Contribution of Ferroptosis to Aging and Frailty

Ferroptosis is a recently characterized cell death phenotype resulting from iron-catalyzed peroxidation of polyunsaturated fatty acid phospholipids. Increased dysfunctional iron metabolism is thought to lead to increased levels of iron and ferroptosis, which in turn leads to cell and organismal death at least in the nematodeCaenorhabditis elegans. Drugs that block lipid peroxidation or scavenge intracellular iron extend healthspan and lifespan inC. elegansindependently of other mechanisms such as thedaf-1/daf-16(insulin/insulin-like growth factor 1 [IGF-1]) pathway, but unlike many aging mechanisms do not alter temporal scaling across the life cycle ofC. elegans, but rather act at specific late points in the organism's life history, temporarily blocking execution of critical dysfunction that results in listless worms. As such, inhibition of ferroptosis may be a means to extend healthspan and treat frailty and possibly neurodegenerative diseases that have a reported role for iron dyshomeostasis. However, a significant effort to understand ferroptosis in the context of mammalian and human biology is necessary. For example, some tumors block ferroptosis to survive. The constraints of balancing iron metabolism are significant and will require careful consideration in any drug development program.