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

ELife
Nicole L. JenkinsGawain McColl

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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Citations

Sep 27, 2020·Rejuvenation Research·James W LarrickAndrew R Mendelsohn
Nov 22, 2020·The Journal of Biological Chemistry·Peng LeiAshley I Bush
Jan 26, 2021·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Scott AytonAshley I Bush
Jan 27, 2021·Nature Reviews. Molecular Cell Biology·Xuejun JiangMarcus Conrad
Jan 28, 2021·Biology·Min Ji KimSung Eun Kim
Mar 7, 2021·Metabolites·Marcos A Perez, Jennifer L Watts
Apr 4, 2021·International Journal of Molecular Sciences·Elena GammellaStefania Recalcati
Nov 21, 2020·Cell Metabolism·Jiashuo Zheng, Marcus Conrad
Sep 24, 2021·Journal of Neurochemistry·Md JakariaScott Ayton

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Methods Mentioned

BETA
MDA
nuclear translocation
X-ray
size-exclusion chromatography
size exclusion chromatography
Extraction
Fluorescence

Software Mentioned

ImageJ
PRISM
GraphPad
XANES
R package rms
φXANES
Fiji
R package flexsurv
GeoPIXE
WormSizer

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