Research Paper Volume 13, Issue 6 pp 7846—7871
Enhancing lifespan of budding yeast by pharmacological lowering of amino acid pools
- 1 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37240, USA
- 2 Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
- 3 Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
- 4 Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, Sichuan University, Chengdu 610000, Sichuan, P. R. China
- 5 Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA
Received: October 5, 2020 Accepted: January 21, 2021 Published: March 21, 2021https://doi.org/10.18632/aging.202849
How to Cite
Copyright: © 2021 Hepowit et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The increasing prevalence of age-related diseases and resulting healthcare insecurity and emotional burden require novel treatment approaches. Several promising strategies seek to limit nutrients and promote healthy aging. Unfortunately, the human desire to consume food means this strategy is not practical for most people but pharmacological approaches might be a viable alternative. We previously showed that myriocin, which impairs sphingolipid synthesis, increases lifespan in Saccharomyces cerevisiae by modulating signaling pathways including the target of rapamycin complex 1 (TORC1). Since TORC1 senses cellular amino acids, we analyzed amino acid pools and identified 17 that are lowered by myriocin treatment. Studying the methionine transporter, Mup1, we found that newly synthesized Mup1 traffics to the plasma membrane and is stable for several hours but is inactive in drug-treated cells. Activity can be restored by adding phytosphingosine to culture medium thereby bypassing drug inhibition, thus confirming a sphingolipid requirement for Mup1 activity. Importantly, genetic analysis of myriocin-induced longevity revealed a requirement for the Gtr1/2 (mammalian Rags) and Vps34-Pib2 amino acid sensing pathways upstream of TORC1, consistent with a mechanism of action involving decreased amino acid availability. These studies demonstrate the feasibility of pharmacologically inducing a state resembling amino acid restriction to promote healthy aging.