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bioRxiv · 10.1101/2025.01.07.631721

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

Pensotti, R.·Sciandrone, B.·Bovio, F.·Schroeter, L.·Maglioni, S.·Thewes, L.·Forcella, M. E.·Fusi, P. A.·Rossi, A.·Berndt, C.·Ventura, N.·Regonesi, M. E. E.
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Abstract

Aging is a natural process characterized by a progressive physiological decline that undermines health and well-being in the elderly population. It is widely accepted that an unbalanced redox state belongs to the hallmarks of aging, but its role as one of the main drivers of ferroptosis is quite recent. Ferroptosis is a form of 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 clearly 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 a C. elegans wild-type strain highlighting how several age-related features differentially decline during aging. A progressive loss of the capability to contrast external stressors, with an increase in hydroxyl radicals and a failure of the glutathione antioxidant system demonstrated the progressive disruption of redox homeostasis in older age. Moreover, we showed that selected genes involved in redox metabolism are downregulated with aging. Among them, mutant strains of the fatty acyl-CoA reductase, fard-1, and of the dehydrogenase, dhs-25, displayed higher sensitivity to a ferroptosis inducer, increased lipid peroxidation, anticipated drop in total glutathione and reduced lifespan. Accordingly, the expression of one of the closest mammalians dhs-25 homolog, the hydroxysteroid 17-Beta Dehydrogenase 8, was downregulated in cells which are more sensitive to ferroptosis. Our results clearly prove a causal role for ferroptosis in C. elegans aging driven by oxidative stress, unveiling novel genes involved in this connection that may constitute targets for possible interventions to improve healthy aging.

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Pensotti, R., Sciandrone, B., Bovio, F., Schroeter, L., Maglioni, S., Thewes, L., Forcella, M. E., Fusi, P. A., Rossi, A., Berndt, C., Ventura, N., Regonesi, M. E. E.. 2025-01-08. Redox homeostasis in ferroptosis and aging: a causal role for fard-1 and dhs-25 in Caenorhabditis elegans. https://doi.org/10.1101/2025.01.07.631721

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