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

View ORCID ProfileClara Correia-Melo, View ORCID ProfileStephan Kamrad, View ORCID ProfileChristoph B. Messner, Roland Tengölics, View ORCID ProfileLucía Herrera-Dominguez, St John Townsend, Mohammad Tauqeer Alam, Anja Freiwald, Kate Campbell, View ORCID ProfileSimran Aulakh, Lukasz Szyrwiel, Jason S. L. Yu, View ORCID ProfileAleksej Zelezniak, View ORCID ProfileVadim Demichev, Michael Muelleder, Balázs Papp, View ORCID ProfileMarkus Ralser
doi: https://doi.org/10.1101/2022.03.07.483228
Clara Correia-Melo
1The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
2Department of Biochemistry, University of Cambridge, Cambridge, UK
3Department of Biochemistry, Charité University Medicine, Berlin, Germany
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  • ORCID record for Clara Correia-Melo
  • For correspondence: clara.correia-melo@charite.de markus.ralser@charite.de
Stephan Kamrad
1The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
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  • ORCID record for Stephan Kamrad
Christoph B. Messner
1The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
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Roland Tengölics
4Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network; Szeged, Hungary
5HCEMM-BRC Metabolic Systems Biology Lab; Szeged, Hungary
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Lucía Herrera-Dominguez
1The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
3Department of Biochemistry, Charité University Medicine, Berlin, Germany
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  • ORCID record for Lucía Herrera-Dominguez
St John Townsend
1The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
3Department of Biochemistry, Charité University Medicine, Berlin, Germany
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Mohammad Tauqeer Alam
6Department of Biology, College of Science, United Arab Emirates University, Al-Ain, UAE
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Anja Freiwald
7Core Facility - High Throughput Mass Spectrometry, Charité University Medicine, Berlin, Germany
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Kate Campbell
2Department of Biochemistry, University of Cambridge, Cambridge, UK
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Simran Aulakh
1The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
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  • ORCID record for Simran Aulakh
Lukasz Szyrwiel
1The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
3Department of Biochemistry, Charité University Medicine, Berlin, Germany
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Jason S. L. Yu
1The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
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Aleksej Zelezniak
1The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
8Department of Biology and Biological Engineering, Chalmers University of Technology, Kemivägen 10, SE-412 96, Gothenburg, Sweden
9Science for Life Laboratory, Tomtebodavägen 23a, SE-171 65, Stockholm, Sweden
10Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
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Vadim Demichev
1The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
2Department of Biochemistry, University of Cambridge, Cambridge, UK
3Department of Biochemistry, Charité University Medicine, Berlin, Germany
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Michael Muelleder
7Core Facility - High Throughput Mass Spectrometry, Charité University Medicine, Berlin, Germany
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Balázs Papp
4Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network; Szeged, Hungary
5HCEMM-BRC Metabolic Systems Biology Lab; Szeged, Hungary
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Markus Ralser
1The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
3Department of Biochemistry, Charité University Medicine, Berlin, Germany
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  • ORCID record for Markus Ralser
  • For correspondence: clara.correia-melo@charite.de markus.ralser@charite.de
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Abstract

Metabolism is fundamentally intertwined with the ageing process. We here report that a key determinant of cellular lifespan is not only nutrient supply and intracellular metabolism, but also metabolite exchange interactions that occur between cells. Studying chronological ageing in yeast, we observed that metabolites exported by young, exponentially growing, cells are re- imported during the stationary phase when cells age chronologically, indicating the existence of cross-generational metabolic interactions. We then used self-establishing metabolically cooperating communities (SeMeCos) to boost cell-cell metabolic interactions and observed a significant lifespan extension. A search for the underlying mechanisms, coupling SeMeCos, metabolic profiling, proteomics and genome-scale metabolic modelling, attributed a specific role to methionine consumer cells. These cells were enriched over time, adopted glycolytic metabolism and increased export of protective metabolites. Glycerol, in particular, accumulated in the communal metabolic environment and extended the lifespan of all cells in the community in a paracrine fashion. Our results hence establish metabolite exchange interactions as a determinant of the ageing process and show that metabolically cooperating cells shape their metabolic environment to achieve lifespan extension.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted March 07, 2022.
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Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan
Clara Correia-Melo, Stephan Kamrad, Christoph B. Messner, Roland Tengölics, Lucía Herrera-Dominguez, St John Townsend, Mohammad Tauqeer Alam, Anja Freiwald, Kate Campbell, Simran Aulakh, Lukasz Szyrwiel, Jason S. L. Yu, Aleksej Zelezniak, Vadim Demichev, Michael Muelleder, Balázs Papp, Markus Ralser
bioRxiv 2022.03.07.483228; doi: https://doi.org/10.1101/2022.03.07.483228
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Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan
Clara Correia-Melo, Stephan Kamrad, Christoph B. Messner, Roland Tengölics, Lucía Herrera-Dominguez, St John Townsend, Mohammad Tauqeer Alam, Anja Freiwald, Kate Campbell, Simran Aulakh, Lukasz Szyrwiel, Jason S. L. Yu, Aleksej Zelezniak, Vadim Demichev, Michael Muelleder, Balázs Papp, Markus Ralser
bioRxiv 2022.03.07.483228; doi: https://doi.org/10.1101/2022.03.07.483228

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