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Characterization of the impact of GMP/GDP synthesis inhibition on replicative lifespan extension in yeast

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Abstract

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.

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Acknowledgements

We thank Dr. Bertrand Daignan-Fornier for sending us the yeast strain carrying the guk1-1 allele of the GUK1 gene. We also thank Dr. Shirin Bahmanyar, Dr. Marc Hammarlund, Dr. Gerald Shadel, Dr. Patrick Sung, Guste Urbonaite, Dr. Ruijie Song, Dr. David Moreno Fortuno, and Acar Lab members for comments and feedback on different stages of this work. EAS acknowledges support through an NSF Graduate Research Fellowship and Gruber Science Fellowship. MA acknowledges funding from the Ellison Medical Foundation (AG-NS-1015-13) and US National Institutes of Health (1DP2AG050461-01 and 1R01GM127870-01).

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Author notes

  1. Ping Liu and Ethan A. Sarnoski contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Cellular and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT, 06511, USA

    Ping Liu, Ethan A. Sarnoski, Tolga T. Olmez, Thomas Z. Young & Murat Acar

  2. Systems Biology Institute, Yale University, 850 West Campus Drive, West Haven, CT, 06516, USA

    Ping Liu, Ethan A. Sarnoski, Tolga T. Olmez, Thomas Z. Young & Murat Acar

  3. Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, 300 George Street, Suite 501, New Haven, CT, 06511, USA

    Murat Acar

  4. Department of Physics, Yale University, 217 Prospect Street, New Haven, CT, 06511, USA

    Murat Acar

Authors
  1. Ping Liu
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  2. Ethan A. Sarnoski
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  3. Tolga T. Olmez
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  4. Thomas Z. Young
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  5. Murat Acar
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Contributions

PL, EAS, and MA contributed to project planning, and design and preparation of the manuscript. EAS and PL contributed to strain construction, data collection, data analysis, and preparation of the figures. TTO contributed to strain construction, data collection, and data analysis. TZY contributed to data collection. PL, EAS, TTO, TZY, and MA interpreted the data and results, and read and approved the manuscript.

Corresponding author

Correspondence to Murat Acar.

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Conflict of interests

The authors declare competing financial interests: EAS and MA have filed a PCT International patent application.

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Communicated by M. Kupiec.

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Liu, P., Sarnoski, E.A., Olmez, T.T. et al. Characterization of the impact of GMP/GDP synthesis inhibition on replicative lifespan extension in yeast. Curr Genet 66, 813–822 (2020). https://doi.org/10.1007/s00294-020-01068-w

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  • DOI: https://doi.org/10.1007/s00294-020-01068-w

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