Redox homeostasis in ferroptosis and aging: a causal role for fard-1 and dhs-25 in Caenorhabditis elegans

Nov 12, 2025Redox biology

Balance of cell oxidation in iron-related cell death and aging: roles of fard-1 and dhs-25 genes in C. elegans

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Ferroptosis is linked to aging in Caenorhabditis elegans, with evidence of disrupted redox homeostasis.

Aging in C. elegans is associated with a progressive decline in healthspan parameters.
Older organisms show increased levels of hydroxyl radicals and decreased levels of glutathione, indicating disrupted redox balance.
Key genes related to redox metabolism are downregulated in aging, contributing to increased sensitivity to ferroptosis.
Loss of specific enzymes, such as those encoded by fard-1 and dhs-25, correlates with higher lipid peroxidation and reduced lifespan.
The expression of a mammalian homolog to dhs-25 is also downregulated in cells more susceptible to ferroptosis.

AI simplified

Aging is a natural process characterized by a progressive physiological decline that undermines health and well-being in the elderly population. Oxidative stress is a widely accepted hallmarks of aging, and its role as one of the main drivers of ferroptosis is quite recent. Ferroptosis is an iron-dependent cell death caused by massive phospholipid peroxidation. The excessive accumulation of intracellular reactive oxygen species and iron, as well as the failure of the main cellular antioxidant systems, cause ferroptotic cell death. While clear roles for ferroptosis in pathological conditions such as cancer or neurodegeneration have been described, its physiological roles and regulators are less understood. Here, using Caenorhabditis elegans as a powerful model organism for aging studies, we uncover a role for ferroptosis in physiological aging mediated by disturbed redox homeostasis. We evaluated healthspan parameters in C. elegans highlighting how several age-related features differentially decline during physiological aging. A progressive loss of the capability to contrast external stressors, with an increase in hydroxyl radicals and a decrease of glutathione demonstrated the disruption of redox homeostasis in older age. Moreover, transcription of selected genes involved in redox metabolism is downregulated with aging. Among them, loss of the fatty acyl-CoA reductase encoded by fard-1 and of the dehydrogenase encoded by dhs-25 display higher sensitivity to ferroptosis, increased lipid peroxidation, lower total glutathione levels and reduced lifespan. Accordingly, the expression of hydroxysteroid 17-beta dehydrogenase 8, one of the closest mammalians dhs-25 homologs, is downregulated in cells which are more sensitive to ferroptosis. Our results clearly prove a causal role for ferroptosis in C. elegans aging driven by mitochondrial redox unbalance, unveiling novel genes involved in this connection that may constitute targets for possible interventions to improve healthy aging.

Full Text

We can’t show the full text here under this license. Use the link below to read it at the source.

View full text (XML) ↗View full text ↗

Redox homeostasis in ferroptosis and aging: a causal role for fard-1 and dhs-25 in Caenorhabditis elegans

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief