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Mechanisms of spermidine-induced autophagy and geroprotection

Nature Aging volume 2, pages 1112–1129 (2022)Cite this article

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Abstract

Aging involves the systemic deterioration of all known cell types in most eukaryotes. Several recently discovered compounds that extend the healthspan and lifespan of model organisms decelerate pathways that govern the aging process. Among these geroprotectors, spermidine, a natural polyamine ubiquitously found in organisms from all kingdoms, prolongs the lifespan of fungi, nematodes, insects and rodents. In mice, it also postpones the manifestation of various age-associated disorders such as cardiovascular disease and neurodegeneration. The specific features of spermidine, including its presence in common food items, make it an interesting candidate for translational aging research. Here, we review novel insights into the geroprotective mode of action of spermidine at the molecular level, as we discuss strategies for elucidating its clinical potential.

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Fig. 1: The intracellular polyamine pathway.
Fig. 2: Major molecular and metabolic effects leading to spermidine-mediated lifespan extension.
Fig. 3: The effects of spermidine on the hallmarks of aging.

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Acknowledgements

All figures were initially created with BioRender.com. S.J.H. acknowledges support from a Longevity Impetus Grant from Norn Group. F.M. is grateful to the Austrian Science Fund FWF (F3012, W1226, P29203, P29262, P27893, P31727) and the Austrian Federal Ministry of Education, Science and Research as well as the University of Graz for grants ‘Unkonventionelle Forschung-InterFast and Fast4Health’ and ‘flysleep’ (BMWFW-80.109/0001-WF/V/3b/2015). T.E. acknowledges support from Austrian Science Fund FWF (P 33957 and TAI 602 1000). We acknowledge the support of the Field of Excellence BioHealth of NAWI Graz and the BioTechMed-Graz flagship project ‘EPIAge’. G.K. is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR)–Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); Gustave Roussy Odyssea, the European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; Institut National du Cancer (INCa); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001.

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Authors and Affiliations

  1. Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria

    Sebastian J. Hofer, Martina Bergmann, Tobias Eisenberg & Frank Madeo

  2. Field of Excellence BioHealth, University of Graz, Graz, Austria

    Sebastian J. Hofer, Tobias Eisenberg & Frank Madeo

  3. BioTechMed Graz, Graz, Austria

    Sebastian J. Hofer, Tobias Eisenberg & Frank Madeo

  4. Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France

    Sebastian J. Hofer & Guido Kroemer

  5. Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France

    Sebastian J. Hofer & Guido Kroemer

  6. Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK

    Anna Katharina Simon

  7. Max Delbrück Center, Berlin, Germany

    Anna Katharina Simon

  8. Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

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Contributions

S.J.H. wrote the first draft. S.J.H., G.K. and F.M. conceptualized the review. M.B. and S.J.H. collected information for the tables. All authors proofread, edited and contributed substantially to the final version.

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Correspondence to Guido Kroemer or Frank Madeo.

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Competing interests

F.M. and G.K. are scientific cofounders of Samsara Therapeutics, a company that develops new pharmacological autophagy inducers. F.M. and T.E. have equity interests in and are advisors of The Longevity Labs (TLL). A.K.S. is consulting for TLL and Oxford Healthspan. G.K. is a scientific cofounder of everImmune, Osasuna Therapeutics and Therafast Bio. G.K. is holding research contracts with Daiichi Sankyo, Eleor, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys and Vascage. S.J.H. and M.B. declare no competing interests.

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Hofer, S.J., Simon, A.K., Bergmann, M. et al. Mechanisms of spermidine-induced autophagy and geroprotection. Nat Aging 2, 1112–1129 (2022). https://doi.org/10.1038/s43587-022-00322-9

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