Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan

Clara Correia-Melo¹, Stephan Kamrad², Roland Tengölics³, Christoph B Messner⁴, Pauline Trebulle⁵, StJohn Townsend⁶, Sreejith Jayasree Varma⁷, Anja Freiwald⁸, Benjamin M Heineike⁹, Kate Campbell¹⁰, Lucía Herrera-Dominguez², Simran Kaur Aulakh⁵, Lukasz Szyrwiel⁶, Jason S L Yu², Aleksej Zelezniak¹¹, Vadim Demichev¹², Michael Mülleder¹³, Balázs Papp³, Mohammad Tauqeer Alam¹⁴, Markus Ralser¹⁵

Affiliations

¹ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK; Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany. Electronic address: claramelo85@gmail.com.
² The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
³ Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network, Szeged 6726, Hungary; HCEMM-BRC Metabolic Systems Biology Lab, Szeged 6726, Hungary.
⁴ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Precision Proteomics Center, Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland.
⁵ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
⁶ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
⁷ Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
⁸ Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany; Core Facility - High Throughput Mass Spectrometry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
⁹ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Quantitative Gene Expression Research Group, MRC London Institute of Medical Sciences (LMS), London W12 0HS, UK; Quantitative Gene Expression Research Group, Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London SW2 2AZ, UK.
¹⁰ Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
¹¹ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden; Randall Centre for Cell & Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK; Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius 10257, Lithuania.
¹² The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK; Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
¹³ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK; Core Facility - High Throughput Mass Spectrometry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
¹⁴ Department of Biology, College of Science, United Arab Emirates University, P.O.Box 15551, Al-Ain, United Arab Emirates.
¹⁵ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK; Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany; The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. Electronic address: markus.ralser@charite.de.

PMID: 36608659
DOI: 10.1016/j.cell.2022.12.007

Free article

Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan

Clara Correia-Melo et al. Cell. 2023.

Free article

. 2023 Jan 5;186(1):63-79.e21.

doi: 10.1016/j.cell.2022.12.007.

Authors

Affiliations

¹ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK; Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany. Electronic address: claramelo85@gmail.com.
² The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
³ Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network, Szeged 6726, Hungary; HCEMM-BRC Metabolic Systems Biology Lab, Szeged 6726, Hungary.
⁴ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Precision Proteomics Center, Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos, Switzerland.
⁵ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
⁶ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
⁷ Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
⁸ Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany; Core Facility - High Throughput Mass Spectrometry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
⁹ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Quantitative Gene Expression Research Group, MRC London Institute of Medical Sciences (LMS), London W12 0HS, UK; Quantitative Gene Expression Research Group, Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London SW2 2AZ, UK.
¹⁰ Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
¹¹ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biology and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden; Randall Centre for Cell & Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK; Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius 10257, Lithuania.
¹² The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK; Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
¹³ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK; Core Facility - High Throughput Mass Spectrometry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
¹⁴ Department of Biology, College of Science, United Arab Emirates University, P.O.Box 15551, Al-Ain, United Arab Emirates.
¹⁵ The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK; Department of Biochemistry, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany; The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. Electronic address: markus.ralser@charite.de.

PMID: 36608659
DOI: 10.1016/j.cell.2022.12.007

Abstract

Metabolism is deeply intertwined with aging. Effects of metabolic interventions on aging have been explained with intracellular metabolism, growth control, and signaling. Studying chronological aging in yeast, we reveal a so far overlooked metabolic property that influences aging via the exchange of metabolites. We observed that metabolites exported by young cells are re-imported by chronologically aging cells, resulting in cross-generational metabolic interactions. Then, we used self-establishing metabolically cooperating communities (SeMeCo) as a tool to increase metabolite exchange and observed significant lifespan extensions. The longevity of the SeMeCo was attributable to metabolic reconfigurations in methionine consumer cells. These obtained a more glycolytic metabolism and increased the export of protective metabolites that in turn extended the lifespan of cells that supplied them with methionine. Our results establish metabolite exchange interactions as a determinant of cellular aging and show that metabolically cooperating cells can shape the metabolic environment to extend their lifespan.

Keywords: chronological aging; eukaryotic longevity; metabolic microenvironment; metabolite exchange interactions.

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Conflict of interest statement

Declaration of interests K.C. is currently employed by AstraZeneca.

Comment in

Strength in diversity: Intra-cellular metabolite sharing enhances longevity.
Lamming DW, Anderson RM. Lamming DW, et al. Cell. 2023 Jan 5;186(1):8-9. doi: 10.1016/j.cell.2022.12.012. Cell. 2023. PMID: 36608660

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Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan

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Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan

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Abstract

Conflict of interest statement

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