Cobalt chloride has beneficial effects across species through a hormetic mechanism.

Severe oxygen and iron deficiencies have evolutionarily conserved detrimental effects, leading to pathologies in mammals and developmental arrest as well as neuromuscular degeneration in the nematode Yet, similar to the beneficial effects of mild hypoxia, non-toxic levels of iron depletion, achieved with the iron chelator bipyridine or through frataxin silencing, extend lifespan through hypoxia-like induction of mitophagy. While the positive health outcomes of hypoxia preconditioning are evident, its practical application is rather challenging. Here, we thus test the potential beneficial effects of non-toxic, preconditioning interventions acting on iron instead of oxygen availability. We find that limiting iron availability through the iron competing agent cobalt chloride has evolutionarily conserved dose-dependent beneficial effects: while high doses of cobalt chloride have toxic effects in mammalian cells, iPS-derived neurospheres, and in , sub-lethal doses protect against hypoxia- or cobalt chloride-induced death in mammalian cells and extend lifespan and delay age-associated neuromuscular alterations in . The beneficial effects of cobalt chloride are accompanied by the activation of protective mitochondrial stress response pathways.