Exploring the association between aging, ferroptosis, and common age-related diseases

Abstract

Aging is a natural biological process that is characterized by the progressive decline in physiological functions and an increased vulnerability to age-related diseases. The aging process is driven by different cell and molecular mechanisms. It has recently been shown that aging is associated with heightened vulnerability to ferroptosis (an intracellular iron-dependent form of programmed cell death). This susceptibility arises from various factors including oxidative stress, impaired antioxidant defences, and dysregulated iron homeostasis. The progressive decline in cellular antioxidant capacity and the accumulation of damaged components contribute to the increased susceptibility of aging cells to ferroptosis. Dysregulation of key regulators involved in ferroptosis, such as glutathione peroxidase 4 (GPX4), iron regulatory proteins, and lipid metabolism enzymes, further exacerbates this vulnerability. The decline in cellular defence mechanisms against ferroptosis during aging contributes to the accumulation of damaged cells and tissues, ultimately resulting in the manifestation of age-related diseases. Understanding the intricate relevance between aging and ferroptosis holds significant potential for developing strategies to counteract the detrimental effects of aging and age-related diseases. This will subsequently act to mitigate the negative consequences of aging and improving overall health in the elderly population. This review aims to clarify the relationship between aging and ferroptosis, and explores the underlying mechanisms and implications for age-related disorders, including neurodegenerative, cardiovascular, and neoplastic diseases. We also discuss the accumulating evidence suggesting that the imbalance of redox homeostasis and perturbations in iron metabolism contribute to the age-associated vulnerability to ferroptosis.