Year: 2026
Type: article
Abstract: Geroprotection aims at extending healthspan by delaying age-associated pathologies. Polyamines including spermine and spermidine are interconvertible metabolites whose longevity-promoting effects have traditionally been attributed to autophagy induction. In addition, recent evidence identifies spermine as an endogenous Fe 2+ chelator that suppresses ferroptosis, thereby complementing the autophagy-inducing activity of spermidine. Indeed, spermidine inhibits EP300 acetyltransferase activity and supports hypusination-dependent activation of TFEB, both leading to autophagy. However, enhanced autophagic flux may increase susceptibility to ferroptosis through ferritinophagy and lipid remodeling. In parallel, polyamine catabolism generates H 2 O 2 and acrolein, both of which facilitate lipid peroxidation and ferroptotic demise. The discovery that spermine directly chelates redox-active Fe 2+ closes a conceptual gap by explaining how polyamine supplementation can promote longevity while avoiding excessive ferroptotic cell loss. Multiple lines of evidence including metabolomics, isotope tracing, cell-free lipid peroxidation systems, Fe 2+ -binding biophysics, mass spectrometry, Raman spectroscopy, nuclear magnetic resonance and disease models demonstrate that spermine limits labile iron and ferroptosis. Together, these findings support a unified model in which spermidine-driven autophagy and spermine-mediated ferroptosis inhibition cooperate to preserve tissue homeostasis and healthspan.
Source: Cell Stress
Institutions: University of Graz, Nawi Graz, BioTechMed-Graz, Centre National de la Recherche Scientifique, Inserm, Université Paris Cité, Université Paris-Saclay, Institut Gustave Roussy, Sorbonne Université, Centre de Recherche des Cordeliers, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,283
Funders: Seerave Foundation, Equipex, European Commission, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Austrian Science Fund, Ligue Contre le Cancer, Institut Universitaire de France, Institut National Du Cancer, Karl-Franzens-Universität Graz, Direction Générale de l’offre de Soins, Ministère des Solidarités et de la Santé, Université de Paris
Awards: G1044593785, G1348591106, G1397743473, G1540355574, G1716190585, G1743485262, G1846858737, G1941370527, G1963894250, G2109069054, G2161503289, G2179318311, G2203660494, Lung cancer prevention and interception, Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception., G2351262490, G2374589210, G2469459663, G2564658597, Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis and prediction of treatment response., G2699422577, G2714391379, G2992841218, G2998623936, G3231222199, Mitochondrial copper targeting to modulate inflammatory macrophages, G3489513111, G3536394303, Pro-autophagic polyphenols and polyamines for longevity, G3745988485, G3772543176, G4007257112, G420978141, G4364925233, G4378222322, G4707887143, G4744413284, G4880911435, G4900465205, G4968846622, G4990482369, G5334831218, G540687550, Microbiota-centered interventions to solve antibiotics-induced primary resistance to immune checkpoint inhibitors, G5468290041, G5495091266, Energizing the failing heart, G5767140378, G5790172013, G5953624409, Causal epigenetic changes during aging and caloric restriction, Potentiation of antimycotics with human-tolerable flavonoids, G6300988664, G6610179393, G668953012, G6718544961, G69196502, G7041469554, G7080048889, G722373514, G7309355080, G7319818416, G7562053067, G7662726268, Metabolic and Cardiovascular Disease, G7914284967, G816800923, G8316913482, G8386792218, G8471630636, Université de Paris, G8809306651, The RUSH (retention using selective hooks) system: a chemical-genetic system for the in vivo manipulation of intercellular communication, G8904710281, G8991455713, G915670629, Metabolic control of aging and disease
OpenAlex ID: W7167836632