Metabolic modelling reveals the aging-associated decline of host–microbiome metabolic interactions in mice
Aging is accompanied by considerable changes in the gut microbiome, yet the molecular mechanisms driving aging and the role of the microbiome remain unclear. Here we combined metagenomics, transcriptomics and metabolomics from aging mice with metabolic modelling to characterize host-microbiome interactions during aging. Reconstructing integrated metabolic models of host and 181 mouse gut microorganisms, we show a complex dependency of host metabolism on known and previously undescribed microbial interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome accompanied by reduced beneficial interactions between bacterial species. These changes coincided with increased systemic inflammation and the downregulation of essential host pathways, particularly in nucleotide metabolism, predicted to rely on the microbiota and critical for preserving intestinal barrier function, cellular replication and homeostasis. Our results elucidate microbiome-host interactions that potentially influence host aging processes. These pathways could serve as future targets for the development of microbiome-based anti-aging therapies.
Authors
- Jan Taubenheim (ORCID: https://orcid.org/0000-0001-7283-1768)
- S. Schmidt (ORCID: https://orcid.org/0000-0002-3157-2605)
- John F. Baines (ORCID: https://orcid.org/0000-0002-8132-4909)
- Thomas Dost (ORCID: https://orcid.org/0000-0001-9904-4975)
- Marco Groth (ORCID: https://orcid.org/0000-0002-9199-8990)
- Otto W. Witte
- Madlen Haase
- Lena Best (ORCID: https://orcid.org/0000-0003-2772-153X)
- Philippe Schmitt‐Kopplin (ORCID: https://orcid.org/0000-0003-0824-2664)
- Andy Mercado-Gamarra (ORCID: https://orcid.org/0009-0006-1243-6348)
- Γεώργιος Μαρίνος (ORCID: https://orcid.org/0000-0002-6443-7696)
- Silvio Waschina (ORCID: https://orcid.org/0000-0002-6290-3593)
- Felix Sommer (ORCID: https://orcid.org/0000-0002-6545-3487)
- Daniela Esser
- Philip Rosenstiel (ORCID: https://orcid.org/0000-0002-9692-8828)
- Johannes Zimmermann (ORCID: https://orcid.org/0000-0002-5041-1954)
- Sören Franzenburg (ORCID: https://orcid.org/0000-0001-6374-4910)
- Christiane Frahm (ORCID: https://orcid.org/0000-0003-2234-7390)
- A. Samer Kadibalban (ORCID: https://orcid.org/0009-0001-9726-543X)
- Alesia Walker (ORCID: https://orcid.org/0000-0002-1477-2023)
- Christoph Kaleta (ORCID: https://orcid.org/0000-0001-8004-9514)
- Rowena Simon (ORCID: https://orcid.org/0000-0002-1588-6268)
- Stefano Flor (ORCID: https://orcid.org/0009-0008-8930-3177)
- Robert Häsler (ORCID: https://orcid.org/0000-0003-4174-8229)
- Sven Künzel
Institutions
- Helmholtz Zentrum München (DE)
- Hochschule für Angewandte Wissenschaften Kiel (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- University Hospital Schleswig-Holstein (DE)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Jena University Hospital (DE)
- Leibniz-Institute for Food Systems Biology at the Technical University of Munich (DE)
- Max Planck Institute for Evolutionary Biology (DE)
- Clinical Research Center Kiel (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Nature Microbiology
- Published
- 2025-03-26
- DOI
- https://doi.org/10.1038/s41564-025-01959-z
- Citations
- 34
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 27.40
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Christian-Albrechts-Universität zu Kiel
- Göteborgs Universitet
- Horizon 2020 Framework Programme