Targeting Aging and Diseases Associated with Ferroptosis and Senescence Through Modulation of Iron, Oxidative Stress and Lipid Peroxidation

Ferroptosis and senescence are unique cellular processes that lead to irreversible cell abnormalities and tissue damage in many diseases, such as cancer, neurodegeneration, cardiac, liver, and kidney damage. Despite distinct differences between the two processes, essential shared features in their causes and development include increased redox iron toxicity and oxidative stress, together with reduced antioxidant capacity, such as decreased glutathione levels and downregulation of glutathione peroxidase. The consequences of these toxicities include increased lipid peroxidation and aggregation, causing cell damage and death in ferroptosis, whereas in senescence, they lead to DNA and other biomolecular damage, resulting in a form of cell growth arrest with specific characteristics, such as the progressive accumulation of senescent cells across tissues in aging. Many potential therapeutic strategies have emerged to regulate ferroptosis and senescence pathways, including targeting and modulating iron toxicity and redox imbalance, and metabolic, transcriptional, genomic, and other associated pathways and factors. Experimental evidence suggests that iron chelating drugs such as deferiprone, deferoxamine, and deferasirox, and other drugs such as sorafenib, may be potential therapeutics for ferroptosis. Similarly, in senescence, in addition to iron chelating drugs that can act as senomorphic and senolytic agents, several other drugs, such as navitoclax and the combination of dasatinib and quercetin, have shown promising results in preliminary clinical trials as senolytic agents, while rapalogs and several nutraceuticals, such as quercetin, have been studied as senomorphic agents. Despite the absence of antioxidant drugs in clinical practice, the development of therapeutic strategies, including the repurposing of iron chelating drugs and the use of natural antioxidants, may be crucial for therapeutic advances in diseases associated with ferroptosis and senescence. The design of new therapeutic strategies based on the modulation of multiple targets, particularly the control of redox iron and oxidative stress toxicity using combinations of iron chelators with other drugs or nutraceuticals, may improve therapeutic outcomes in many diseases associated with ferroptosis, senescence, and aging. In each case, target selection and specific considerations may apply within the context of personalized medicine.