Implication of ferroptosis in aging

Abstract

Life is indeed continuously going through the irreversible and inevitable process of aging. The rate of aging process depends on various factors and varies individually. These factors include various environmental stimuli including exposure to toxic chemicals, psychological stress whereas suffering with various illnesses specially the chronic diseases serve as endogenous triggers. The basic underlying mechanism for all kinds of stresses is now known to be manifested as production of excessive ROS, exhaustion of ROS neutralizing antioxidant enzymes and proteins leading to imbalance in oxidation and antioxidant processes with subsequent oxidative stress induced inflammation affecting the cells, tissues, organs and the whole body. All these factors lead to conventional cell death either through necrosis, apoptosis, or autophagy. Currently, a newly identified mechanism of iron dependent regulated cell death called ferroptosis, is of special interest for its implication in pathogenesis of various diseases such as cardiovascular disease, neurological disorders, cancers, and various other age-related disorders (ARD). In ferroptosis, the cell death occur neither by conventional apoptosis, necrosis nor by autophagy, rather dysregulated iron in the cell mediates excessive lipid peroxidation of accumulated lethal lipids. It is not surprising to assume its role in aging as previous research have identified some solid cues on the subject. In this review, we will highlight the factual evidences to support the possible role and implication of ferroptosis in aging in order to declare the need to identify and explore the interventions to prevent excessive ferroptosis leading to accelerated aging and associated liabilities of aging.

Fig. 1. A vicious cycle of aging mechanism, promoted by underlying chronic diseases and ferroptosis.

Illustration showing ferroptosis as a catalytic factor for induction of a vicious cycle of accelerated aging and chronic disease progression with underlying imbalance of oxidant and antioxidant defense mechanisms.

Fig. 2. Proposed mechanism of interaction between iron dyshomeostasis, ferroptosis, and hepcidin in aging.

Age related decline of immunity and redox imbalances leads to chronic inflammation and induction of hepcidin resulting in iron dyshomeostasis and ferroptosis that contributes to accelerated aging and age related frailty and debility.

Fig. 3. Epigenetic regulation of ferroptosis.

Intracellular mechanism of ferroptosis regulated at various levels. In mitochondria, glutaminolysis increase ROS production via unkown mechanism and contributes to ferroptosis. At nuclear level, histone modifications such as ubiquitination, demethylation, or deacetylation; DNA transcriptional regulation via hypomethylation at specific loci, transcriptional factors, lncRNA; and metabolic regulation through proteins; inhibit ferroptosis.

Fig. 4. Illustration of possible therapeutic intervention targets to control ferroptosis induced accelerated aging.

Besides the currently known classes of ferroptosis inhibitors such as radical trapping agents, anti-oxidants, anti-inflammatory agents, hepcidin inhibitors and ferropotin-1 activators, still there is a need of effective anti-ferroptotic compounds that could be used to prevent accelerated and debilitated aging.