Review Article Modulating Ferroptosis in Aging: The Therapeutic Potential of Natural Products Sherif Hamidu ,1 Seth Kwabena Amponsah ,2 Abigail Aning,1 Latif Adams,3 Justice Kumi ,1 Eunice Ampem-Danso ,1 Fatima Hamidu,4 Mustapha Abdul Mumin Mohammed,5 Gabriel Tettey Ador,6 and Sanjida Khatun7 1Department of Clinical Pathology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana 2Department of Medical Pharmacology, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana 3Department of Microbiology and Immunology, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana 4Faculty of Medicine, International University of Africa, Khartoum, Sudan 5Department of Internal Medicine, Central Hospital of Biel, Biel, Switzerland 6Department of Nutrition, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra, Ghana 7Biotechnology and Genetic Engineering, Faculty of Life Science, Mawlana Bhashani Science and Technology University, Santosh, Tangail, Bangladesh Correspondence should be addressed to Sherif Hamidu; shamidu@noguchi.ug.edu.gh and Seth Kwabena Amponsah; skamponsah@ug.edu.gh Received 8 April 2025; Revised 12 June 2025; Accepted 27 June 2025 Academic Editor: Udhaya Kumar Siva Kumar Copyright © 2025 Sherif Hamidu et al. Journal of Aging Research published by John Wiley & Sons Ltd. Tis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Aging is a multifactorial process driven by accumulating cellular damage. Ferroptosis—an iron-dependent, lipid peroxidation- mediated form of cell death—has emerged as a critical contributor to age-related tissue degeneration. Tis review synthesizes current evidence linking ferroptosis to key aging hallmarks, including oxidative stress, chronic infammation, mitochondrial dysfunction, and dysregulated iron metabolism. Central to these interactions is the age-associated decline in antioxidant defenses (e.g., glutathione, glutathione peroxidase 4 [GPx4]) and paradoxical iron dynamics, where systemic defciency coexists with intracellular overload, promoting reactive oxygen species (ROS) generation via the Fenton reaction. Natural products such as resveratrol, curcumin, and epigallocatechin gallate (EGCG) exhibit promising anti-ferroptotic efects through mechanisms including iron chelation, ROS scavenging, and upregulation of endogenous antioxidants. Preclinical and clinical studies indicate their potential in reducing lipid peroxidation and enhancing cellular resilience in aging contexts. However, challenges such as poor bioavailability and tissue-specifc iron dysregulation remain.Tis review explores how combinatorial approaches—targeting multiple ferroptosis pathways—may ofer synergistic therapeutic benefts. Collectively, ferroptosis inhibition emerges as a promising strategy to mitigate age-associated tissue damage and promote healthy aging. Keywords: aging; ferroptosis; iron metabolism; lipid peroxidation; natural products; oxidative stress Wiley Journal of Aging Research Volume 2025, Article ID 8832992, 18 pages https://doi.org/10.1155/jare/8832992 https://orcid.org/0000-0003-1341-4029 https://orcid.org/0000-0001-7411-0972 https://orcid.org/0000-0002-5929-2322 https://orcid.org/0009-0003-0780-3914 mailto:shamidu@noguchi.ug.edu.gh mailto:skamponsah@ug.edu.gh https://creativecommons.org/licenses/by/4.0/ http://crossmark.crossref.org/dialog/?doi=10.1155%2Fjare%2F8832992&domain=pdf&date_stamp=2025-07-04 1. Introduction Aging is a multifaceted biological process characterized by progressive accumulation of molecular and cellular damage. Te hallmarks of aging include dysbiosis and altered in- tercellular communication, with downstream consequences such as mitochondrial dysfunction, chronic infammation, and loss of proteostasis (Figure 1) [1]. Among these hallmarks, emerging evidence highlights ferroptosis—an iron-dependent regulated cell death driven by lipid peroxidation—as a critical yet underappreciated contributor to age-related tissue de- generation [2, 3]. Ferroptosis intersects with multiple aging pathways, including mitochondrial dysfunction (via redox imbalance), deregulated nutrient sensing (e.g., impaired glutathione synthesis), and epigenetic alterations (e.g., nuclear factor erythroid 2-related factor 2 [Nrf2] signaling suppres- sion) [4–6]. Natural products, such as polyphenols, favo- noids, and terpenoids, have been found to possess anti-aging properties. Tese natural products exhibit dual activity: ameliorate canonical aging hallmarks and suppress ferrop- tosis by scavenging lipid radicals, chelating iron, or upre- gulating antioxidant defenses [7, 8]. Indeed, the nexus between ferroptosis, aging hallmarks and natural products needs to be clearly aligned. For instance, an active compound from turmeric (curcumin) known to mitigate chronic infammation and telomere attrition also inhibits ferroptosis by activating the Nrf2-glutathione peroxidase 4 (GPX4) axis [3, 8, 9]. Similarly, resveratrol, a sirtuin-activating molecule that enhances proteostasis and autophagy, concur- rently blocks ferroptotic death by modulating iron metabolism [10, 11]. Tis overlap suggests that some natural products with anti-aging properties exert their efects, in part, through fer- roptosis inhibition.Tismay be a unifed strategy to target both the causes and consequences of aging. In this review, we explore natural products and their ability to cause ferroptosis suppression; proposing the therapeutic utility of this in age-related diseases. By clearly defning the hallmarks of aging with ferroptosis pathways, we aim to unravel how nature-derived compounds could delay aging and resolve the ferroptotic “tipping point” that accelerates cellular collapse. Tis review article specifcally aligns with the scope of the Journal of Aging Research by critically evaluating the in- tricate relationship between ferroptosis and the aging pro- cess, and by exploring the therapeutic potential of natural products in modulating this cellular death pathway. Our comprehensive summary aims to provide novel insights into the mechanistic underpinnings of age-related diseases and propose translational strategies for healthy aging, thereby contributing to the journal’s mission of advancing knowl- edge in gerontology and geriatric medicine. 1.1. Aging: An Unavoidable Biological Process. As one ages, there is gradual decline in the functional capacity of cells, tissues, and organ systems, thereby heightening the risk of frailty, disease, and eventual death [12, 13]. Aging arises from a complex network of intrinsic mechanisms, including dis- ruptions in the balance between pro-oxidant and antioxidant forces [14], shifts in anabolic and catabolic processes [15, 16], disturbances in energy metabolism [17], and the concurrent activation of various immune responses [18]. Collectively, these factors foster a persistent, low-level infammatory state that leads to immune senescence, setting of a self-reinforcing cycle that accelerates further deterioration [19]. Recognized hall- marks of aging across species include genomic instability, telomere shortening, epigenetic changes, loss of proteostasis, impaired nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell depletion, and altered cell-to-cell com- munication [20–22]. Notably, many of these hallmarks such as mitochondrial dysfunction and redox imbalance converge with ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation, which exacerbates age-related decline [23, 24]. However, the intricate process of aging remains only partially understood, with many aspects yet to be unraveled. 1.2. Evolving Mechanisms of Aging. Originally described by Denham Harman in the 1950s, the free radical theory posits that aging results from the cumulative oxidative damage inficted by reactive oxygen species (ROS) generated during normal cellular metabolism, which progressively shortens lifespan [25, 26]. Alongside this widely recognized concept, new ideas propose that the inherent imperfections of biological systems also contribute to aging [25]. Cells continuously get damaged due to intrinsic heterogeneity and imperfect fdelity of biological processes, eventually leading to senescence [27, 28]. Te rate at which these damages accrue is contingent upon the efciency of metabolic and genetic repair systems. Recent fndings indicate that ROS alone cannot fully account for the aging process [29]. Ferroptosis, a form of regulated necrosis driven by iron overload and lipid peroxidation, has emerged as another important contributor to aging, particu- larly in tissues prone to redox imbalance (e.g., brain and liver) [3, 4, 30]. It is, therefore, relevant to explore other pathways of cellular damage that play roles in initiating, sustaining, and advancing aging [31]. 1.3. Chronic Infammation, Aging, and Disease. Te term “infamm-aging,” introduced in 2000 [32], characterizes aging as a process accompanied by a continuous, low-grade, systemic, and unresolved infammatory state that gradually increases pro-infammatory markers [33]. Tis persistent infammation is believed to be a key determinant of both the rate of aging and overall lifespan. Several studies have im- plicated such sustained, mild infammation as a signifcant risk factor for age-related conditions including atheroscle- rosis, arthritis, cancer, diabetes, osteoporosis, dementia, vascular disorders, obesity, and metabolic syndrome [33, 34]. Aging is further associated with an imbalance in redox homeostasis, where the chronic upregulation of pro- infammatory mediators (e.g., TNF-α, IL-1β, IL-6, COX-2, iNOS) and the activation of pathways like NF-κB occur alongside diminished antioxidant defenses [35, 36]. Tis infammatory milieu not only accelerates cellular senescence but also primes cells for ferroptosis by depleting glutathione (a key antioxidant) and increasing labile iron pools [37]. Te precise cause-and-efect relationship between chronic 2 Journal of Aging Research 9025, 2025, 1, D ow nloaded from https://onlinelibrary.w iley.com /doi/10.1155/jare/8832992 by U niversity of G hana - A ccra, W iley O nline L ibrary on [22/07/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense infammation and age-associated diseases remains unclear; however, current evidence suggests a vicious cycle of en- hanced frailty, accelerated aging, and premature death (Figure 2). 1.4. Iron Metabolism and Aging. Recently, there is a lot of attention on iron dysregulation and aging. Indeed, imbalances in iron metabolism are common in older individuals. For instance, iron defciency anemia, marked by low serum ferritin and reduced systemic iron, is prevalent among the elderly and is associated with adverse outcomes such as cardiovascular dis- ease, increased falls and fractures, cognitive decline, diminished quality of life, and heightened mortality risk [38–40]. Beyond poor nutrition and the use of certain medications, elevated circulating hepcidin levels, often stemming from chronic in- fammation, may also contribute to systemic iron depletion [41]. Nonetheless, further research is needed to clarify the complex interactions between aging, iron status, and the reg- ulation of hepcidin (a key regulator for the entry of iron into the circulation of mammals) [38, 39]. Additionally, aging is ac- companied by increased intracellular iron accumulation, which, due to redox imbalances, can trigger ferroptosis—a form of cell death that exacerbates age-related functional decline and mortality [40]. Tis paradox highlights the potential of natural products (e.g., curcumin, quercetin) to modulate iron ho- meostasis and inhibit ferroptosis by chelating excess iron or upregulating antioxidant defenses [42, 43]. Te paradox of low systemic iron combined with elevated intracellular iron might be driven by hepcidin upregulation in response to chronic infammation [42]. Tus, targeting hepcidin and its regulatory pathways could represent a promising strategy to mitigate age- related decline and associated diseases. 1.5. Age-Related Iron Dysregulation and Ferroptosis. Eukaryotic cells rely on iron to support essential biological functions including energy production, deoxyribonucleic acid (DNA) synthesis, replication, and detoxifcation. Although iron is indispensable for growth and development, its levels are strictly controlled by a network of transporters, storage pro- teins, and regulators to prevent both defciency and toxicity [44, 45]. Despite these rigorous homeostatic mechanisms, the body lacks an efcient excretion system for iron [45]. Iron loss occurs primarily through bleeding or the natural shedding of cells, resulting in aminimal daily loss (about 1mg) compared to approximately 4 g stored in the body, while the duodenum absorbs roughly 1mg of iron per day [44, 46, 47]. Insufcient iron during development can impair key physiological pro- cesses, while excessive iron retention in adulthood is linkedwith accelerated aging. Contributing factors to iron overload in aging include: (i) reduced metabolic demand for iron by cofactor- dependent enzymes; (ii) decreased hemoglobin levels, which account for about 60% of total body iron; and (iii) the relative Hallmarks of aging Chronic inflammation Altered intercellular communication Dysbiosis Telomere attrition Genome instability & mutation Epigenetic alterations Stem cell exhaustion Aging Loss of proteostasis Cellular senescence Mitochondrial dysfunction Deregulated nutrient sensing Disabled macroautophagy Primary hallmarks Antagonistic factors Integrative hallmarks Figure 1: Interconnected hallmarks of aging. Tis schematic diagram depicts the multifaceted processes contributing to aging, encompassing key hallmarks such as dysbiosis, chronic infammation, mitochondrial dysfunction, and disrupted proteostasis. It emphasizes how imbalances in nutrient sensing, genomic integrity, epigenetic regulation, and autophagy converge to drive cellular senescence, stem cell depletion, and systemic decline. Antagonistic factors (e.g., chronic infammation) and integrative features (e.g., altered intercellular communication) further intensify age- associated dysfunction through a self-perpetuating cycle. Highlighted pathways—including mitochondrial dysfunction and redox imbal- ance—intersect with ferroptosis, ofering mechanistic insights into the aging process and potential therapeutic targets. Journal of Aging Research 3 9025, 2025, 1, D ow nloaded from https://onlinelibrary.w iley.com /doi/10.1155/jare/8832992 by U niversity of G hana - A ccra, W iley O nline L ibrary on [22/07/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense iron overload observed in post-menopausal women. Over a lifetime, the buildup of iron in somatic tissues can disrupt cellular functions, trigger cell death, and promote aging [44, 47]. Compounds found in natural products such as polyphenols (e.g., resveratrol) and favonoids (e.g., epigallocatechin gallate [EGCG]) may counteract this iron buildup by restoring iron homeostasis and suppressing ferroptosis, thereby delaying age- related pathologies [43]. It is hypothesized that this age- associated iron imbalance may be associated with ferroptosis, a unique, iron-dependent form of regulated cell death. 1.6. Ferroptosis: A Distinct Mode of Cell Death. Traditionally, cell death can be categorized into necrosis, apoptosis, and autophagy [48]. However, other non- apoptotic mechanisms exist, one of which is ferroptosis. Defned as an iron-dependent form of regulated necrosis, ferroptosis is triggered by extensive lipid peroxidation that damages cellular membranes [31]. Its involvement in con- ditions such as cardiovascular diseases, cancers, and neu- rological disorders is well documented [31, 37]. As a result, ferroptosis inhibitors, including natural products like ferrostatin-1 and liproxstatin-1, have been discovered [49]. Te term “ferroptosis” was introduced in 2012 following the discovery of small molecules that selectively inhibited the growth of RAS-mutant cancer cells [50]. Early hypotheses regarding ferroptosis emerged from observations in nutrient-deprived cancer cells [51] and from studies on “oxytosis”—a phenomenon where neurons die due to glu- tamate toxicity coupled with inhibition of the amino acid antiporter SLC7A11/xCT/system xc− [52, 53]. 2. Types of Cell Death: From Apoptosis to Ferroptosis and Beyond Cell death can occur through several pathways (Figure 3), each defned by unique morphological and biochemical signatures [48]. Te principal modes include: • Apoptosis: A form of programmed cell death marked by cell shrinkage, chromatin condensation, and DNA frag- mentation. Apoptosis plays a vital role in development and tissue homeostasis by eliminating damaged cells in a controlled manner that minimizes infammation. • Necrosis: Traditionally considered an uncontrolled and passive process, necrosis results from acute cellular injury. It is characterized by cell swelling, loss of membrane in- tegrity, and subsequent infammation due to the re- lease of cellular contents. • Regulated Necrosis (Necroptosis): Although similar to necrosis in terms of outcome, necroptosis is a programmed process mediated by Aging Ferroptosis Ferroptosis AntioxidantPathological cycleROS Figure 2: Pathological cycle in aging. Schematic diagram illustrating the vicious cycle of ferroptosis during aging and its contribution to chronic diseases. Excessive reactive oxygen species and iron-dependent lipid peroxidation trigger ferroptosis, driving pathological processes that accelerate age-related organ damage. Antioxidant interventions can disrupt this cycle, highlighting a potential therapeutic strategy to mitigate chronic disease progression in aging populations. 4 Journal of Aging Research 9025, 2025, 1, D ow nloaded from https://onlinelibrary.w iley.com /doi/10.1155/jare/8832992 by U niversity of G hana - A ccra, W iley O nline L ibrary on [22/07/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense specifc signaling molecules such as RIPK1, RIPK3, and MLKL. Tis pathway is often activated when apoptotic machinery is inhibited, and this is implicated in various infammatory conditions. • Autophagy-Associated Cell Death: Autophagy generally serves as a protective recycling mechanism when cells are under stress. However, when excessively activated or dysregulated, it can lead to cell death. Te precise role of autophagic cell death in physiological conditions remains unclear. • Pyroptosis: An infammatory cell death mode primarily observed in immune cells. Pyroptosis involves the activation of infammatory caspases and the formation of pores in the cell membrane, resulting in cell lysis and the release of pro-infammatory cytokines. • Ferroptosis: Distinct from the above, ferroptosis is an iron- dependent, regulated form of cell death triggered by the accumulation of lipid peroxides. Unlike apoptosis or necroptosis, ferroptosis is defned by its reliance on iron metabolism, failure of the glutathione-dependent antioxidant defense (especially GPx4), and extensive membrane damage. Emerging studies highlight nat- ural compounds such as curcumin and resveratrol as dual-acting agents that inhibit ferroptosis by both chelating iron and enhancing GPx4 activity, ofering a strategic avenue to decelerate aging [24, 31]. Its emergence as a signifcant cell death mechanism has spurred intense research into its roles in various diseases, including neurodegeneration, cancer, and—importantly—aging. 2.1. Mechanism of Ferroptosis. Ferroptosis is a distinct, iron-dependent form of regulated cell death that difers from apoptosis and necroptosis, occurring independently of apoptotic (e.g., BAX, BAK, and caspases) and nec- roptotic (e.g., MLKL, RIPK1, and RIPK3) efectors [48, 50]. While ferroptosis plays a tumor-suppressive role by eliminating malignant cells, it is also implicated in various diseases, where it contributes to pathogenic mechanisms that were previously unexplained. Te progression of ferroptosis involves four key steps (Figure 4): 1. Cysteine Uptake Inhibition: Te system Xc− anti- porter, which imports cystine (Cys) in exchange for glutamate (Glu), is inhibited. Tis reduces in- tracellular cysteine levels, limiting the synthesis of glutathione (GSH), a crucial antioxidant. 2. Glutathione and GPX4 Depletion: Reduced GSH synthesis leads to decreased activity of GPX4, an enzyme that normally prevents lipid peroxidation. Cell death Cell death (healthy) Programmed cell death Unprogrammed cell death Apoptosis Necroptosis Pyroptosis Necrosis Ferroptosis Autophagy Figure 3: Classifcation of cell death mechanisms.Tis fgure classifes various forms of cell death, including apoptosis, necrosis, pyroptosis, autophagy-associated death, necroptosis, and ferroptosis. Apoptosis is a noninfammatory programmed cell death; necrosis is uncontrolled and infammatory. Pyroptosis involves infammatory caspases, while ferroptosis is characterized by iron accumulation and lipid perox- idation. Each pathway is regulated by distinct molecular mechanisms. Journal of Aging Research 5 9025, 2025, 1, D ow nloaded from https://onlinelibrary.w iley.com /doi/10.1155/jare/8832992 by U niversity of G hana - A ccra, W iley O nline L ibrary on [22/07/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense 3. Excessive Lipid ROS Accumulation: With GPX4 inactivated, polyunsaturated fatty acids (PUFAs) undergo peroxidation, forming toxic lipid peroxides (PUFA-OOH), which accumulate. Tis step is driven by enzymes such as lipoxygenases, cytochrome P450 oxidoreductases, and non-enzymatic Fenton chem- istry, where Fe2+ reacts with hydrogen peroxide (H2O2) to generate ROS. 4. Iron Overload and ROS-Driven Peroxidation: In- creased intracellular iron, facilitated by transferrin (Tf) uptake and its conversion from Fe3+ to Fe2+ via STEAP3 and DMT1, fuels lipid peroxidation through the Fenton reaction, exacerbating oxidative damage and ultimately leading to ferroptosis. A defning ultrastructural feature of ferroptosis, ob- served via transmission electron microscopy, includes shrunken mitochondria with increased membrane density and reduced cristae structure, signifying impaired cellular energetics [53]. Beyond the four key steps of ferroptosis, the integral role of mitochondria, their function, damage, and repair mechanisms, are increasingly recognized as critical nodes in this unique form of cell death. A defning ultrastruc- tural feature of ferroptosis, observed via transmission electron microscopy, includes shrunken mitochondria with increased membrane density and reduced cristae structure, signifying impaired cellular energetics [53]. Mitochondrial dysfunction, characterized by excessive mitochondrial ROS production, disruption of mito- chondrial membrane potential, and impaired bio- energetics, directly fuels the lipid peroxidation cascades central to ferroptosis. Tis mitochondrial involvement is particularly relevant in aging, where mitochondrial dysfunction is a well-established hallmark, contributing to cellular senescence and tissue degeneration [7, 53]. Furthermore, compromised mitochondrial quality con- trol mechanisms, such as dysregulated mitophagy (the selective removal of damaged mitochondria), can exac- erbate ferroptosis susceptibility in aging cells. Terefore, understanding and targeting mitochondrial integrity and function represents a crucial avenue for modulating ferroptosis in age-related contexts. Despite extensive research, critical aspects of ferroptosis regulation remain unresolved, highlighting its potential therapeutic impli- cations in both oncology and degenerative diseases. Ferroptosis signaling pathwayTransferrin (Tf) with 2 iron molecules Tf Cys Glu Gln Transferrin receptor Glutamate-cystine antiporter (Xc) SLC1A5 Endosomal uptake Fe3+ Fe2+ Cys Glu GLS Gln STEAP3 GCL GSS + Gly DMT1 Ferritin storage GSH PUFA-OH GPX4 PUFA-OOH Lipid Fenton reaction Lipoxygenases P450 oxidoreductase Lipid peroxidation Ferroptosis Tf Figure 4: Ferroptosis signaling pathway. Tis schematic diagram outlines the molecular cascade of ferroptosis. Cystine uptake via the system Xc⁻ antiporter is inhibited, reduced GSH synthesis. Tis impairs GPx4, an enzyme that detoxifes lipid peroxides. Te resulting lipid peroxidation is amplifed by iron (Fe2⁺)-driven Fenton reactions, producing ROS. Tf- mediated iron uptake and its reduction via STEAP3 and DMT1 contribute to intracellular iron overload, further exacerbating ferroptosis. Abbreviations: GSH-glutathione; GPx4-glutathione peroxidase 4; ROS-reactive oxygen species; Tf-transferrin; DMT1-divalent metal transporter 1; STEAP3-six-transmembrane epithelial antigen of prostate 3. 6 Journal of Aging Research 9025, 2025, 1, D ow nloaded from https://onlinelibrary.w iley.com /doi/10.1155/jare/8832992 by U niversity of G hana - A ccra, W iley O nline L ibrary on [22/07/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense Natural antioxidants such as silymarin and α-lipoic acid may counteract ferroptosis by replenishing glutathione levels or scavenging lipid radicals. Emerging evidence suggests that ferroptosis can spread paracrine-like signals through aldehydes such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), which react with cellular mac- romolecules at sites distant from the initial damage [54]. 2.2. Oxidative Stress, Ferroptosis, and Aging. Elevated iron levels can precipitate ferroptosis by catalyzing ROS pro- duction through the Fenton reaction.Tis suggests that both increased iron uptake and excessive iron storage may contribute to ferroptotic cell death [55, 56]. Specifcally, the divalent ferrous ion (Fe2+) reacts with hydrogen peroxide (H2O2) or organic peroxides (ROOH) to generate potent radicals such as hydroxyl (HO∙) or lipid alkoxy (RO∙), which are central to the ROS burden in cells [57]. Aging is closely associated with oxidative damage to biomolecules like DNA, ribonucleic acid (RNA), and proteins [29]. Given that aging is heavily infuenced by oxidative stress, and that cells ex- perience a declining capacity to counteract this stress with time [58], it is plausible that ferroptosis plays a role in aging. Natural iron chelators like deferoxamine and polyphenols (e.g., quercetin, EGCG) may disrupt this cycle by seques- tering labile iron, thereby attenuating Fenton-driven ROS and ferroptosis [57]. Te classic profle of ferroptosis, characterized by iron- dependent lipid peroxidation that can be mitigated by iron chelators and lipid antioxidants, places ROS as a primary culprit in attacking PUFAs in cell membranes. Although several pathways have been proposed for ROS generation in this context, the precise mechanism by which iron induces ROS remains unknown [59]. Notably, some agents that boost intracellular and mitochondrial ROS do not specif- cally trigger ferroptosis but rather initiate other forms of cell death, such as necrosis or apoptosis [60, 61]. Tis raises the question of whether all lethal lipid peroxidation events should be classifed as ferroptosis or if only specifc lipid oxidation processes meet this criterion. Natural antioxidants like vitamin E and coenzyme Q10 (CoQ10), which prefer- entially neutralize lipid peroxides, have shown promise in selectively inhibiting ferroptosis while sparing other cell death pathways, highlighting their therapeutic potential in age-related disorders [62]. As such, it remains critical to identify the exact lipids and their precursors involved in ferroptosis. 2.3. Natural Compounds Targeting Ferroptosis. Natural products and medicinal plants have been used to treat various diseases including infections and cancers [63–65]. As antioxidant defenses wane with aging [7], cells become increasingly vulnerable to ferroptotic damage, accelerating tissue degeneration and diseases like neurodegeneration and cardiovascular disorders. Natural products, with pleiotropic antioxidants [66, 67], anti-infammatory and iron-chelating properties [68] ofer promise in decreasing ferroptotic damage. Reports show that key compounds (Figure 5) that mitigate ferroptosis in aging focus on Nrf2 signaling pathway (Figure 6). 2.3.1. Resveratrol: Activating Nrf2 to Restore Redox Balance. Resveratrol, a polyphenol prevalent in grapes and red wine, exerts its antioxidant efects by activating the Nrf2 pathway [69]. Tis activation leads to increased synthesis of GSH and upregulation of HO-1, which together help neutralize lipid peroxides and chelate labile iron. In aged neuronal models, resveratrol was found to reduce lipid peroxidation by ap- proximately 40% and enhanced GPx4 activity, thereby protecting cells from ferroptosis [70–73]. Additionally, there is compelling evidence that shows that resveratrol extended the lifespan of C. elegans by suppressing mitochondrial ROS and mitigating iron accumulation, underscoring its dual function as both an iron modulator and Nrf2 activator: a combination that renders it a potent inhibitor of ferrop- tosis in aging tissues [74–76]. 2.3.2. Curcumin: Chelating Iron and Boosting GPx4. Curcumin, a bioactive compound derived from turmeric, functions as both an efective iron chelator and a modulator of antioxidant defenses. Its unique β-diketone structure allows it to bind excess iron, thereby preventing the Fenton reaction and the consequent production of ROS [77]. Ad- ditionally, curcumin upregulates GPx4, the key enzyme responsible for detoxifying lipid hydroperoxides. In aged mice, curcumin supplementation led to a 30% increase in GPx4 expression and a reduction in hippocampal markers of ferroptosis, which was associated with improved cognitive performance [78]. Furthermore, a clinical trial in 2022 re- ported that elderly subjects taking curcumin exhibited a 25% decrease in serum MDA, a biomarker of lipid peroxidation, further supporting its protective role [79, 80]. Tese fndings underscore curcumin’s dual action as an iron chelator and GPx4 enhancer; highlighting its potential to combat age- related neurodegeneration. 2.3.3. EGCG: Targeting Lipid Peroxidation. EGCG, a cate- chin in green tea, exhibits potent antioxidant properties by scavenging lipid radicals and inhibiting pro-oxidant en- zymes, including NADPH oxidase [81]. Additionally, EGCG has been shown to upregulate antioxidant systems, such as superoxide dismutase, catalase, and GSH, thereby enhancing the body’s defense against oxidative stress [81]. In aged rat models, EGCG administration resulted in a signifcant re- duction of lipid peroxidation markers and preservation of mitochondrial integrity [82]. Furthermore, in rats, EGCG has demonstrated neuroprotective efects by inhibiting neuronal cell death and improving cerebral function fol- lowing traumatic brain injury [82]. Tese fndings highlight EGCG’s multifaceted role in directly inhibiting lipid per- oxidation and modulating iron-related pathways. 2.3.4. Sulforaphane: Amplifying Endogenous Antioxidants. Sulforaphane, a bioactive compound abundant in broccoli sprouts, enhances the body’s antioxidant defenses by Journal of Aging Research 7 9025, 2025, 1, D ow nloaded from https://onlinelibrary.w iley.com /doi/10.1155/jare/8832992 by U niversity of G hana - A ccra, W iley O nline L ibrary on [22/07/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense OHHO OH HO OH O O O O OH OH HO HO HO HO O O OH OH O S S NH3C HO OH HO HO O O OH OH OH HO HO O O OH OH OH O O OH OH CH2 CH2 OH OH OH HOHO O O O O O H3C OH OHO O HO OH OH O O HO HO O O OH OH H3C CH3 HO O O CH3 CH3 OH OH OH OH HO HO HO HO HO O O O OH OHO O H3C H3C CH3 CH3 CH3 CH3 CH3H3C H3C H3C H3C OH OH O CH3 CH3 CH3CH3CH3 CH3 H3C CH3 CH3 OH O H3C HO O OH OH HO HO O O O O I II III IV V VI VII VIII XI XII XIX XX XIII XIV XV XVI XVII XVIII IX X O Figure 5: Chemical structures of natural compounds modulating ferroptosis. Images generated using ChemSketch illustrate the molecular structures of 20 key natural compounds known to inhibit ferroptosis by targeting iron metabolism, lipid peroxidation, and antioxidant pathways. Te compounds are listed as follows: (I) resveratrol; (II) curcumin; (III) EGCG; (IV) sulforaphane; (V) quercetin; (VI) coenzyme Q10; (VII) lycopene; (VIII) fsetin; (IX) baicalein; (X) honokiol; (XI) silymarin; (XII) astaxanthin; (XIII) apigenin; (XIV) luteolin; (XV) gingerol; (XVI) ursolic acid; (XVII) ellagic acid; (XVIII) pterostilbene; (XIX) carnosol; and (XX) theafavins. Tese compounds exert pleiotropic efects such as activating Nrf2, enhancing GPx4, and scavenging ROS.” Abbreviations: EGCG-epigallocatechin gallate; GPx4- glutathione peroxidase 4; ROS-reactive oxygen species; Nrf2-nuclear factor erythroid 2-related factor 2. 8 Journal of Aging Research 9025, 2025, 1, D ow nloaded from https://onlinelibrary.w iley.com /doi/10.1155/jare/8832992 by U niversity of G hana - A ccra, W iley O nline L ibrary on [22/07/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense activating the Nrf2 pathway. Tis activation leads to in- creased synthesis of GSH, a crucial endogenous antioxidant, and upregulation of various cytoprotective proteins [83]. A study demonstrated that sulforaphane induces the trans- location of Nrf2 into the nucleus, increasing the expression of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting enzyme in GSH synthesis, thereby raising intracellular GSH levels [84]. Tese fndings highlight sulforaphane’s potential in enhancing antioxidant capacity, ofering protection against oxidative stress and age-related cellular decline. 2.3.5. Quercetin: Iron Sequestration and Sirtuin 1 (SIRT1) Activation. Quercetin, a favonoid abundantly found in apples and onions, not only chelates free iron to reduce its intracellular levels but also activates SIRT1, a key longevity- associated deacetylase that bolsters cellular stress resistance. In studies using senescent fbroblasts, quercetin treatment reduced intracellular iron by approximately 25% and sup- pressed ACSL4, an enzyme critical for pro-ferroptotic PUFA synthesis, through a mechanism involving SIRT1 activation [85]. Moreover, a 2022 study demonstrated that quercetin improved cardiac function in aged mice by inhibiting fer- roptosis, underscoring its dual role in both iron sequestration and the epigenetic regulation of genes that drive ferroptotic cell death [86]. Together, these fndings highlight quercetin’s promising therapeutic potential in mitigating age-related tissue dysfunction through the combined actions of iron chelation and enhanced stress resistance via SIRT1. 2.3.6. CoQ10: Preserving Mitochondrial Resilience. CoQ10 is a lipid-soluble antioxidant integral to mito- chondrial electron transport and cellular energy production. Beyond its role in adenosine triphosphate (ATP) synthesis, CoQ10 exhibits iron-chelating properties that mitigate ox- idative stress, particularly within mitochondria. In models of iron overload-induced damage, CoQ10 administration was found to alleviate oxidative injury by chelating excess iron, thereby reducing ROS production and preserving mito- chondrial integrity [87]. Additionally, CoQ10 infuences the activity of SIRT1, an NAD+ -dependent deacetylase asso- ciated with longevity and metabolic regulation. Studies in- dicate that CoQ10 defciency can compromise SIRT1 activity, suggesting that adequate CoQ10 levels are essential for optimal SIRT1 function [88]. Furthermore, a clinical trial demonstrated that supplementation with CoQ10 and Constitutive conditions Nrf2 activation Actin Ubiquitination Resveratrol Sulforaphane Gingerol Nrf2 release Nrf2 nuclear translocation Antioxidant proteins expression Nrf2 Nrf2 Nrf2 ARECytoplasm Degraded Nrf2 Ferroptosis Aging Longevity Expression of antioxidant proteins (GSH AND HO-1) BY Nrf2 • Curcumin • Silymarin Increases the expression of GPx4 Nrf2 Nrf2 Keap1 Keap1 RBX1 Cul3 sMaf Nrf2Nrf2 Nucleus Transferrin (Tf) with 2 iron molecules Tf Cys Glu Gln Transferrin receptor Glutamate-cystine antiporter (Xc) SLC1A5 Endosomal uptake Fe3+ Fe2+ Cys Glu GLS Gln STEAP3 GCL GSS + Gly DMT1 Ferritin storage GSH PUFA-OH GPX4 PUFA-OOH Lipid Fenton reaction Lipoxygenases P450 oxidoreductase Lipid peroxidation Ferroptosis Tf Stimulates Nrf2 Keap1 Keap1 Natu ral products Figure 6: Activation of Nrf2 and its role in antioxidant defense against ferroptosis. Tis schematic diagram illustrates the regulation of Nrf2 under constitutive conditions (left panel) and upon activation (middle and right panels). Under basal conditions, Nrf2 is ubiquitinated and degraded via the Keap1-Cul3-RBX1 complex. Upon activation by compounds such as resveratrol, sulforaphane, and gingerol, Nrf2 is released from Keap1, translocates to the nucleus, and binds to ARE, leading to the expression of antioxidant proteins. Te right panel highlights the role of Nrf2 in regulating GSH and HO-1, which protect against lipid peroxidation and ferroptosis. Additionally, curcumin and silymarin enhance GPx4 expression, a key enzyme mitigating lipid peroxidation. Abbreviations: Nrf2-nuclear factor erythroid 2-related factor 2; Keap1-Kelch-like ECH-associated protein 1; ARE-antioxidant response element; GSH-glutathione; HO-1-heme oxygenase-1; GPx4-glutathione peroxidase 4. Journal of Aging Research 9 9025, 2025, 1, D ow nloaded from https://onlinelibrary.w iley.com /doi/10.1155/jare/8832992 by U niversity of G hana - A ccra, W iley O nline L ibrary on [22/07/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense Ta bl e 1: M ec ha ni sm s of na tu ra lc om po un ds in in hi bi tin g fe rr op to sis . C om po un d So ur ce M ec ha ni sm of ac tio n in fe rr op to si s Im pa ct on ag in g R ef er en ce Re sv er at ro l G ra pe s, re d w in e A ct iv at es N rf 2 pa th w ay ,u pr eg ul at es G Px 4 an d H O -1 ;c he la te s la bi le ir on . Re du ce s lip id pe ro xi da tio n by 40 % in ne ur on s; ex te nd s lif es pa n in C. el eg an s. [6 9] C ur cu m in Tu rm er ic Bi nd s ir on vi a β- di ke to ne gr ou ps , in hi bi ts fe nt on re ac tio ns ;e nh an ce s G Px 4 ex pr es sio n. 30 % in cr ea se in G Px 4 le ve ls; re du ce s se ru m M D A by 25 % in el de rly su bj ec ts . [7 8] Ep ig al lo ca te ch in ga lla te (E G C G ) G re en te a Sc av en ge s lip id ra di ca ls; in hi bi ts 15 -L O X ,b lo ck in g PU FA ox id at io n; do w nr eg ul at es Tf R1 to lim it ir on up ta ke . Lo w er s 4- H N E by 35 % in ag ed br ai ns ; pr es er ve s m ito ch on dr ia li nt eg ri ty . [9 0, 91 ] Su lfo ra ph an e Br oc co li sp ro ut s A ct iv at es N rf 2, bo os tin g G SH sy nt he sis an d fe rr op to sis su pp re ss in g pr ot ei n 1 (F SP 1) ex pr es sio n (G Px 4- in de pe nd en t fe rr op to sis su pp re ss io n) . 50 % in cr ea se in he pa tic FS P1 ;2 0% ri se in pl as m a G SH in el de rly co ho rt s. [8 3] Q ue rc et in A pp le s, on io ns C he la te s fr ee ir on ;a ct iv at es SI RT 1 to do w nr eg ul at e A C SL 4 (p ro -f er ro pt ot ic en zy m e) . 25 % re du ct io n in in tr ac el lu la r ir on ; im M D A pr ov es ca rd ia c fu nc tio n in ag ed m ic e. [9 2, 93 ] C oe nz ym e Q 10 D ie ta ry su pp le m en ts N eu tr al iz es lip id pe ro xi de s in m em br an es ;s us ta in s m ito ch on dr ia l el ec tr on tr an sp or tt o re du ce RO S. 20 % re du ct io n in pl as m a M D A ; im pr ov es m ito ch on dr ia lm em br an e po te nt ia li n el de rly su bj ec ts . [9 4, 95 ] Ly co pe ne To m at oe s Sc av en ge s RO S; pr ot ec ts m em br an es fr om lip id pe ro xi da tio n. 30 % re du ct io n in ox id at iv e da m ag e m ar ke rs in el de rly su bj ec ts . [9 6, 97 ] Fi se tin St ra w be rr ie s, ap pl es Re du ce s in tr ac el lu la r RO S; en ha nc es an tio xi da nt de fe ns es . 25 % de cr ea se in RO S; de la ys ce llu la r se ne sc en ce in ag in g m od el s. [9 8– 10 0] Ba ic al ei n Sc ut el la ria ba ic al en sis In hi bi ts lip id pe ro xi da tio n; m iti ga te s ir on -in du ce d ox id at iv e st re ss . Im pr ov es ne ur on al su rv iv al ;r ed uc es fe rr op to sis m ar ke rs in ox id at iv e st re ss m od el s. [1 00 –1 03 ] H on ok io l M ag no lia ba rk Su pp re ss es ir on -in du ce d RO S; in hi bi ts lip id pe ro xi da tio n. 30 % re du ct io n in RO S ge ne ra tio n; pr ot ec ts ag ai ns ta ge -a ss oc ia te d ne ur al da m ag e. [1 04 –1 06 ] Si ly m ar in M ilk th ist le En ha nc es G Px 4 ac tiv ity ;s ca ve ng es lip id pe ro xi de s vi a fa vo no lig na ns . Re du ce s liv er fe rr op to sis by 35 % in ag ed ro de nt s; im pr ov es he pa tic fu nc tio n. [1 07 ] A st ax an th in M ic ro al ga e, se af oo d N eu tr al iz es sin gl et ox yg en an d lip id ra di ca ls; st ab ili ze s m ito ch on dr ia l m em br an es . 30 % lo w er RO S in ag ed sk el et al m us cl e; de la ys sa rc op en ia . [1 08 –1 10 ] A pi ge ni n Pa rs le y, ch am om ile C he la te s ir on ;a ct iv at es SI RT 3 to en ha nc e m ito ch on dr ia la nt io xi da nt de fe ns es . Re du ce sn eu ro na lf er ro pt os is by 25 % in A lz he im er ’s m od el s. [1 11 –1 13 ] Lu te ol in C el er y, br oc co li In hi bi ts N O X 4- m ed ia te d RO S pr od uc tio n; up re gu la te s FS P1 . Pr ot ec ts ag ed en do th el ia lc el ls; re du ce s va sc ul ar in fa m m at io n. [1 14 –1 16 ] G in ge ro l G in ge r M od ul at es N rf 2/ A RE pa th w ay ; su pp re ss es A C SL 4- dr iv en PU FA in co rp or at io n. 20 % re du ct io n in ca rd ia c fe rr op to sis m ar ke rs in ag ed ra ts . [1 17 –1 19 ] 10 Journal of Aging Research 9025, 2025, 1, D ow nloaded from https://onlinelibrary.w iley.com /doi/10.1155/jare/8832992 by U niversity of G hana - A ccra, W iley O nline L ibrary on [22/07/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense Ta bl e 1: C on tin ue d. C om po un d So ur ce M ec ha ni sm of ac tio n in fe rr op to si s Im pa ct on ag in g R ef er en ce U rs ol ic ac id A pp le pe el s, ro se m ar y A ct iv at es A M PK to in hi bi tm TO R an d re du ce ir on ab so rp tio n; en ha nc es au to ph ag y. Im pr ov es m us cl e he al th in ag ed m ic e; re du ce s m ito ch on dr ia lR O S. [1 20 ,1 21 ] El la gi c ac id Po m eg ra na te ,b er ri es C he la te s ir on ;i nh ib its lip id pe ro xi da tio n vi a di re ct ra di ca l sc av en gi ng . 25 % lo w er liv er ir on co nt en ti n ag ed m ic e; re du ce s he pa tic fb ro sis . [1 22 –1 24 ] Pt er os til be ne Bl ue be rr ie s A ct iv at es SI RT 1 to de ac et yl at e an d st ab ili ze G Px 4; m im ic s ca lo ri c re st ri ct io n. Ex te nd s lif es pa n in dr os op hi la ;r ed uc es br ai n lip id pe ro xi da tio n. [1 25 –1 27 ] C ar no so l Ro se m ar y In hi bi ts 5- LO X an d C O X -2 ;r ed uc es ar ac hi do ni c ac id pe ro xi da tio n. 30 % re du ct io n in in fa m m at or y m ar ke rs in ag ed jo in ts . [1 28 –1 30 ] T ea fa vi ns Bl ac k te a C he la te s ir on ;i nh ib its xa nt hi ne ox id as e- dr iv en RO S pr od uc tio n. Pr ot ec ts ag ed ki dn ey s fr om fe rr op to sis ; re du ce s se ru m cr ea tin in e by 20 % . [1 31 ,1 32 ] N ot e: K ey ta rg et s in cl ud e ir on ch el at io n, N rf 2/ G Px 4 ac tiv at io n, an d lip id pe ro xi da tio n bl oc ka de .M ec ha ni st ic di ve rs ity :c om po un ds ta rg et ir on m et ab ol ism (e .g ., qu er ce tin ,e lla gi c ac id ), lip id pe ro xi da tio n (e .g ., EG C G ,a st ax an th in ), an d an tio xi da nt de fe ns e (e .g ., su lfo ra ph an e, re sv er at ro l). C lin ic al re le va nc e: cu rc um in ,C oQ 10 ,a nd ly co pe ne ha ve hu m an tr ia ld at a; ot he rs ar e su pp or te d by pr ec lin ic al m od el s. Sy ne rg y po te nt ia l: pa ir in g ir on ch el at or s (e .g ., qu er ce tin ) w ith N rf 2 ac tiv at or s (e .g ., su lfo ra ph an e) m ay en ha nc e ef ca cy .B io av ai la bi lit y ch al le ng es :S om e co m po un ds (e .g ., cu rc um in ,r es ve ra tr ol ) re qu ir e fo rm ul at io n im pr ov em en ts fo r op tim al de liv er y. Journal of Aging Research 11 9025, 2025, 1, D ow nloaded from https://onlinelibrary.w iley.com /doi/10.1155/jare/8832992 by U niversity of G hana - A ccra, W iley O nline L ibrary on [22/07/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense selenium led to increased SIRT1 concentrations in elderly subjects, highlighting its potential in modulating pathways linked to aging and cellular stress responses [89]. Collec- tively, these fndings underscore CoQ10’s multifaceted role in preserving mitochondrial resilience through iron chela- tion and SIRT1 activation. 2.4. Natural Products and Potential Antiaging Properties. Natural compounds such as resveratrol, sulforaphane, curcumin, quercetin, EGCG, and CoQ10 have demonstrated the ability to modulate ferroptosis pathways (Table 1), of- fering potential therapeutic avenues for mitigating aging- related cellular damage. Tese compounds target critical aspects of ferroptosis, including iron metabolism, lipid peroxidation, and antioxidant defense mechanisms. For instance, resveratrol and sulforaphane enhance the Nrf2- GPx4 signaling pathway, counteracting age-associated GSH depletion [133]. Curcumin and quercetin exhibit iron- chelating properties, thereby reducing Fenton chemistry- induced oxidative stress. EGCG and CoQ10 stabilize cellular membranes against lipid peroxidation, preserving mito- chondrial integrity. Combining resveratrol with quercetin may synergistically enhance their efcacy. Ongoing clinical trials, like the SPRINTT project, are investigating multi- component interventions, including physical activity and nutritional counseling, to prevent mobility disability in frail older adults [134]. Tese studies aim to validate the thera- peutic potential of such natural compounds in aging populations. 3. Discussion Te inexorable progression of aging occurs as a result of molecular and cellular dysregulation, among which fer- roptosis has emerged as playing a role in redox imbalance, chronic infammation, and tissue degeneration [4]. Fer- roptosis has been found as both a consequence and accel- erator of aging, partly explaining the cumulative cellular damage of age-related pathologies. Here, we contextualize these fndings within aging biology and highlight the therapeutic potential of natural compounds in modulating ferroptotic pathways. Aging is marked by the progressive erosion of homeo- static systems, including redox regulation, proteostasis, and nutrient sensing. Central to this decline is the dysregulation of iron metabolism, which creates a permissive environment for ferroptosis. Elevated intracellular iron, a hallmark of aging, catalyzes the Fenton reaction, generating hydroxyl radicals that propagate lipid peroxidation inmembranes rich in PUFAs [135, 136]. Te age-associated decline in GSH and GPx4, critical guardians against lipid peroxide accumula- tion, renders cells vulnerable to ferroptotic death [137]. Tis vulnerability is exacerbated by chronic infammation (“infamm-aging”), which does not only deplete antioxidant reserves but also upregulates hepcidin, trapping iron within cells and further fueling oxidative damage [138, 139]. Our review aligns with recent studies implicating ferroptosis in neurodegenerative diseases [140], cardiovascular dysfunction [141], and sarcopenia [135], suggesting its broad role in age-related morbidity. Compounds from natural products, with their pleio- tropic mechanisms, represent a promising strategy to dis- rupt ferroptosis and its contribution to aging (Table 1). For instance: • Resveratrol activates the Nrf2 pathway, upregulating GPx4 and HO-1 to neutralize lipid peroxides and chelate labile iron [9]. In preclinical models, resver- atrol reduced hippocampal lipid peroxidation by 40%, which led to improved cognitive function in aged mice [69]. • Curcumin directly binds iron via its β-diketone structure, inhibiting Fenton chemistry, while en- hancing GPx4 expression [78]. A 2022 clinical trial demonstrated a 25% reduction in serum MDA in el- derly subjects supplemented with curcumin [146]. • EGCG is known to scavenge lipid radicals and inhibit 15-lipoxygenase (15-LOX), blocking PUFA oxidation [90, 91]. In aged rat brains, EGCG lowered 4-HNE by 35%, preserving mitochondrial integrity [90, 91]. Tese compounds exemplify a multitarget approach, addressing iron homeostasis, antioxidant defense, and in- fammatory signaling simultaneously. Such synergy is crit- ical in aging, where single-target therapies often fail to address the multifactorial nature of decline. While pre- clinical data are compelling, clinical validation remains limited. For example, sulforaphane, an Nrf2 activator, has been shown to increase Nrf2 transcription, activation, nu- clear translocation, DNA-binding, and antioxidant gene expression in epithelial cells isolated from elderly humans [147]. Similarly, CoQ10 supplementation has been observed to reduce lipid peroxidation levels in humans [148]. A key challenge lies in the paradoxical iron dynamics of aging: systemic iron defciency (e.g., anemia) coexisting with in- tracellular iron overload, complicating therapeutic iron modulation. Natural chelators like quercetin may ofer a balanced approach, but their interaction with dietary iron absorption needs rigorous evaluation. Tis review comprehensively synthesizes the burgeoning evidence linking ferroptosis, an iron-dependent form of regulated cell death, with the multifaceted process of aging. Our review highlights that ferroptosis is not merely a con- sequence of aging but an active contributor to age-related pathologies, intricately interwoven with established hall- marks such as oxidative stress, mitochondrial dysfunction, chronic infammation, and dysregulated iron metabolism. We have explored how age-associated declines in antioxi- dant defenses, particularly glutathione and GPx4, alongside paradoxical iron dynamics, create a fertile ground for fer- roptosis activation. Further delving into the mechanisms, the dysregulation of iron homeostasis during aging, characterized by systemic iron defciency alongside intracellular iron accumulation, signifcantly contributes to the Fenton reaction-driven production of ROS and subsequent lipid peroxidation. Tis interplay underscores ferroptosis as a critical 12 Journal of Aging Research 9025, 2025, 1, D ow nloaded from https://onlinelibrary.w iley.com /doi/10.1155/jare/8832992 by U niversity of G hana - A ccra, W iley O nline L ibrary on [22/07/2025]. See the T erm s and C onditions (https://onlinelibrary.w iley.com /term s-and-conditions) on W iley O nline L ibrary for rules of use; O A articles are governed by the applicable C reative C om m ons L icense therapeutic target. Te natural products reviewed here- in—such as resveratrol, curcumin, and EGCG—demon- strate remarkable pleiotropic mechanisms of action. Tey not only chelate excess iron and scavenge ROS but also upregulate endogenous antioxidant systems like Nrf2- mediated pathways, thereby directly interfering with key ferroptotic drivers. Te therapeutic potential of modulating ferroptosis in aging extends beyond single pathway inhibition. Our fndings suggest that strategies focusing on combinatorial regimens, perhaps pairing Nrf2 activation with iron chela- tion or lipid peroxidation inhibitors, could ofer synergistic benefts in mitigating age-related tissue damage. Future research should prioritize deciphering the precise molecular targets and signaling pathways of these natural compounds within specifc aging tissues and validating their efcacy through robust clinical trials with clear biomarkers of fer- roptosis inhibition. Ultimately, the precise targeting of ferroptosis pathways through natural interventions holds signifcant promise as a novel strategy to promote healthy aging and prevent age-related diseases. 4. Conclusion Ferroptosis ofers a unifying mechanism for oxidative stress, infammation, and metabolic dysfunction in aging. Natural products, with their ability to target multiple nodes of ferroptosis, present a compelling alternative to mitigate age- related decline. While there are few studies that have shown the therapeutic potential of natural products in mitigating ferroptosis, and hence, age-related pathologies, integration of these compounds into therapeutic regimens could re- defne aging interventions, shifting the paradigm from disease treatment to proactive antiaging efects. 4.1. Strengths and Limitations. Tis review provides a com- prehensive and timely synthesis of the emerging un- derstanding of ferroptosis in the context of aging and explores the therapeutic potential of natural products. Key strengths include: • A thorough literature survey integrating ferroptosis with established hallmarks of aging. • Detailed summarization of current animal studies and clinical trials related to natural products and ferrop- tosis in aging (as presented in tables). • Identifcation and elucidation of the mechanisms of action for various natural products in modulating ferroptosis. • Highlighting the potential for novel nutraceutical lead compounds or health supplements for the aging population. Despite these strengths, certain limitations in the current understanding and research warrant consideration: • Challenges persist in optimizing the bioavailability and delivery of many natural products, which can impact their efcacy in modulating ferroptosis in vivo. • Further research is needed to address tissue-specifc iron dysregulation associated with aging and the use of these natural products, as iron metabolism can vary signifcantly across diferent organs. • While preclinical data is promising, more robust and larger-scale human clinical trials are required to de- fnitively establish the therapeutic efcacy and safety of these natural compounds for ferroptosis inhibition in aging populations. • Te precise molecular targets and comprehensive signaling pathways by which all natural products exert their anti-ferroptotic efects are still being elucidated, necessitating further mechanistic studies. Data Availability Statement Te data that support the fndings of this study are available from the corresponding authors upon reasonable request. Ethics Statement Te authors have nothing to report. Conflicts of Interest Te authors declare no conficts of interest. Author Contributions Sherif Hamidu� conceptualization; writing – original draft; writing – review and editing. Seth Kwabena Amponsah�writing – original draft; writing – review and editing; supervision. Abigail Aning�writing – original draft. Latif Adams�writing – original draft. Justice Kumi�writing – original draft. Eunice Ampem-Danso�writing – original draft. Fatima Hamidu�writing – original draft. Mustapha Abdul Mumin Mohammed�writing – original draft. Gabriel Tettey Ador�writing – original draft. Sanjida Khatun�writing – original draft. Funding No funding was received for this manuscript. References [1] C. Caruso, G. Accardi, M. Emanuela Ligotti, S. Vasto, and G. 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