Ferroptosis-related stress during aging and its relevance to disease

Aging is a progressive and complex process of physiological changes that accumulate over time and end up undermining organismal performance. In many cases, this leads to the development of age-related diseases. Therefore, the identification of the exact mechanisms connecting aging to disease will be critical for the advancement of biomedical research in the field. Recently, a growing number of reports have linked ferroptosis, a form of non-apoptotic regulated cell death, to numerous age-related human pathologies. Although key molecular events associated with ferroptosis have been consistently observed with aging in various tissues, the interaction between ferroptosis and aging remains mostly unexplored. In this review, we investigate this interplay by examining reported findings from three different perspectives: (1) the manifestation of ferroptosis with age; (2) the acceleration of aging when ferroptosis is experimentally enhanced; and (3) the potential to slow, stop, or reverse aging through ferroptosis-targeted therapeutic interventions. Based on this analysis, we hypothesize that, although ferroptosis is defined as a cell death pathway, ferroptosis-related processes can operate at a chronic, sublethal level during aging. Importantly, the persistence of this stress might increase the susceptibility of organisms to age-associated diseases by undermining fundamental cellular functions that are critical to their healthspan, even in the absence of overt cell death. The implications for the design and development of new treatments for a broad range of age-related diseases where ferroptosis-related stress could play a central role is discussed.