Review
Targeting the Electron Transport System for Enhanced Longevity
| Title: | Targeting the Electron Transport System for Enhanced Longevity |
|---|---|
| Authors: | Radovic, Marko, Gartzke, Lucas P, Wink, Simon E, van der Kleij, Joris A, Politiek, Frouwkje A, Krenning, Guido |
| Source: | Radovic, M, Gartzke, L P, Wink, S E, van der Kleij, J A, Politiek, F A & Krenning, G 2025, 'Targeting the Electron Transport System for Enhanced Longevity', Biomolecules, vol. 15, no. 5, 614. https://doi.org/10.3390/biom15050614 |
| Publication Year: | 2025 |
| Collection: | University of Groningen research database |
| Subject Terms: | Humans, Longevity/drug effects, Electron Transport/drug effects, Metformin/pharmacology, Animals, Mitochondria/metabolism, Sirolimus/pharmacology, Reactive Oxygen Species/metabolism, Oxidative Phosphorylation/drug effects |
| Description: | Damage to mitochondrial DNA (mtDNA) results in defective electron transport system (ETS) complexes, initiating a cycle of impaired oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) production, and chronic low-grade inflammation (inflammaging). This culminates in energy failure, cellular senescence, and progressive tissue degeneration. Rapamycin and metformin are the most extensively studied longevity drugs. Rapamycin inhibits mTORC1, promoting mitophagy, enhancing mitochondrial biogenesis, and reducing inflammation. Metformin partially inhibits Complex I, lowering reverse electron transfer (RET)-induced ROS formation and activating AMPK to stimulate autophagy and mitochondrial turnover. Both compounds mimic caloric restriction, shift metabolism toward a catabolic state, and confer preclinical-and, in the case of metformin, clinical-longevity benefits. More recently, small molecules directly targeting mitochondrial membranes and ETS components have emerged. Compounds such as Elamipretide, Sonlicromanol, SUL-138, and others modulate metabolism and mitochondrial function while exhibiting similarities to metformin and rapamycin, highlighting their potential in promoting longevity. The key question moving forward is whether these interventions should be applied chronically to sustain mitochondrial health or intermittently during episodes of stress. A pragmatic strategy may combine chronic metformin use with targeted mitochondrial therapies during acute physiological stress. |
| Document Type: | review |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 2218-273X |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/40427507; info:eu-repo/semantics/altIdentifier/hdl/https://hdl.handle.net/11370/ba16c68f-7ad9-4011-90d6-dde37981aaf8; info:eu-repo/semantics/altIdentifier/pissn/2218-273X; info:eu-repo/semantics/altIdentifier/eissn/2218-273X |
| DOI: | 10.3390/biom15050614 |
| Availability: | https://hdl.handle.net/11370/ba16c68f-7ad9-4011-90d6-dde37981aaf8 https://research.rug.nl/en/publications/ba16c68f-7ad9-4011-90d6-dde37981aaf8 https://doi.org/10.3390/biom15050614 https://pure.rug.nl/ws/files/1326108163/biomolecules-15-00614-v2.pdf |
| Rights: | info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: | edsbas.6D993E40 |
| Database: | BASE |
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