Life span extension by glucose restriction is abrogated by methionine supplementation: Cross-talk between glucose and methionine and implication of methionine as a key regulator of life span
Authors: Zhibing Chen
Rachel B Brem
Michael Polymenis
Silvia Rouskin
Mark A McCormick
Brian K Kennedy
Jonathan S Weissman
Ke Zou
Arjun Sasikumar
Jiashun Zheng
Changhui Deng
Hao Li
Kevin Dervishi
Matt Kaeberlein
Qi Ouyang
Journal: Science Advances (2020)
Discipline: Multidisciplinary
Keywords: Caloric restriction; life span extension; glucose restriction; yeast; replicative life span
Affiliations: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA., The State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing, China., Peking-Tsinghua Center for Life Sciences at Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China., Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California Institute for Quantitative Biomedical Research and Howard Hughes Medical Institute, San Francisco, CA 94158, USA., Harvard Medical School, Boston, MA 02115, USA., Department of Biochemistry and Molecular Biology, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, Albuquerque, NM 87131, USA., Buck Institute for Research on Aging, Novato, CA 94945, USA., Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, CA 94158, USA., Department of Pathology, University of Washington, Seattle, WA 98195, USA., Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA., Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Centre for Healthy Longevity, National University Health System, Singapore., Singapore Institute for Clinical Sciences, A*STAR, Singapore.

Abstract:  Caloric restriction (CR) is known to extend life span across species; however, the molecular mechanisms are not well understood. We investigate the mechanism by which glucose restriction (GR) extends yeast replicative life span, by combining ribosome profiling and RNA-seq with microfluidic-based single-cell analysis. We discovered a cross-talk between glucose sensing and the regulation of intracellular methionine: GR down-regulated the transcription and translation of methionine biosynthetic enzymes and transporters, leading to a decreased intracellular methionine concentration; external supplementation of methionine cancels the life span extension by GR. Furthermore, genetic perturbations that decrease methionine synthesis/uptake extend life span. These observations suggest that intracellular methionine mediates the life span effects of various nutrient and genetic perturbations, and that the glucose-methionine cross-talk is a general mechanism for coordinating the nutrient status and the translation/growth of a cell. Our work also implicates proteasome as a downstream effector of the life span extension by GR. 

Retracted: No

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