TY - JOUR
T1 - Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan
AU - Correia-Melo, Clara
AU - Kamrad, Stephan
AU - Tengölics, Roland
AU - Messner, Christoph B.
AU - Trebulle, Pauline
AU - Townsend, St John
AU - Jayasree Varma, Sreejith
AU - Freiwald, Anja
AU - Heineike, Benjamin M.
AU - Campbell, Kate
AU - Herrera-Dominguez, Lucía
AU - Kaur Aulakh, Simran
AU - Szyrwiel, Lukasz
AU - Yu, Jason S.L.
AU - Zelezniak, Aleksej
AU - Demichev, Vadim
AU - Mülleder, Michael
AU - Papp, Balázs
AU - Alam, Mohammad Tauqeer
AU - Ralser, Markus
N1 - Funding Information:
We thank the Francis Crick Science and Technology Platforms (STP), specially Hefin Rhys, Sukhveer Purewal, and Ana Água-Doce from the Flow Cytometry STP; Paull Driscoll, Nathalie Legrave, and James Macrae from the Metabolomics STP; Teresa Higgins, Gareth Houghton-Brown, and Magdalena Sokalska from the Media STP for all the technical support and advice; and Hezi Tenemboim and our colleagues for critically reading the manuscript. This work was supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK (FC001134), the UK Medical Research Council (FC001134), and the Wellcome Trust (FC001134), and received specific funding from the European Research Council (ERC) under grant agreement ERC-SyG-2020 951475 (to M.R.), the Wellcome Trust (IA 200829/Z/16/Z to M.R.),), the Ministry of Education and Research (BMBF), as part of the National Research Node “Mass spectrometry in Systems Medicine (MSCoreSys)”, under grant agreements 031L0220 (to M.R.) and 161L0221 (to V.D.), and the European Commission (EC) as part of CoBioTech project Sycolim ID#33 (BMBF 161B0931) to MR supporting C.C.-M., S.K., M.M., C.B.M., P.T., S.J.T., S.J.V., A.F., B.M.H., L.H.-D., S.K.A., L.S., J.S.L.Y., V.D., and M.M. C.B.M. is also supported by the Precision Proteomics Center Davos that receives funding from the Swiss canton of Grisons . P.T. is also supported by funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no 101026830 . A.F. is also supported by the Life Science Stiftung (Charite 2019.01 ). M.T.A. is also supportedby the United Arab Emirates University , Al Ain, UAE (startup grant G00003688 ). R.T. is also supported by the National Research, Development and Innovation Office PD 128271 ; and B.P. is also supported by the National Research, Development and Innovation Office Élvonal Program KKP 129814 , the “Lendület” program of the Hungarian Academy of Sciences LP2009-013/2012 , and the European Union’s Horizon 2020 research and innovation program grant no. 739593 . A.Z. was also supported by the SciLifeLab funding and Marius Jason Jakulis (MJJ) foundation . For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
Funding Information:
We thank the Francis Crick Science and Technology Platforms (STP), specially Hefin Rhys, Sukhveer Purewal, and Ana Água-Doce from the Flow Cytometry STP; Paull Driscoll, Nathalie Legrave, and James Macrae from the Metabolomics STP; Teresa Higgins, Gareth Houghton-Brown, and Magdalena Sokalska from the Media STP for all the technical support and advice; and Hezi Tenemboim and our colleagues for critically reading the manuscript. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001134), the UK Medical Research Council (FC001134), and the Wellcome Trust (FC001134), and received specific funding from the European Research Council (ERC) under grant agreement ERC-SyG-2020 951475 (to M.R.), the Wellcome Trust (IA 200829/Z/16/Z to M.R.),), the Ministry of Education and Research (BMBF), as part of the National Research Node “Mass spectrometry in Systems Medicine (MSCoreSys)”, under grant agreements 031L0220 (to M.R.) and 161L0221 (to V.D.), and the European Commission (EC) as part of CoBioTech project Sycolim ID#33 (BMBF 161B0931) to MR supporting C.C.-M. S.K. M.M. C.B.M. P.T. S.J.T. S.J.V. A.F. B.M.H. L.H.-D. S.K.A. L.S. J.S.L.Y. V.D. and M.M. C.B.M. is also supported by the Precision Proteomics Center Davos that receives funding from the Swiss canton of Grisons. P.T. is also supported by funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no 101026830. A.F. is also supported by the Life Science Stiftung (Charite 2019.01). M.T.A. is also supportedby the United Arab Emirates University, Al Ain, UAE (startup grant G00003688). R.T. is also supported by the National Research, Development and Innovation Office PD 128271; and B.P. is also supported by the National Research, Development and Innovation Office Élvonal Program KKP 129814, the “Lendület” program of the Hungarian Academy of Sciences LP2009-013/2012, and the European Union's Horizon 2020 research and innovation program grant no. 739593. A.Z. was also supported by the SciLifeLab funding and Marius Jason Jakulis (MJJ) foundation. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Conceptualization, C.C.-M. and M.R.; methodology, C.C.-M. S.K. SJ.T. M.M. S.J.V. C.B.M, and V.D.; investigation, C.C.-M, S.K. R.T. C.B.M. M.M. S.J.V. A.F. K.C. L.H.-D. S.K.A. L.S. J.S.L.Y. and B.P.; formal analysis, C.C.-M. P.T. B.M.H. V.D. A.Z. S.J.T. and M.T.A.; writing – original draft, C.C.-M. and M.R.; writing – review & editing, C.C.-M. and M.R. with the support of all authors; funding acquisition, M.R.; supervision, C.C.-M. and M.R. K.C. is currently employed by AstraZeneca. We support inclusive, diverse, and equitable conduct of research.
Publisher Copyright:
© 2022 The Author(s)
PY - 2023/1/5
Y1 - 2023/1/5
N2 - 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.
AB - 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.
KW - chronological aging
KW - eukaryotic longevity
KW - metabolic microenvironment
KW - metabolite exchange interactions
UR - http://www.scopus.com/inward/record.url?scp=85145415828&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2022.12.007
DO - 10.1016/j.cell.2022.12.007
M3 - Article
AN - SCOPUS:85145415828
SN - 0092-8674
VL - 186
SP - 63-79.e21
JO - Cell
JF - Cell
IS - 1
ER -