Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging Caenorhabditis elegans

Abstract

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in Caenorhabditis elegans. Here, we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant aging rate. Because excess age-related iron elevation in somatic tissue, particularly in brain, is thought to contribute to degenerative disease, post-developmental interventions to limit ferroptosis may promote healthy aging.

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Affiliated Institutions

• Florey Institute of Neuroscience and Mental Health AU
• The University of Melbourne AU
• La Trobe University AU
• The University of Sydney AU
• Australian Nuclear Science and Technology Organisation AU
• Walter and Eliza Hall Institute of Medical Research AU
• Australian Synchrotron AU
• Helmholtz Zentrum München DE
• Robert Bosch (Australia) AU

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