Aging, the time-dependent accumulation of molecular damage, is the primary limiting factor of human lifespan. Slowing down damage accumulation or its prevention therefore 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 show that inhibition of GMP synthesis is a novel lifespan extension mechanism in yeast. We further discover that proteasome activation extends lifespan in part through GMP insufficiency. GMP synthesis inhibition exerts its lifespan extension effect independently of the canonical nutrient-sensing and sirtuin pathways regulating lifespan. Exposing longitudinally aging yeast cells to GMP synthesis inhibition in an age-dependent manner, we demonstrate that the lifespan extension by GMP insufficiency is facilitated by slowing, rather than reversing, the aging process in cells. While GMP and its downstream metabolites are involved in many cellular processes in cells, our results rule out the combined effect of global transcription and translation on cellular lifespan. These findings elucidate the involvement of nucleotide metabolism in the aging process. The existence of clinically-approved GMP synthesis inhibitors elicits the potential of a new class of therapeutics for aging-related disorders.
Aging is the primary risk factor for human morbidity and mortality throughout the developed world1–3. Prevention or elimination of the molecular damage that causes aging therefore represents a promising therapeutic paradigm to combat the plethora of diseases that manifest late in life. Target-based drug discovery has advanced several therapeutic candidates to human trials, including metformin4 and mTOR inhibitors5. While these treatments hold promise, additional interventions are necessary to fully minimize the health effects of advanced age.
In recent years, phenotype-based discovery approaches6,7 have identified many compounds capable of extending lifespan in model organisms1. These compounds are a starting point for therapeutic development, but the mechanism of action for many of them remains unknown, reducing their therapeutic potential. One such compound is mycophenolic acid (MPA), an FDA-approved immunosuppressant that extends the replicative lifespan (RLS) of the yeast Saccharomyces cerevisiae6.
Here, we seek to understand the mechanism behind MPA’s ability to extend replicative lifespan. We find that guanine reverses MPA’s pro-longevity effect, indicating that reduction in cellular GMP pools is responsible for the lifespan extension. We then investigate if MPA’s RLS extension mechanism overlaps with previously-described aging pathways, elucidating that it partially overlaps with the effect exerted by activated proteasome. We characterize a set of cellular processes and phenotypes in terms of how they are affected by MPA and whether or not they can facilitate the observed RLS extension.
R E S U L T S A T S O U R C E: bioRxiv
