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Research Paper|Volume 17, Issue 6|pp 1429—1451

Spermidine supplementation and protein restriction protect from organismal and brain aging independently

YongTian Liang1,2, Anja Krivograd1,3, Sebastian J. Hofer4,5,6,7, Laxmikanth Kollipara8, Thomas Züllig4, Albert Sickmann8,9,10, Tobias Eisenberg4,5,6, Stephan J. Sigrist1,2,3
  • 1Institute for Biology/Genetics, Freie Universität Berlin, Berlin 14195, Germany
  • 2NeuroCure Cluster of Excellence, Charité Universitätmedizin Berlin, Berlin 10117, Germany
  • 3Leibniz-German Center for Neurodegenerative Diseases (DZNE) Berlin 10117, Germany
  • 4Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz 8010, Styria, Austria
  • 5BioTechMed Graz, Graz 8010, Styria, Austria
  • 6Field of Excellence BioHealth, University of Graz, Graz 8010, Styria, Austria
  • 7Max Delbrück Center for Molecular Medicine (MDC), Berlin 13125, Germany
  • 8Leibniz-Institut Für Analytische Wissenschaften – ISAS – e.V., Dortmund 44139, Germany
  • 9Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen, AB24 3FX, UK
  • 10Medizinische Fakultät, Medizinische Proteom-Center (MPC), Ruhr-Universität Bochum, Bochum 44801, Germany
Received: November 18, 2024Accepted: May 24, 2025Published: June 7, 2025
https://doi.org/10.18632/aging.206267

Copyright: © 2025 Liang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Brain aging and cognitive decline are significant biomedical and societal concerns. Both dietary restriction, such as limiting protein intake, and fasting, which restricts the timing of food consumption, have been proposed as strategies to delay aspects of aging. Recent studies suggest that intermittent fasting effects are mediated by the endogenous polyamine spermidine. Spermidine supplementation promotes mitochondrial integrity and functionality in aging brains by supporting hypusination of the translational initiation factor eIF5A. However, how molecular mechanisms underlying fasting mimicking interventions and protein restriction converge remain unclear, yet biomedically relevant.

In this study, we combined low- and high-protein diets (2% versus 12% yeast in food) with spermidine supplementation in aging Drosophila fruit flies. Effective hypusination was essential for normal life expectancy on both 2% and 12% yeast diets. Spermidine supplementation increased longevity, protected against age-related locomotion decline on both diets and improved memory scores in older flies regardless of protein intake. Notably, spermidine did not reduce the positive effects of the 12% protein diet on fecundity.

Our findings suggest that while both protein restriction and spermidine supplementation improve brain mitochondrial function, they largely operate through distinct mechanisms in modulating Drosophila brain aging. These results offer a basis for potential synergistic lifestyle interventions targeting age-related brain decline.