Arguably one of the most indispensable trace elements, iron is a requirement for DNA synthesis, oxygen delivery and energy metabolism, as well as immune function. Nonetheless, iron must be delicately handled and tightly regulated to mitigate toxic consequences. The Goldilocks paradox lies in its reactive nature. As a transition metal, the iron atom is surrounded by loose valence electrons. This property enables iron to shift between ferrous and ferric states, swapping electrons with other molecules like oxygen to act as a reducing agent. When iron donates its electrons to oxygen, it becomes oxidized ferric iron. Conversely, when ferrous iron interacts with hydrogen peroxide, the Fenton reaction takes place whereby highly reactive hydroxyl radicals are generated. Aging is correlated with iron accumulation, potentiating the opportunity for iron’s inherent reactivity to wreak havoc. Iron overload contributes to oxidative stress, chronic inflammation, and mitochondrial impairment. As lipid peroxidation accumulates and cell membranes lose structural integrity, cells undergo ferroptosis. Futhermore, lipid peroxidation creates toxic aldehydes that promote cellular senescence. Iron dysregulation can thereby facilitate ferro-aging, a cascade triggered by iron excess that sequentially elicits reactive oxygen species production, lipid peroxidation, tissue dysfunction, and finally cellular senescence and/or ferroptosis.
Studies have demonstrated that altered iron homeostasis need not be the underlying factor evoking cellular senescence. Regardless of the instigating cause, senescent cells universally exhibit unusually elevated levels of intracellular iron, and continue to accrue iron beyond the onset of senescence. Senescent cells display dysregulated iron uptake, retention, turnover, and efflux, characterized by a rise in ferritin that has since been used as a senescence biomarker. Moreover, the lysosomal impairment of senescent cells hinders proper ferritonophagy, whereby ferritin is degraded in order to release stored iron. Trapped iron is interpreted as iron deficiency, leading to upregulation of transferrin receptor 1 (TfR1) in an effort to capture and retain more iron. Sequestered iron also prevents ferritonophagy by inhibiting free iron’s induction of lipid peroxidation. Exploitation of antioxidant defense systems by senescent cells serves to augment glutathione peroxidase 4, an anti-ferroptotic protein that further bolsters ferritonophagy evasion. To add insult to injury, iron efflux mediated by a balance between hepcidin and ferroportin is also afflicted in senescent cells, further contributing to iron accumulation.
As intracellular iron collects, so do reactive oxygen species in parallel. Mitochondria are a key target, and their damage exacerbates reactive oxygen species production while also diminishing ATP availability. Injured mitochondria release their DNA which is recognized by cyclic GMP-AMP synthase (cGAS), activating the cGAS-STING pathway implicated in the senescence-associated secretory phenotype (SASP). DNA damage also stimulates the DNA damage response (DDR) and associated stimulation of p53 tumor suppressor protein, downstream expression of cyclin-dependent kinase inhibitor p21, and cell cycle arrest. Dysfunctional mitochondria are also coopted to act as iron reservoirs. Senescence has been observed to enhance mitoferrin levels and subsequent iron import into the mitochondria while also inhibiting iron-sulfur cluster synthesis. Free mitochondrial iron cross-links with flawed protein and lipid byproducts to form lipofuscin granules, effectively trapping iron to drive more iron uptake. A vicious cycle is cultivated when severely injured mitochondria undergo defective or incomplete autophagy. Their copious internal iron reacts with polyunsaturated fatty acids, cross-links with lipids and proteins, and produces additional lipofuscin aggregates.
Ferroptosis and cellular senescence exhibit a complex relationship, with ferroptosis both contributing to and resulting from cellular senescence. Senescent cells display functional decline of a variety of processes, including glutathione synthesis. Their attenuated antioxidant protection makes them especially vulnerable to iron-mediated lipid peroxidation and consequent ferroptosis. Diminished levels of RSL1D1 destabilizes ferritin and provokes ferroptosis as well as senescence-like phenotypes. TfR1, on the contrary, is elevated in senescent cells, triggering iron uptake and iron accrual. p53 promotes senescence as well as ferroptosis, while loss of certain sirtuin family member expression removes their safeguard against ferroptosis progression. The incidence of ferroptosis facilitates release of damage-associated molecular patterns and lipid peroxidation byproducts that act as an impetus for cellular senescence. The positive feedback loop persists, with compounds released by senescent cells poisoning their neighbors and increasing susceptibility to ferroptosis.
The dynamic interaction between ferroptosis and cellular senescence and their shared regulatory network highlight the requisite sophistication of therapeutic interventions. Merely countering oxidative damage will not suffice, and instead a two pronged approach must be implemented whereby both upstream iron homeostasis and downstream senescence are coordinately targeted. A combination of iron chelation, modulation of iron import, storage, and export, and restoration of ferritonophagy will be necessary to effectively attenuate iron overload and its related impacts. Further addressing lipid peroxidation, a central component of ferroptosis and cellular senescence, has been accomplished through the administration of vitamin C and quercetin. Vitamin C inhibits ACSL4-mediated lipid peroxidation, while quercetin upregulates the glutathione-GPX4 axis and NrF2 signaling. Vitamin E also mitigates iron accumulation, lipid peroxidation, and mitochondrial dysfunction. Syringaldehyde, a degradation product of lignin, and 3-bromo-4,5-dihydroxybenzaldehyde, derived from marine red algae, also lower oxidative stress and lipid peroxidation. Senolytics serve to reduce senescent cell burden, with dasatinib plus quercetin being the most potent compound identified to date. Vitamin D receptor agonists, taurine, perilla seed meal extract, and saffron have additionally been used to decrease senescent phenotypes. Finally, platelet-derived exosomes, melatonin, rapamycin, and gut microbiota-produced hydrogen gas may also protect against cellular senescence.
The ferro-aging cascade remains highly complex, with ferroptosis and cellular senescence being heavily intertwined. Identifying the critical dominant mechanisms will prove challenging in the complex landscape of aging. New technologies will help disentangle and elucidate individual branches of the ferro-aging network, allowing for improved detection, early intervention, and effective therapeutics.
Gao S, Qi L, Bai W, et al. Ferro-Aging: A Novel Paradigm Linking Iron Overload, Lipid Peroxidation and Cellular Senescence. Free Radic Biol Med. Published online June 5, 2026. doi:10.1016/j.freeradbiomed.2026.06.012