低了它们的治疗潜力。使用系统方法，我们在这里描述了 GMP 途径对酵母寿命的影响，并阐明了 GMP 合成抑制作为寿命延长机制。我们进一步发现蛋白酶体激活部分通过 GMP 途径延长寿命。GMP 合成抑制发挥其寿命延长作用，独立于调节寿命的规范营养感应途径。以年龄依赖性方式将纵向老化的酵母细胞暴露于 GMP 途径抑制中，我们证明了通过减缓而不是逆转细胞的衰老过程来促进寿命延长。使用具有较低 GMP 到 GDP 转换活性的 GUK1 突变体，我们观察到寿命延长，表明 GDP 水平降低本身也可以延长酵母寿命。这些发现阐明了核苷酸代谢在衰老过程中的参与。临床批准的 GMP 途径抑制剂的存在激发了一类新的治疗衰老相关疾病的潜力。这些发现阐明了核苷酸代谢在衰老过程中的参与。临床批准的 GMP 途径抑制剂的存在激发了一类新的治疗衰老相关疾病的潜力。这些发现阐明了核苷酸代谢在衰老过程中的参与。临床批准的 GMP 途径抑制剂的存在激发了一类新的治疗衰老相关疾病的潜力。