Metal ions in aging and ocular diseases: biology, pathophysiology, and therapeutic strategies

Abstract

Metal ions are indispensable for sustaining normal cellular functions and preserving tissue integrity, as they participate in enzymatic catalysis, signal transduction, and antioxidant defense. However, dysregulation of metal ion homeostasis, particularly during aging, disrupts cellular balance and significantly drives the development and progression of age-related ocular diseases, including age-related macular degeneration, glaucoma, diabetic retinopathy, and cataracts. Specifically, metal ions modulate key stress responses that are central to aging and ocular pathogenesis. Excessive accumulation of redox-active metals triggers the generation of reactive oxygen species that induce oxidative damage to lipids, proteins, and DNA. Meanwhile, deficiencies in essential metals, such as iron, zinc, copper, and calcium, impair antioxidant enzyme activity and disrupt DNA repair, exacerbating cellular dysfunction and senescence. The therapeutic potential of these metal chelators and antioxidants in restoring their balance, alleviating oxidative stress, and slowing the progression of age-related ocular diseases has been well documented. A deeper understanding of how metal ions influence these processes is crucial for developing more targeted and effective treatments. This article systematically reviews the roles of metal ions in age-related ocular diseases, with a focus on their effects on stress responses and potential therapeutic strategies.

Introduction

Metal ions play an indispensable role in various biological processes within living organisms. As essential cofactors for numerous enzymes and metalloproteins, metal ions modulate cellular structure and function by mediating electron transfer, enzymatic catalysis, and intracellular signal transduction¹. For example, zinc serves not only as a critical cofactor for a broad range of enzymes but also acts as a key regulator of gene transcription via interactions with zinc-finger proteins under the control of SLC30 (ZnT) for the excretion of zinc and SLC39 (ZIP) for the zinc intake². Copper, as an important redox metal, is involved in cellular energy metabolism, particularly in mitochondria, where copper ions are integral components of the electron transport chain responsible for cellular energy production³. Additionally, the homeostasis of metals like iron and zinc is critical for cellular antioxidant defense, immune responses, and DNA repair⁴. This diverse and mechanistically distinct involvement of metal ions across cellular processes emphasizes their essential functional roles, not just in normal physiological function, but also in maintaining cellular integrity under stress conditions.

Aging is a complex biological process characterized by the progressive decline in cellular, tissue, and organ functions⁵. As individuals age, the body faces an increasing number of biological stresses, particularly oxidative stress and chronic inflammation⁵. Oxidative stress is a key factor in aging, as mitochondrial dysfunction leads to increased reactive oxygen species (ROS) production, which subsequently damages lipids, proteins, and DNA⁶. During aging, the body’s antioxidant capacity gradually declines, leading to the accumulation of free radicals and triggering a series of pathological changes⁷. Chronic low-grade inflammation (inflammaging) is another prominent feature of aging, affecting systemic immune responses and potentially impairing the function of various tissues, especially in the context of age-related ocular diseases, such as age-related macular degeneration (AMD) and glaucoma^8–10.

Metal ions contribute to aging-associated stress responses through two mechanistically distinct routes. On the one hand, excess redox-active metals, particularly the excessive accumulation of iron and copper, exacerbate oxidative stress, leading to cellular damage and the development of aging-related phenotypes¹¹. On the other hand, metal ions hold critical functional relevance in the nervous system, especially during aging and in the pathogenesis of ocular diseases. The retina is highly dependent on precise metal ion homeostasis, most notably iron, copper, and zinc, which are crucial for the antioxidant defense of retinal pigment epithelial (RPE) cells and light protection in the retina^12–14. Disruption of metal ion homeostasis can lead to oxidative damage in the retina and other ocular tissues, which is closely associated with the progression of various age-related ocular diseases¹³.

Therefore, there is a complex interplay between metal ions, aging, and ocular diseases. Understanding how metal ions influence oxidative stress and inflammation during aging and their impact on the onset and progression of ocular diseases will provide important insights for developing new therapeutic strategies (Fig. 1).

Fig. 1. The interplay between essential metal ion dyshomeostasis and age-related ocular diseases.

It illustrates how dyshomeostasis of metal ions (Fe, Zn, Cu, Ca) during aging contributes to four major age-related ocular pathologies, including AMD, glaucoma, DR, and cataracts. Therapeutic strategies aim to restore metal ion balance through the use of metal chelators and supplements, while alleviating oxidative stress through antioxidant methods, thereby maintaining homeostasis and preventing the progression of age-related ocular diseases. AMD age-related macular degeneration, DR diabetic retinopathy.

Biological functions of metal ions

As indispensable enzymatic and regulatory cofactors, metal ions serve core functional and mechanistic roles in a wide range of physiological and biochemical processes essential for cellular function and overall organismal health. Key metal ions such as iron, copper, zinc, and calcium are central to maintaining cellular integrity, regulating enzymatic activity, and supporting metabolic pathways. These metal ions work in tandem to orchestrate fundamental cellular processes that ensure the proper functioning of cells and tissues across all biological systems¹⁵.

Functional roles and action mechanisms of metal ions

Metal ions are integral to a variety of essential biochemical processes that regulate cellular functions. Based on their biological functions, metal ions exert three fundamental types of roles: structural, catalytic, and regulatory. Structurally, metal ions stabilize the three-dimensional folding of proteins and nucleic acids. As core components of metal-binding motifs, they maintain protein conformation and support specific interactions with DNA or other biomolecules. A typical example is zinc, which binds to cysteine and histidine residues in zinc-finger motifs to stabilize the compact structure of transcription factors, enabling them to recognize and bind to DNA, thereby regulating gene expression^2,16. Similarly, calcium ions can bind to calcium-binding proteins, inducing conformational changes that allow these proteins to interact with target enzymes and regulate their activity^17,18. Catalytically, metal ions act as essential cofactors at enzyme active sites: they mediate electron transfer, polarize substrates, stabilize reaction transition states, and facilitate bond cleavage or formation. For instance, iron is a key component of heme groups in catalase and cytochrome c oxidase. Catalase uses iron to decompose hydrogen peroxide into water and oxygen, while cytochrome c oxidase relies on iron to facilitate electron transfer in the mitochondrial respiratory chain¹⁹. Magnesium, as a common cofactor for ATP-dependent enzymes, stabilizes ATP molecules and participates in the catalytic cycle of enzymes such as DNA polymerases and kinases²⁰. Functionally, metal ions serve as regulatory signals and binding targets, modulating enzyme activity, gene expression, and intracellular signaling cascades²¹. Zinc ions can modulate the activity of enzymes involved in cell proliferation and apoptosis, as well as regulate the expression of zinc transporters through the unfolded protein response, thereby maintaining cellular zinc homeostasis²². Copper ions, although required in trace amounts, can regulate oxidative defense pathways by modulating the activity of copper-containing superoxide dismutase²³.

The specific mechanisms by which metal ions exert their structural, catalytic, and regulatory roles are closely related to their binding modes with biomolecules. At the catalytic site of enzymes, they form coordination complexes with amino acid residues and substrates, mediating the catalytic reaction process²⁴. As cofactors, metal ions can be tightly bound to metalloenzymes, such as copper in superoxide dismutase, and iron in hemoglobin. Or loosely bound to metal-activated enzymes, such as magnesium in DNA polymerases. As binding targets, they interact with specific metal-binding proteins to trigger conformational changes and functional activation. These binding modes are determined by the chemical properties of metal ions and the structural characteristics of biomolecules, ensuring the specificity and efficiency of metal ion function¹⁵.

Roles of metal ions in enzymatic catalysis, cellular signaling, and oxidative defense

With these structural, catalytic, and regulatory foundations, the precise balance of metal ions is vital for maintaining cellular integrity, with disruptions often leading to disease⁴. As central mediators of enzymatic catalysis, metal ions, including iron and magnesium, are functionally indispensable. Beyond systemic oxygen transport, iron is the core component of Iron-Sulfur clusters and heme-containing cytochromes. In the context of aging, the degradation of these clusters disrupts the electron transport chain (ETC), particularly at Complex I, leading to electron leakage and subsequent mitochondrial bioenergetic failure^25,26. Magnesium, on the other hand, stabilizes ATP and supports a variety of ATP-dependent reactions, including DNA replication, protein synthesis, and cellular signaling²⁰. Similarly, zinc is pivotal not only for the structural integrity of proteins, particularly through zinc-finger motifs, but also for its role in regulating gene expression, cell signaling, and immune responses¹⁶. Zinc’s influence has extended to DNA transcription and repair, where it ensures proper cellular function and genomic stability. Moreover, its involvement in cell signaling is particularly crucial, as it modulates the activity of enzymes involved in cell proliferation and apoptosis^2,27. Copper, although required in smaller amounts, plays essential roles in both energy production and antioxidant defense. It is a key component of enzymes such as cytochrome c oxidase in the mitochondria, which is involved in oxidative phosphorylation²⁸. In addition, copper is crucial for the formation of connective tissues, where it aids in the cross-linking of collagen and elastin²⁹. Beyond structural roles, copper is also central to antioxidant defense, with copper-containing superoxide dismutase neutralizing harmful superoxide radicals and protecting cells from oxidative stress²³. Besides, the importance of calcium cannot be overstated, as it acts as a universal second messenger in intracellular signaling pathways¹⁷. Calcium regulates a wide array of cellular activities, including neurotransmitter release, muscle contraction, and cell division^30,31. Its ability to trigger specific signaling cascades makes it a critical mediator in the dynamic regulation of cellular processes¹⁸. Furthermore, the role of calcium in maintaining the function of ion channels and pumps ensures proper cellular homeostasis and ion balance³².

These metal ions are also integral to cellular defense systems, particularly in combating oxidative stress. Superoxide dismutase (SOD), which relies on zinc and copper at its active site, catalyzes the dismutation of superoxide radicals, converting them into less harmful molecules³³. Similarly, catalase, which uses iron, decomposes hydrogen peroxide into water and oxygen, mitigating the potential damage caused by ROS¹⁹. Metallothioneins, proteins that bind zinc and copper, further protect cells by sequestering metal ions, preventing oxidative damage, and maintaining metal homeostasis³⁴.

Regulation of metal ion uptake, release, storage, and redistribution

The maintenance of metal ion homeostasis relies on sophisticated regulatory networks governing their uptake, release, storage, and intracellular/inter-organ redistribution, which are dynamically modulated across different life stages. These regulatory mechanisms ensure that metal availability aligns with cellular and systemic demands while preventing toxic accumulation, and their dysfunction directly contributes to aging-related pathologies.

For iron, uptake is tightly controlled at the intestinal epithelium: dietary non-heme iron (Fe³⁺) is reduced by DCYTB and transported via DMT1, with the proton gradient from NHE3 facilitating this process, while heme iron is absorbed through HCP1 or HRG-1 and released as Fe²⁺ ³⁵. Systemically, iron binds to transferrin (Tf) and is taken up by cells through Tf receptor 1 (TfR1)-mediated endocytosis³⁶. Iron release from cells is exclusively mediated by ferroportin, enhanced by ferroxidases hephaestin and ceruloplasmin, with hepcidin acting as the central regulator by inducing ferroportin ubiquitination and degradation^37,38. And its storage occurs primarily in ferritin, with poly(rC) binding proteins facilitating iron delivery, and NCOA4-mediated ferritinophagy releasing stored iron under deficiency^39,40. Intracellular and inter-organ redistribution is coordinated by hepatocytes (main storage organ)⁴¹, macrophages (iron recycling)⁴², and placental transfer (via TfR1, STEAP3/4 ferrireductases, and ferroportin)⁴³.

Moreover, copper uptake is mediated by CTR1, with intracellular delivery by chaperones (ATOX1, CCS, COX17) targeting specific enzymes^44,45. Intestinal copper export to the circulation is via ATP7A⁴⁶, while hepatocytes use ATP7B for biliary excretion⁴⁷. Its release from cells is linked to ATP7A/ATP7B translocation, regulated by copper concentration and post-translational modifications, with circulating copper primarily bound to CP^48,49. As there is no dedicated storage organ, copper storage is limited to metallothioneins (MTs), and redistribution involves liver-hepatocyte interactions and blood-brain barrier transport via CTR1 and ATP7A^50,51. Besides, zinc uptake is mediated by SLC39 (ZIP) transporters (e.g., ZIP4 for intestinal absorption, ZIP14 for hepatocytes/immune cells), while release is controlled by SLC30 (ZnT) transporters⁵². And its storage mainly occurs in MTs and vesicular compartments, with the pancreas, liver, and skeletal muscle acting as systemic reservoirs². As for redistribution, it is dynamic: ZIP transporters are upregulated, and ZnT downregulated during deficiency, with the liver regulating systemic levels by releasing stored zinc bound to albumin or α2-macroglobulin⁵³. In terms of calcium, its uptake occurs through voltage-gated calcium channels, store-operated calcium entry channels, and transient receptor potential channels (e.g., TRPV6 for intestinal absorption, enhanced by vitamin D and calbindin-D9k/28k)^54–56. Release from intracellular stores (ER, mitochondria) is mediated by ITPR1-3 and RyRs, with mitochondrial uptake via the MCU complex^57,58. Storage is primarily in the ER via SERCA pumps⁵⁹. Inter-organ redistribution is coordinated by the “calcium triad” (skeleton, kidneys, intestines), with bones as the major reservoir, kidneys reabsorbing via TRPV5 and calbindin-D28k, and intestines adjusting absorption based on demand^60,61.

Notably, metal-regulatory networks are interconnected, such as copper modulates iron metabolism via CP-mediated ferroxidation⁶², zinc influences copper/calcium transporters⁶³, and calcium signaling regulates iron/zinc trafficking⁶⁴. Aging-induced disruption of this cross-talk amplifies metal dyshomeostasis, driving oxidative stress, cellular senescence, and age-related diseases^65,66. Understanding coordinated metal regulation provides a framework for targeting these pathways to mitigate aging and its related pathologies.

Metal ion dysregulation-induced stress responses

Dysregulation of metal ions disrupts cellular function and triggers a range of stress responses, which play a critical role in the development of various diseases. Excessive accumulation of redox-active metals, such as iron and copper, leads to the production of ROS through Fenton reactions, resulting in oxidative damage to cellular macromolecules, including DNA, proteins, and lipids, all of which accelerate cellular aging^67,68. In contrast, metal ion deficiencies impair antioxidant defenses, reducing the cell’s ability to neutralize ROS and exacerbating oxidative stress⁴. While zinc does not directly generate ROS, it indirectly supports cellular defense by aiding DNA repair and modulating immune responses². Disruptions in metal ion homeostasis, whether through excess or deficiency, contribute to oxidative stress, a hallmark of numerous diseases, including neurodegenerative disorders, cardiovascular diseases, and cancer^4,69,70. When metal ion homeostasis is disrupted, cells undergo a cascade of stress responses, including oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction, each of which is mechanistically linked to metal ion misbalance^71,72. These stress responses further induce DNA damage, impaired protein folding, and disrupted metabolic homeostasis, all of which directly accelerate disease progression and cellular senescence by perturbing normal cellular functions⁷³. In conclusion, metal ion dyshomeostasis is a pivotal pathogenic factor driving the initiation and progression of stress-related pathological processes.

Metal ion homeostasis and diseases

Maintaining metal ion homeostasis is crucial for normal cellular function, and disruptions in this balance are implicated in a wide range of diseases. In the Golgi lumen, metal ions such as Ca²⁺, Mn²⁺, Zn²⁺, and Cu²⁺ act as essential cofactors for enzymes, with their functions dependent on tightly regulated metal concentrations⁷⁴. The regulation of metal Ion homeostasis is controlled by ATPase pumps, ion channels, and metal-binding proteins⁷⁴. In contrast, mutations in these regulatory pathways would impair ion transport, leading to pathological conditions. For example, both zinc deficiency and overload could induce ER stress and trigger the unfolded protein response (UPR), activating transcription factors like ATF4, ATF6, and XBP1, thereby altering the expression of zinc transporters (ZnT and ZIP)^22,75,76. Therefore, dysregulation of zinc homeostasis has been associated with several diseases such as cancer, diabetes, Alzheimer’s disease, and other aging-related conditions. Moreover, copper dysregulation is also a key factor in diseases. Mutations in copper transporters are well-recognized in Wilson disease and Menkes disease, where defects in ATP7A phosphorylation impair copper trafficking⁷⁷. Additionally, aberrant copper homeostasis contributes to Alzheimer’s and Parkinson’s diseases, tumor progression, and angiogenesis^78–80.

Together, these findings emphasize the vital role of metal ion homeostasis in cellular physiology and highlight its disruption as a common pathogenic mechanism in various diseases. Metal ions are not only crucial for individual biochemical reactions but also regulate the overall cellular environment, influencing energy production, gene expression, and defense against oxidative stress. Therefore, precise regulation of metal ions is essential for maintaining cellular health and preventing disease progression.

Metal ions in the aging process

Aging is a multifactorial process marked by the gradual deterioration of cellular functions and homeostasis. One of the central features of aging is the accumulation of cellular damage due to oxidative stress, inflammation, and metabolic dysfunction^81–83. Metal ions, essential for numerous physiological functions, play a crucial role in modulating these aging processes. Dysregulation of metal ion homeostasis has been identified as a significant contributor to the onset and progression of aging-related phenotypes and age-associated diseases⁸⁴.

Aging characteristics: from cellular senescence to SASP

Aging is a natural and inevitable physiological process, mainly accompanied by a decline in physical strength and cognitive ability, significantly increasing the incidence and mortality of human diseases and aggravating the economic burden on society⁸⁵. The main hallmarks of aging include DNA damage, telomere deficiency, epigenetic alterations, cellular homeostasis disruption, senescence, mitochondrial dysfunction, disruption of stem cell capacity, nutritional disorders, and chronic inflammation⁸⁶.

Cellular senescence, a state of irreversible cell cycle arrest, is a hallmark of aging. The accumulation of cellular senescence predominantly contributed to aging. The common morphological alterations of senescent cells are composed of enlarged cell size with irregular shape, depolarization of the plasma membrane, increased lysosomal content, accumulation of mitochondria, and nuclear deformations⁸⁷. Senescent cells accelerate the release of pro-inflammatory cytokines (such as IL-1β, IL-6, and IL-8), chemokines (such as CCL2, CCL5, and CXCL1), growth factors (such as TGFβ, GDF15, and HGF), and this suite of factors is referred to as the senescence-associated secretory phenotype (SASP)⁸⁸. While SASP cytokines may vary across cell types, their production largely depends on stress-induced NF-κB and MAPK signaling pathways⁸⁹, and is mediated by mTOR-dependent protein translation^90,91.

Compared to these largely natural senescence processes, senescent cells generated by chronic or therapeutically induced stimuli pose greater harm. Chronic senescence arises from prolonged, gradual accumulation of macromolecular damage triggered by various stressors, including protein misfolding and aggregation, dysfunction of the nuclear lamina, epigenetic changes, and multiple types of DNA damage, such as telomere shortening⁹². This persistent damage can lead to more severe consequences over time. Similarly, chronically senescent cells may develop a more disruptive and “evolved” SASP, a set of inflammatory signals and molecules, compared to those seen in acute, short-term senescence, potentially amplifying tissue inflammation and accelerating age-related diseases⁹³. Therefore, understanding the transition from physiological cellular senescence to the amplified inflammatory SASP in chronic contexts is crucial for unraveling the mechanisms driving age-related pathologies and developing targeted interventions.

Metal ion metabolism dysregulation in aging

During aging, systemic metabolism of iron, zinc, and copper changes. The average serum ferritin concentration (reflecting body iron stores) increases, while serum and plasma zinc decrease and copper blood concentration rises^94,95. Among them, the detrimental effects of iron during the aging process primarily stem from abnormal cellular iron absorption, trafficking, or storage, thereby impacting various systems of the body. Most organisms, such as Caenorhabditis elegans⁹⁶, Saccharomyces cerevisiae⁹⁷, Homo sapiens⁹⁸, and Rattus norvegicus⁹⁹, have been found to accumulate iron as they age. Iron accumulation could further aggravate cell senescence in a multitude of these species^100–102. Conversely, the abundance of senescent cells has been found to influence the iron levels in aging tissue by impairing ferritinophagy¹⁰³. Moreover, a recent report suggests that high levels of iron in the blood are related to reduced healthy lifespan, multivariate genome scanning¹⁰⁴.

In the aging process, copper homeostasis becomes disrupted, leading to either copper deficiency or accumulation, both of which can result in oxidative damage^105,106. Excessive copper accumulation can interfere with mitochondrial function, increase the production of ROS, and disrupt metabolic processes¹⁰⁷. This contributes to the decline in cellular function observed during aging, particularly in energy-demanding tissues such as the brain and muscles¹⁰⁸. As for calcium, which is central to numerous cellular processes, including muscle contraction and neurotransmission. However, the ability to regulate calcium ions declines in aging, leading to impaired tissue structure and function¹⁰⁹. This calcium dysregulation is not isolated but often occurs in conjunction with changes in other metals, such as zinc¹¹⁰. Zinc plays a crucial role in cellular signaling, enzymatic activity, and protein synthesis, all of which are vital for tissue maintenance and repair. With age, zinc absorption and homeostasis become less stable, contributing to weakened immune function, impaired tissue repair, and compromised organ function¹¹¹. Furthermore, inadequate zinc levels also exacerbate inflammation, a hallmark of aging¹¹¹.

The interplay between these metals is also critical, as they are tightly regulated within the body, often influencing one another’s functions in aging. A disruption in the balance of one metal can affect the others, amplifying the aging process^64,112,113. For example, disturbed calcium levels can impact zinc and copper metabolism, while zinc deficiency can further exacerbate copper-induced oxidative damage^114,115. Therefore, understanding the complex relationship between these metal ions and aging processes offers valuable insights into potential therapeutic strategies. Restoring the balance of metal ions may help mitigate the effects of aging, prevent or slow down age-related conditions (Fig. 2).

Fig. 2. Dysregulation of metal ion homeostasis drives pathological processes in aging cells.

Iron dyshomeostasis promotes ROS generation and depletes the GPX4/GSH system, leading to lipid peroxidation and the induction of ferroptosis. Disrupted copper metabolism causes oxidative stress, mitochondrial dysfunction, and ER stress. Zinc supplementation inhibits oxidative stress, which could contribute to senescence through promoting mitochondrial dysfunction, suppressing the Nrf2-mediated antioxidant response, leading to DNA double-strand breaks, and activating the NF-κB pathway. Furthermore, intracellular calcium fluxes and calcium signaling promote senescence by regulating key senescence effector pathways.

Age-induced changes in ocular homeostasis of metal ions

Metal ions play a pivotal role in ocular physiology by supporting critical cellular processes and enabling the proper functioning of antioxidant enzymes^116,117. Thus, their imbalance profoundly affects retinal aging-related processes, influencing cellular longevity, tissue integrity, and the development of age-related diseases. As antioxidant levels decrease with age due to metal ion dysregulation, elevated oxidative stress inflicts widespread damage across ocular tissues¹¹⁸.

As for iron, some evidence has indicated that its levels in the mammalian retinas increase with aging¹¹⁹. Compared to young animals, iron content in the RPE of rats increased threefold¹²⁰, while it in the neuroretina increased 1.3-fold¹²¹. These increases did not correlate with changes in iron blood levels, suggesting tissue-specific iron-induced aging mechanisms¹²⁰. Moreover, aging has been associated with zinc deficiencies. A 9% reduction in total RPE zinc and a 45% reduction in the solubilizable zinc (separate from pigment granule fractions) in eyes from donors more than 70 years of age compared with younger donors. And there is also a decrease in the zinc storage in RPE cells from the macular areas¹²². Several in vitro studies have also demonstrated that RPE cells contain less endogenous zinc ions and zinc influx transporters Zip2 and Zip4 with aging¹²³. As a result, zinc deficiency not only increases oxidative stress in the retina but also results in the accumulation of lipopigment in the aging RPE^124,125. Copper is also associated with retinal physiology and functions. It is involved in Fenton’s reaction, generating highly reactive hydroxyl radicals¹²⁶. Excessive copper could result in retinal inflammation, cell membrane damage, and mitochondrial dysfunction. Interactions between copper and nitric oxide synthase, N-methyl-D-aspartic acid, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors may contribute to retinal neuron death, aggravating the retinal aging process¹³.

In addition, several heavy metals have been found to be involved in retinal pathology¹²⁷. For example, Cadmium accumulation in the retina/RPE/choroid of aged subjects was significantly higher than in younger examinees, indicating its accumulation potentially contributes to the aging process¹²⁸. This excessive accumulation may be mediated by the age-related decline in metallothionein levels in the macular RPE cells of aged subjects as compared to younger examinees, partially due to a decrease in bioavailable zinc content¹²⁹. Besides, lead (Pb) was also shown to selectively accumulate in the retina with levels exceeding those in aqueous, vitreous, and choroid by 166-, 739-, and 5-fold, respectively¹³⁰. It has been confirmed that Pb may be associated with several age-related ocular diseases, such as AMD and DR^131–134.

In summary, metal ions are deeply integrated into the aging process, impacting key mechanisms like oxidative stress, cellular senescence, and tissue degeneration. Maintaining metal ion homeostasis is essential for mitigating aging-related cellular damage and preventing the progression of age-associated diseases. Further research into how metal ions contribute to aging will not only enhance our understanding of the aging process but also provide potential therapeutic targets for age-related diseases.

Metal ions in age-related ocular diseases

Metals like iron, zinc, copper, and calcium are essential for maintaining normal cellular function and ocular physiology. These metal ions, while crucial for physiological processes, can contribute to oxidative stress, proteostasis failure, ferroptosis, and aberrant angiogenesis when their balance is disturbed. The dual role of metals, as both essential cofactors and potent inducers of cellular injury, complicates their involvement in ocular diseases. Dysregulated metal homeostasis, therefore, emerges as a unifying mechanism underlying major age-related eye conditions. Given their dual role as both essential cofactors and potent mediators of cellular injury, metal ions exert complex regulatory functions in aging and ocular diseases, with disrupted metal homeostasis serving as a potential mechanism underlying age-related ocular conditions. Increasing body of evidence points to the pivotal role of metal dysregulation in the pathogenesis of age-related ocular diseases, including cataract, AMD, diabetic retinopathy, and corneal damage (Fig. 3). Moreover, to systematically summarize the detailed and specific associations between metal ion dyshomeostasis and age-related ocular diseases pathogenesis, the expression patterns, core homeostasis regulation mechanisms, and key pathogenic links of these metal ions in aging and diseases are comprehensively outlined in Table 1.

Fig. 3. Metal ion dysregulation-driven pathogenic mechanisms in age-related ocular diseases.

Aging and environmental stress disrupt Fe, Cu, Zn, and Ca homeostasis across ocular tissues. In the cornea, ROS from cigarette smoke induces lipid peroxidation, protein aggregation, and ferroptosis. In the lens, Ca²⁺ overload activates calpains, promoting crystallin cleavage and cataract formation. Retinal metal imbalance enhances ROS via Fenton/Haber–Weiss reactions, causing DNA damage, mitochondrial dysfunction, and photoreceptor/RPE degeneration relevant to AMD and DR. Elevated intraocular pressure increases Fe-dependent oxidative stress in retinal ganglion cells, weakening GPX4/GSH defenses and triggering ferroptosis during glaucoma progression.

Table 1.

Metal ion dynamic profiles, homeostasis regulation, and links to pathogenic mechanisms in aging and ocular diseases

Ion Type	Dynamic profiles in aging and ocular diseases	Homeostasis regulation mechanisms	Dysregulated mechanisms in aging and ocular diseases
Iron	- Uptake: Enhanced in aging retina; increased in retinal endothelial cells, vascular endothelium, and RPE cells (RP, DR, AMD) and corneal epithelial cells (DED)269,275,276. - Release: Increased iron storage proteins in aging retinal cells; elevated in ferroptosis-related states (DR, AMD, RP)140,277,278. - Storage: Accumulated in RPE cells, drusen, Bruch’s membrane, and neural retinal layers (aging); abnormally increased in retina (DR), RPE cells (AMD)275,276. - Intracellular and inter-organ redistribution: Disrupted in aging retina (vulnerable region accumulation); intensified/abnormal in retinal tissue and RPE cells (DR, AMD, RP)275,276.	1. Core pathways: - Uptake: TF-TFRC endocytosis279, DMT1-mediated transport280, SLC39A14-dependent NTBI uptake (iron overload)281. - Storage: Ferritin/FTMT (mitochondrial storage)282. - Release: FPN-mediated export; ferritinophagy (NCOA4-dependent) degrades ferritin to release iron283. 2. Regulatory interactions: - Systemic: Hepcidin-HIF axis284. - Intracellular: IRE/IRP modulates mRNA translation of TFRC/DMT1/ferritin/FPN285; HIF regulates their transcription. - Cross-metal interaction: Copper (ceruloplasmin) oxidizes Fe²⁺ to Fe³⁺ for TF binding286.	1. Steady-state dysregulation: - Aging: Impaired antioxidant defense and iron accumulation → oxidative stress; disrupted redistribution → vulnerable region damage140. - Diseases: Iron overload induces ferroptosis via Fenton reaction (ROS/lipid peroxidation); storage/release abnormalities amplify cell injury287. 2. Pathogenesis link: - DR: Breaks BRB integrity, promotes vascular leakage/neovascularization; activates NF-κB pathway278. - AMD/RP: Induces RPE and photoreceptor ferroptosis; impairs neuronal function140,277. - DED: Damages corneal epithelial cells via oxidative stress269.
Zinc	- Uptake: Enhanced in aging retina and RPE cells162; deficiency in retinal endothelial cells/RPE cells (DR, AMD)288 and retinal tissue (RP); abnormally elevated in RGCs (glaucoma)289. - Release: Increased from synaptic vesicles/MTs in aging retinal cells162; enhanced from RGCs under oxidative stress (glaucoma)290. - Storage: Abnormal accumulation in RPE cells, synaptic vesicles, and MTs (aging)162; reduced in RPE cells (AMD, MT3 deficiency)157; disrupted in retinal neurons (RP)291. - Intracellular and inter-organ redistribution: Disrupted in aging retina (RPE/synaptic region accumulation); intensified/abnormal in retinal tissue/RPE cells (DR, AMD) and photoreceptors (RP)157,288; dysregulated in RGCs (glaucoma)290.	1. Core pathways: - Uptake: SLC39A (ZIP) family (ZIP1/3/6/7/10/13) mediated influx; ZIP4/ZIP14-dependent non-transferrin-bound zinc uptake292. - Storage: Metallothioneins (MT1-MT4) for cytoplasmic storage293; ZnT7/ZnT8 mediates Golgi/secretory vesicle storage294. - Release: SLC30A (ZnT) family (ZnT1/3/5/6/7)-mediated efflux292; MTs release zinc under oxidative stress14. 2. Regulatory interactions: - Systemic: MTF-1 regulates ZIP/ZnT and MT expression in response to zinc levels295. - Intracellular: ERK1/2, PI3K/Akt pathways regulate ZIP/ZnT activity296,297. - Cross-metal interaction: Zinc interacts with copper (ceruloplasmin) to modulate metal balance298; regulates iron metabolism via ZIP8/ZIP14-mediated iron uptake299.	1. Steady-state dysregulation: - Aging: Impaired ZIP/ZnT expression and MT function → zinc accumulation → oxidative stress; disrupted synaptic zinc release → retinal neurodegeneration162. - Diseases: Zinc overload induces ferroptosis via lipid peroxidation; insufficient storage → free zinc toxicity; redistribution disorders amplify retinal cell damage300. 2. Pathogenesis link: - AMD: Zinc deficiency in RPE cells impairs antioxidant defense; free zinc promotes amyloid-β aggregation and RPE cell death157. - DR: Abnormal uptake/redistribution disrupts BRB integrity; activates NF-κB pathway → inflammation and vascular leakage288. - Glaucoma: Zinc release from RGCs activates apoptotic pathways; disrupts calcium signaling → RGC loss290. - RP: Dysregulated redistribution induces photoreceptor ferroptosis and neuronal loss291.
Copper	- Uptake: Enhanced intracellular copper accumulation in aging retinal cells and RPE cells (AMD)301; increased copper transporter activity in corneal epithelial cells (DED)302. - Release: Dysregulated copper export due to ATPase dysfunction contributes to pathological intracellular retention during aging (AMD)190; reduced copper release in aqueous humor (glaucoma)169. - Storage: Accumulated in RPE cells and Bruch’s membrane during aging303,304; abnormally elevated in retina (DR)305 and RPE cells (AMD)303. - Intracellular and inter-organ redistribution: Disrupted copper trafficking in aging RPE cells and retinal vascular endothelial cells (DR)105,106.	1. Core pathways: - Uptake: CTR1-mediated copper influx across plasma membrane190. - Storage: Metallothionein-mediated intracellular sequestration34. - Release: ATP7A/ATP7B-mediated export and vesicular trafficking regulate copper efflux and distribution301. 2. Regulatory interactions: - Systemic: Copper levels coordinated with systemic metal metabolism through ceruloplasmin-dependent oxidation processes192. - Intracellular: Copper-induced ROS activates redox-sensitive signaling pathways67,105. - Cross-metal interaction: Copper modulates iron homeostasis via ferroxidase-mediated Fe²⁺ oxidation192.	1. Steady-state dysregulation: - Aging: Copper accumulation combined with impaired antioxidant defense → oxidative stress; disrupted redistribution → mitochondrial dysfunction and retinal cell vulnerability13,126. - Diseases: Excess copper amplifies lipid peroxidation and degenerative retinal injury; abnormal storage/release exacerbates cellular damage106,306. Pathogenesis link: - AMD: Copper imbalance promotes oxidative stress and inflammatory activation in RPE cells, enhances VEGF expression, and contributes to choroidal neovascularization13,220. - DR: Copper-induced ROS production and endothelial dysfunction aggravate BRB breakdown, vascular leakage, and inflammatory signaling305. - Glaucoma: Copper-associated mitochondrial dysfunction and oxidative stress activate apoptotic pathways in retinal ganglion cells234.
Calcium	- Uptake: Enhanced Ca²⁺ influx in aging retinal and lens epithelial cells; increased intracellular Ca²⁺ levels in degenerative retinal conditions (RP) and lens (cataract)204,211. - Release: Increased release from ER and mitochondrial stores in aging retinal tissues and degenerative states217. - Storage: Impaired ER and mitochondrial buffering capacity in aging retinal cells (AMD)217. - Intracellular and inter-organ redistribution: Disrupted calcium signaling in aging retina; intensified imbalance in photoreceptors and RPE cells during degenerative diseases (RP)211,212.	1. Core pathways: - Uptake: Voltage-gated and receptor-operated Ca²⁺ channels mediate influx17,18. - Storage: SERCA-dependent ER storage and mitochondrial buffering systems109. - Release: IP3R- and ryanodine receptor-mediated ER Ca²⁺ release31. 2. Regulatory interactions: - Systemic: Endocrine regulation maintains systemic calcium balance17. - Intracellular: Ca²⁺ acts as a second messenger regulating apoptosis, metabolism, and oxidative stress signaling307. - Cross-metal interaction: Calcium signaling interacts with ROS-mediated pathways, influencing redox homeostasis308.	1. Steady-state dysregulation: - Aging: Impaired buffering + sustained cytosolic Ca²⁺ elevation → mitochondrial dysfunction and oxidative stress; redistribution abnormalities increase retinal vulnerability109. - Diseases: Calcium overload activates calpains and apoptotic pathways; abnormal storage/release amplifies retinal and lens epithelial injury208,209,213. Pathogenesis link: - Cataract: Elevated intracellular Ca²⁺ activates calpains, leading to crystallin proteolysis and lens opacity204,205. - AMD: Dysregulated Ca²⁺ homeostasis enhances RPE cell apoptosis and mitochondrial dysfunction141. - RP: Photoreceptor Ca²⁺ overload (cGMP-Ca²⁺ imbalance) triggers degeneration cascades and cell death213.

AMD age-related macular degeneration; BRB, blood-retinal barrier, Ca²⁺ calcium ion, cGMP cyclic guanosine monophosphate, CTR1 copper transporter 1, DED dry eye disease, DR diabetic retinopathy, DMT1 divalent metal transporter 1, ER endoplasmic reticulum, ERK1/2 extracellular signal-regulated kinase 1/2, FPN ferroportin, FTMT ferritin mitochondrial, HIF hypoxia-inducible factor, IP3R inositol trisphosphate receptor, IRE/IRP iron-responsive element/iron-regulatory protein, MT metallothionein, MTF-1 metal-regulatory transcription factor 1, NF-κB nuclear factor kappa-B, NCOA4 nuclear receptor coactivator 4, RGC retinal ganglion cell, ROS reactive oxygen species, RPE retinal pigment epithelium, RP retinitis pigmentosa, SERCA sarco/endoplasmic reticulum Ca²⁺-ATPase, SLC30A (ZnT) solute carrier family 30 (zinc transporter), SLC39A (ZIP) solute carrier family 39 (zinc importer), TF transferrin, TFRC transferrin receptor, VEGF vascular endothelial growth factor.

Iron (Fe)

Iron is indispensable for retinal function, supporting enzymatic activity, mitochondrial metabolism, and cellular homeostasis. Its levels are tightly controlled by transferrin receptors, ferritin, ferroportin, ceruloplasmin, and hephaestin, which regulate uptake, storage, and export across RPE, Müller glia, and photoreceptors¹³⁵. Iron is predominantly localized in the RPE, choroid, and photoreceptor inner segments, with higher concentrations in the RPE compared to the neural retina¹³⁶. This distribution supports its critical roles in retinal metabolism and visual function^136,137. When this homeostasis is disrupted, excess iron catalyzes the Fenton reaction, producing ROS that induce oxidative damage to proteins, lipids, and DNA. The resultant hydroxyl radicals trigger lipid peroxidation and ferroptosis, a regulated form of cell death dependent on iron and characterized by glutathione depletion and GPX4 inactivation^138,139.

Experimental and clinical studies consistently report iron accumulation in the aging macula, particularly within RPE cells and photoreceptors of AMD patients, where it contributes to drusen formation, RPE dysfunction, and photoreceptor loss^140–146. Moreover, several studies show that mice lacking both ceruloplasmin and hephaestin develop progressive retinal iron accumulation, RPE hypertrophy, and photoreceptor loss, whereas hepcidin or HFE knockout mice exhibit age-dependent retinal iron overload, further confirming that systemic and local iron-regulatory proteins jointly maintain retinal iron homeostasis^147–149. Similar pathogenic roles of iron overload have been implicated in retinal detachment and other degenerative retinopathies^150,151. Moreover, iron dysregulation activates inflammatory and angiogenic pathways via NF-κB and HIF-1α signaling, linking oxidative stress to neovascular AMD progression^152,153. Recent studies show that ferroptosis, an iron-dependent form of oxidative cell death, plays a critical role in retinal ganglion cell (RGC) loss in glaucoma, particularly due to elevated IOP. Among them, hydrogen sulfide (H₂S) has been found to regulate iron metabolism, reduce oxidative stress, and prevent ferroptosis, making H₂S donors a promising multi-target therapy for glaucoma¹⁵⁴. Similarly, iron accumulation in corneal epithelial cells, triggered by environmental factors like cigarette smoke and heated tobacco products (HTPs), promotes oxidative stress and ferroptosis¹⁵⁵. Exposure to these substances induces lipid peroxidation and cell death, but ferroptosis inhibitors and iron chelators can protect corneal cells, suggesting potential treatments targeting iron pathways to prevent corneal injury¹⁵⁵.

These findings highlight iron dysregulation as a critical pathogenic axis in age-related ocular diseases and suggest that therapeutic strategies aimed at limiting iron overload or modulating ferroptotic pathways may hold promise for preserving retinal and corneal integrity.

Zinc (Zn)

Zinc is highly enriched in ocular tissues and contributes to enzymatic activity, structural integrity, and immune regulation. It is particularly abundant in the RPE, choroid, and the outer and inner plexiform layers of the retina¹⁵⁶. In these locations, zinc is essential for antioxidant defense, primarily through its involvement in the zinc-metallothionein (Zn-MT) system, which neutralizes reactive oxygen species and protects retinal cells from oxidative stress^14,157,158. Zinc also stabilizes cellular membranes and supports the activity of antioxidant enzymes, such as superoxide dismutase¹⁵⁹.

Zinc dysregulation has been linked to pathological processes in the aging retina. In AMD, zinc accumulates in drusen and sub-RPE deposits, where it promotes complement component aggregation and amplifies local complement activation, a key driver of chronic inflammation and disease progression^160,161. Zinc deficiency, conversely, impairs the visual cycle and dark adaptation, partly through reduced RPE enzyme activity and oxidative imbalance^162,163. Clinical evidence from the Age-Related Eye Disease Study (AREDS) and AREDS2 demonstrated that systemic zinc supplementation reduces the risk of progression to advanced AMD by approximately 25% over five years^164,165. At the molecular level, zinc supplementation upregulates metallothioneins (MT1/2) and ZnT transporters, which buffer excess zinc and protect against oxidative stress^14,115,166. However, excessive zinc may competitively inhibit copper absorption, leading to secondary copper deficiency and altered angiogenic responses¹⁶⁷.

In glaucoma, serum zinc levels are closely associated with oxidative stress¹⁶⁸. Moreover, aqueous humor zinc concentrations are significantly elevated in primary glaucoma patients and correlate with disease severity, suggesting that zinc regulation could play a crucial role in the prevention and management of glaucoma¹⁶⁹. Emerging evidence highlights a critical role of mobile Zn²⁺ in RGC survival and optic nerve regeneration. After optic nerve injury, Zn²⁺ rapidly increases in the inner plexiform layer, mainly released from amacrine cells via ZnT3. Reducing Zn²⁺ promotes RGC survival and axon regeneration by suppressing ROS, activating Nrf2, and inhibiting excessive autophagy^170,171. Besides, in cataract development, zinc homeostasis is implicated. Cataractous lenses have higher zinc concentrations than healthy ones, and zinc induces non-amyloid aggregation of human γD-crystallin via a reversible metal-bridging mechanism^172,173. Biallelic ZNF526 variants and lens-specific Znhit1 deletion are also found to be associated with bilateral cataracts, with Znhit1 deficiency causing lens epithelial apoptosis, fibrosis, and opacity¹⁷⁴. Copper-Zinc superoxide dismutase deficiency accelerates lens opacity, suggesting the role of zinc in lens antioxidant defense¹⁷⁵.

Zinc homeostasis disorder is also a key factor in the pathogenesis of DR. On the one hand, zinc deficiency impairs the activity of Cu/Zn-SOD and other antioxidant enzymes, and inhibits MT synthesis, leading to excessive ROS accumulation, retinal lipid peroxidation, and pericyte apoptosis^176,177. On the other hand, it loses the inhibition of the NF-κB pathway, resulting in up-regulation of VEGF expression, which induces retinal neovascularization and vascular leakage^178,179. In addition, ischemic injury in DR reduces ZnT8 expression, and zinc deficiency also impairs insulin action and aggravates hyperglycemia, forming a vicious cycle to exacerbate retinal microvascular damage¹⁸⁰. These findings link zinc metabolism and related proteins to age-related ocular pathogenesis.

Collectively, zinc plays a complex and dualistic role in retinal pathology; excessive deposition can exacerbate complement-mediated damage, while controlled supplementation appears to offer protection. A deeper understanding of zinc transporter regulation (ZIP and ZnT families) and metallothionein dynamics could be crucial in restoring retinal zinc homeostasis and preventing secondary metal imbalances.

Copper (Cu)

Copper is an essential trace element required for antioxidant defense, enzymatic catalysis, and physiological angiogenesis; however, dysregulation or excess of copper promotes multiple, mechanistically distinct forms of ocular injury^181,182. Recent bioinorganic and cellular studies have delineated several copper-driven pathogenic mechanisms in the eye.

One major mechanism involves the direct interaction of copper with structural lens proteins. Human lens γ-crystallins (γD, γC, and γS) possess discrete Cu²⁺ binding sites that catalyze the reduction of Cu²⁺ to Cu⁺ under aerobic conditions, concomitantly generating protein-based radicals, notably Tyr-derived species. This redox chemistry promotes oxidative cross-linking, partial unfolding, loss of native β-sheet structure, and formation of disulfide-bridged aggregates, producing high-molecular-weight complexes that scatter light and impair lens transparency^183–185. Moreover, elevated copper levels observed in cataractous lenses, particularly in smokers, are consistent with a pathogenic role for copper-mediated redox cycling in cataractogenesis¹⁸⁶. Notably, copper homeostasis is associated with DR. Epidemiological data show that higher dietary copper intake correlates with a lower risk of DR in diabetic adults¹⁸⁷. In DR models, the copper chaperone COX17 is downregulated under high-glucose conditions, and its overexpression preserves mitochondrial function and reduces retinal injury¹⁸⁸. Additionally, high glucose can activate the STAT1/SLC31A1 pathway, which promotes cuproptosis-induced M1 polarization in microglial cells and contributes to DR pathogenesis¹⁸⁹. These findings suggest that copper homeostasis and copper-dependent signaling pathways are involved in DR regulation.

Copper also serves as a critical regulator of ocular angiogenesis. Through transporters and metalloenzymes, copper maintains endothelial homeostasis and promotes vascular remodeling. The high-affinity copper importer CTR1 (SLC31A1) functions as a redox sensor in endothelial cells, facilitating VEGFR2 activation and enhancing VEGF-driven neovascularization, while the copper-exporting ATPase ATP7A prevents autophagic degradation of VEGFR2, thereby sustaining VEGF signaling^190,191. Additionally, copper-dependent enzymes such as lysyl oxidase contribute to extracellular matrix cross-linking, further influencing angiogenic processes. Genetic or functional loss of CTR1 or ATP7A markedly impairs VEGF-mediated angiogenesis, underscoring copper’s indispensability for both physiological and pathological vascular responses in the eye^192–195.

At toxic levels, copper induces pronounced neuronal and retinal injury. Excessive copper exposure, as in Wilson’s disease or from intraocular copper foreign bodies, provokes mitochondrial dysfunction, elevated ROS production, and excitotoxic signaling via NMDA receptor activation, collectively leading to retinal neuronal loss and degeneration^196–198. These observations indicate that copper exerts context-dependent effects in ocular tissues, supporting essential metabolism and angiogenesis at physiological concentrations but driving redox damage, protein aggregation, and neurotoxicity when its homeostasis is perturbed. Beyond these copper-centered mechanisms, copper closely interacts with iron metabolism to amplify oxidative injury. Copper and iron participate in redox cycling that accelerates the formation of highly reactive oxygen species through Haber–Weiss and Fenton-type reactions, generating hydroxyl radicals that attack lipids and proteins^199,200. Copper further regulates iron handling indirectly via ceruloplasmin, which oxidizes Fe²⁺ to Fe³⁺ and facilitates ferroportin-mediated iron export; disruption of copper balance can thus alter the labile iron pool and sensitize tissues to iron-catalyzed oxidative stress^192,201.

Mechanistically, copper has been shown to promote ferroptosis not only by enhancing metal-catalyzed lipid peroxidation but also by inducing autophagic degradation of GPX4, the central enzyme that detoxifies lipid hydroperoxides²⁰². The combined effects of increased redox-active metals, enhanced Fenton chemistry, and loss of GPX4-mediated protection create a highly permissive environment for ferroptotic cell death in retinal and neuronal cells. Such metal-driven oxidative synergy likely contributes to disease progression in age-related retinal degenerations and ischemia–reperfusion injury^{140,144,202,203}. From a therapeutic perspective, precise modulation of copper and iron homeostasis may be critical. Effective interventions should attenuate metal-induced oxidative injury and ferroptotic pathways while preserving copper-dependent physiological processes such as enzymatic activity and reparative angiogenesis.

Calcium (Ca)

Calcium homeostasis is critical for maintaining lens and retinal cell integrity. Dysregulation of intracellular calcium, particularly within the lens, plays a central role in age-related cataract²⁰⁴. Excessive Ca²⁺ activates calpains, a family of calcium-dependent proteases, which cleave crystallins and disrupt the cytoskeleton, leading to protein aggregation, insolubilization, and progressive lens opacification^205–207. Calpain hyperactivation has been consistently implicated as a major driver of crystallin insolubilization and cataract formation²⁰⁵. Beyond proteolytic activation, calcium can directly interact with lens crystallins to induce conformational instability and redox imbalance^208,209. Human γD-crystallin contains specific Ca²⁺ binding sites that trigger local unfolding, exposure of cysteine residues, and oxidation-dependent aggregation. These calcium-induced structural and redox alterations synergize with oxidative stress to accelerate the formation of light-scattering aggregates, providing a molecular basis for Ca²⁺-driven lens opacity^209,210.

Calcium dysregulation also exerts profound effects on the retina. Sustained calcium overload activates calcineurin and interferes with photoreceptor outer segment renewal, contributing to photoreceptor apoptosis in degenerative diseases^211–213. Moreover, chronic Ca²⁺ elevation in RPE disrupts mitochondrial bioenergetics, enhances oxidative stress, and promotes lipofuscin accumulation, features associated with AMD^141,214. Disturbed calcium signaling further impairs photoreceptor phagocytosis and activates the NLRP3 inflammasome, linking calcium overload to para-inflammatory and senescent responses in aging retinal tissues^215,216. Recent studies have further revealed that persistent cytosolic Ca²⁺ elevation can directly initiate neuronal mitophagy through the Ca²⁺–calcineurin–AMPK signaling cascade, leading to excessive mitochondrial fragmentation and bioenergetic crisis^217,218. In RGCs and other neurons, mitochondrial Ca²⁺ overload disrupts the mitochondrial membrane potential and triggers opening of the permeability transition pore, resulting in uncontrolled mitophagy and neuronal apoptosis²¹⁷. Autosomal dominant optic atrophy (ADOA) is a neurodegenerative disease characterized primarily by mitochondrial dysfunction, which is largely driven by calcium dysregulation^217,219. Calcium chelation or inhibition of calcineurin markedly restores mitochondrial distribution and prevents cell death, underscoring the pathogenic role of Ca²⁺-dependent mitophagy in ocular neurodegeneration.

Collectively, calcium signaling acts as a double-edged sword in ocular health, supporting essential visual and metabolic functions under normal conditions but promoting degeneration when dysregulated. Targeting calcium homeostasis through calpain inhibition, Ca²⁺ channel modulation, or stabilization of crystallin and mitochondrial integrity represents a promising strategy to prevent or slow cataract and retinal degeneration.

Potential therapeutic strategies based onmetal ion modulation in age-related ocular diseases

Therapeutic strategies for age-related ophthalmic diseases like AMD, DR, cataracts, and glaucoma focus on modulating dysregulated metal ions such as iron, copper, and zinc to restore homeostasis, reduce oxidative stress, and prevent cellular damage. Key interventions include metal chelators, supplements, and antioxidants, which are explored in detail in the following sections (Fig. 4).

Fig. 4. The therapeutic strategies targeting metal ion dysregulation in ocular diseases.

It details specific compounds and strategies in eye diseases, which primarily function as metal chelators or antioxidants. EDTA ethylenediaminetetraacetic acid disodium, AMD age-related macular degeneration, MT1F/MT1E metallothioneins, CNV choroidal neovascularization, DR diabetic retinopathy, GSPE grape seed proanthocyanidin extract, DED dry eye disease.

Metal chelators and supplements as potential treatments

The accumulation of metal ions plays a significant role in the pathogenesis of various eye diseases, contributing to oxidative damage and cellular dysfunction. Targeting these metal ions through chelators and supplements offers a promising approach for managing these conditions and improving patient outcomes.

Age-related macular degeneration (AMD)

In AMD, iron and copper accumulation in the RPE exacerbates oxidative damage, leading to drusen formation and photoreceptor loss^13,220. Iron chelators address this by reducing labile iron pools. Xu et al. have shown the protective role of deferiprone in a very low-density lipoprotein receptor (VLDLR) knockout nAMD murine model. Specifically, it can not only mitigate iron overload and significantly reduce retinal neovascularization and vascular leakage but also suppress retinal inflammation¹⁵³. Furthermore, Faizi et al. found deferasirox-nanosuspension into novel microneedles is a promising technique for effectively delivering deferasirox to the posterior segment of the eye in a minimally invasive manner, potentially improving therapeutic access to the macula²²¹. Lesion site-targeted melanin-like nanoparticles, ConA-MelNPs, designed as a ferroptosis inhibitor, effectively protect RPE from oxidative stress and ferroptosis in dry AMD by chelating iron ions. In preclinical models, they significantly improved retinal function and demonstrated good biosafety, offering a promising therapeutic option for atrophic retinal diseases²²².

As for copper, its chelator also demonstrated a protective effect on retinal function in the AMD mouse model²²³. These mechanisms collectively reduce oxidative stress, suggesting the role of iron and copper chelators in alleviating early AMD progression. Calcium ions also play a crucial role in the cellular response to RPE ER stress. Spermidine could inhibit the increase in cytosolic Ca²⁺ levels induced by H₂O₂ in human RPE cells, exhibiting a similar effect to that of a cytosolic Ca²⁺ chelator and significantly reversing H₂O₂-induced cellular dysfunction²²⁴. Moreover, zinc supplementation showed direct effects on the RPE^14,163, which may be the breakthrough point to prevent progression to advanced AMD in the future. Moreover, metallothioneins (MT1F and MT1E) are well-recognized mediators of zinc supplementation in the RPE via mediating oxidative-stress-induced RPE damage and differentiation of RPE^14,225. In a multicenter double-masked clinical trial, zinc supplementation was evaluated for its long-term efficiency on AMD progression and visual acuity, and confirmed a reduced risk of both at least moderate vision loss (≥3 lines), more severe vision loss (worse than 20/100), and reduced mortality in participants assigned to zinc¹⁶⁴. Other large population-based cohort studies have confirmed the beneficial effects of higher intake of dietary zinc on incident AMD²²⁶. Recent clinical research indicated that oral zinc acetate dihydrate supplementation could be beneficial in managing early AMD by modifying oxidative stress levels and potentially reducing drusen size²²⁷. Therefore, zinc’s role in preventing RPE atrophy positions it as a preventive cornerstone, potentially synergizing with chelators for multimodal therapy.

Glaucoma

Glaucoma involves elevated intraocular pressure triggering RGC ferroptosis via iron overload and oxidative stress. Iron chelators counteract this by depleting ferrous iron, a key ferroptosis driver. Yao et al. demonstrated the protective effect of deferiprone on RGCs via chelating abnormally elevated ferrous iron in the retina to inhibit RGC ferroptosis and protect visual function²²⁸. Other evidence has also shown that deferiprone could rescue RGCs and glaucomatous degeneration in a mouse model of glaucoma^229,230. Similarly, deferasirox could protect retinal neurons by mitigating Fe²⁺ accumulation, reducing the expression of oxidative stress markers, and decreasing RGC loss²³¹. Deferoxamine protects the structural and functional soundness of the retina by inhibiting ferroptosis through the simultaneous inhibition of hemochromatosis and the initiation of transferrin²³². Currently, these iron chelators are undergoing a series of studies in animal experiments and may potentially enter clinical trials in the future. A recent study has designed iron-chelating and ROS-scavenging polymers with thioketal and thioester bonds delivering Lip-1 and self-assembled into NPs Lip-1, which could effectively inhibit ferroptosis in RGCs by reducing oxidative stress and upregulating GPX4. This triple-action approach shows promising potential as a therapeutic strategy for glaucoma²³³.

Besides, treatment with the copper chelator tetrathiomolybdate could reduce retinal thinning, neurovascular damage, apoptosis, gliosis, and oxidative stress after IR injury²³⁴. Moreover, an epidemiological study has suggested the protective effects of zinc against glaucoma¹⁶⁸, which serves as a basis for considering personalized nutritional therapy for the prevention and supportive treatment of patients with glaucoma. They found zinc treatment not only lowered nitric oxide (NO), but also influenced cytokines to lessen oxidative stress byproducts²³⁵. Collectively, the neuroprotective effects of these agents extend beyond chelation, highlighting their potential in slowing glaucomatous neurodegeneration.

Diabetic retinopathy (DR)

Hyperglycemia in DR elevates copper, promoting vascular permeability and RPE dysfunction through ER stress and mitochondrial imbalance. There was a statistically highly significant increase in serum copper levels in cases of retinopathy compared to controls in cases of DM with retinopathy²³⁶. Therefore, Cu chelators may be effective in alleviating oxidative stress and preventing the progression of DR. Penicillamine, a copper chelator, could inhibit ER stress and inflammation via restoring the mitochondrial dynamics in RPE cells induced by high glucose²³⁷. Moreover, zinc plays a crucial role in antioxidant defense and may help prevent oxidative stress, a known contributor to eye diseases such as diabetic retinopathy¹⁸¹. Zinc supplements broadly combat oxidative stress in DR, integrating with systemic antioxidant strategies to protect vascular endothelium¹⁸¹. Therefore, copper chelators and zinc supplements may help alleviate oxidative stress and potentially prevent the progression of diabetic retinopathy.

Cataracts

Age-related cataracts feature lens protein aggregation driven by oxidative and calcium-mediated insults. Previous studies have identified intracellular calcium as a therapeutic target for age-related cataract. It has been hypothesized that topical administration of methylsulfonylmethane (MSM, also referred to as C-KAD) would improve visual function for patients with early-stage cataracts by making ethylenediaminetetraacetic acid disodium (EDTA) more bioavailable to chelate calcium out of the light-scattering particle²³⁸. This approach exploits calcium’s role in crystallin denaturation, offering a non-surgical intervention. Moreover, zinc supplementation could attenuate this by restoring redox balance¹⁸¹. Application of grape seed extract and Zincovit tablets could reduce MDA levels and restore GSH levels of the lens in rats with age-related cataracts²³⁹. In summary, targeting calcium with treatments like MSM, EDTA, and zinc supplementation may help improve vision and reduce damage in age-related cataracts.

Corneal damage

Iron dysregulation, characterized by abnormal accumulation or disordered acquisition, is common in corneal injuries, and targeting iron homeostasis via metal chelators and iron-regulating supplements is a promising therapeutic strategy. In fungal keratitis, topical application of iron chelators such as deferiprone can reduce fungal growth in the cornea by 60%, and dual therapy with statins (targeting siderophore biosynthesis) further enhances the therapeutic effect to 75%; natural iron chelators like lipocalin-1 and lactoferrin also effectively restrict fungal growth by sequestering fungal siderophores²⁴⁰. For corneal alkali burn, phytic acid (PA), a natural small molecule with efficient ferrous ion chelating capacity, promotes corneal epithelial repair by inhibiting ferroptosis²⁴¹. In dry eye disease (DED), astaxanthin (AST) reduces Fe²⁺ overload by upregulating ferritin expression, thereby alleviating hyperosmotic stress-induced corneal epithelial damage²⁴². In Fuchs endothelial corneal dystrophy, dysregulation of iron-sulfur cluster (ISC) synthesis leads to iron accumulation in corneal endothelial cells (CECs), and targeting ISC-related proteins such as ferredoxin 1 may reduce CEC susceptibility to ferroptosis²⁴³. Collectively, these agents exert therapeutic effects by reducing excessive iron accumulation, inhibiting pathogenic iron acquisition, and restoring iron homeostasis.

Antioxidant strategies against oxidative stress induced by metal ions

Antioxidants may function as a complementary approach to mitigate ROS generated during metal-mediated oxidative stress²⁴⁴. This multifaceted defense restores cellular redox equilibrium, with both preclinical studies and clinical trials validating long-term benefits in a variety of ocular diseases.

Age-related macular degeneration (AMD)

Liproxstatin-1 and Ferrostatin-1 A, the lipid peroxidation inhibitors, can mitigate cigarette smoke extract-induced Fe²⁺ overload, ROS accumulation, and lipid peroxidation damage to protect RPE cells in the AMD model²⁴⁵. Moreover, ferrostatin-1 has also been found to enhance RPE cell survival and prevent subsequent photoreceptor degeneration in dry AMD²⁴⁶. α-Lipoic acid (ALA), a naturally occurring organosulfur compound, functions as a potent antioxidant and modulator of cellular redox balance²⁴⁷. Several studies suggest that ALA may have therapeutic potential in AMD treatment. A randomized controlled trial indicated that ALA supplementation improved visual function and quality of life in patients with dry AMD²⁴⁸, likely by enhancing retinal antioxidant defenses²⁴⁹. In the AMD mouse model, ALA also significantly preserved retinal structure, maintained visual function, and reduced oxidative stress and iron accumulation, further confirming the findings observed in clinical trials²⁵⁰.

The effect of antioxidants has also been demonstrated in other large-scale clinical trials. In the AREDS large multicenter clinical trial, treatment with a combined supplement containing high doses of zinc and antioxidants (ascorbic acid [vitamin C], vitamin E, β-carotene, and copper) reduced the risk of progression to advanced AMD by around 25% after an average 6.3-year follow-up¹⁶⁴. In the follow-up study (AREDS2), in which the carotenoids lutein and zeaxanthin were added to the AREDS formula, people in the lowest quintile in terms of dietary lutein and zeaxanthin intake benefited most from the addition of these carotenoids, with around 10% reduced risk of progression to advanced AMD^251,252. Furthermore, when β-carotene was replaced with lutein, the incremental benefit increased to 18%, probably because of reduced competitive carotenoid absorption. Therefore, lutein and zeaxanthin could be an appropriate carotenoid substitute in the AREDS supplement than β carotene, also allowing the potential increased risk of lung cancer from β carotene in past smokers to be avoided²⁵¹. Recent multicenter randomized placebo-controlled trials further confirmed the positive effect of oral micronutrient supplementation to slow geographic atrophy progression toward the central macula in AMD²⁵³. In conclusion, naturally derived antioxidants have shown efficacy in slowing AMD progression and improving visual function, positioning them as promising dietary therapeutic strategies for the future.

Glaucoma

Glaucoma is characterized by progressive RGCs degeneration, largely driven by oxidative stress pressure, which exacerbates cellular damage and disrupts retinal homeostasis. As a strong reducing agent, hydrogen sulfide (H2S) is vital in various pathological and physiological processes, including reducing inflammation, mitigating oxidative stress, and restoring energy balance^254–256. Previous studies have shown that H2S effectively mitigates pressure-induced ferroptosis and oxidative stress for RGCs in glaucoma by regulating iron metabolism, reducing ROS accumulation, and enhancing the activity of key ferroptosis regulators. This multi-target mechanism offers a promising therapeutic strategy for protecting RGCs and slowing disease progression in glaucoma^154,257.

Diabetic retinopathy (DR)

Recent studies have highlighted the potential of various antioxidants in mitigating metal ion-related damage in diabetic retinopathy. 20(R)-ginsenoside Rg3 has been shown to activate the Nrf2/HO-1 axis and inhibit ER stress, effectively alleviating retinal endothelial cell apoptosis in diabetic mice²⁵⁸. Similarly, Ferrostatin-1 has demonstrated significant efficacy in reversing high-glucose-induced ferroptosis, enhancing the viability of photoreceptors²⁵⁹. Moreover, a randomized, multicenter, double-blind trial has revealed the beneficial effects of grape seed proanthocyanidin extract (GSPE), known for its antioxidant and radical scavenging activities, in patients with non-proliferative diabetic retinopathy²⁶⁰. Nrf2 is a key factor involved in the oxidative stress response within cells and participates in regulating the expression of key genes related to ferroptosis²⁶¹. Corilagin, a natural compound found in various medicinal plants, has also been shown to increase Nrf2 protein levels and its downstream antioxidant enzymes in the retina of diabetic mice. This not only maintains retinal barrier integrity but also reverses the elevation of ROS and lipid peroxides, key factors in diabetic retinopathy²⁶². Together, these findings emphasize the therapeutic potential of antioxidants in modulating oxidative stress and metal ion dysregulation, suggesting they may serve as key modulators in the prevention and treatment of diabetic retinopathy.

Cataracts

Antioxidants have shown promise in protecting against metal ion-induced damage in cataracts. 6-acyl-4-aryl-alkyl-5,7-dihydroxycoumarins, a class of coumarin derivatives, have been demonstrated to protect lens γ-crystallins from UVC-induced damage and metal chelation through their unique structure of 6-CO and 5-OH on the benzopyrone ring²⁶³. Similarly, Astaxanthin (ASTX), a carotenoid with strong antioxidant properties, plays a key role in protecting porcine lens crystallins from oxidative damage caused by iron-mediated hydroxyl radicals and calcium ion-activated proteases²⁶⁴. Moreover, a novel metal-phenolic epigallocatechin gallate zinc antioxidant nanoparticle, when used as eye drops, has significantly improved lens opacity in cataract model animals²⁶⁵. In summary, these innovative antioxidants show significant potential in mitigating metal ion-related lens damage, paving the way for future strategies targeting oxidative stress to slow the progression of cataracts.

Corneal damage

Excessive iron ions in corneal tissues trigger oxidative stress by promoting the production of ROS and lipid peroxidation, which further mediate ferroptosis and exacerbate corneal injury. Thus, antioxidant strategies are crucial for targeting iron-induced corneal damage. In bacterial keratitis, ferroptosis is a key pathogenic mechanism, and combination therapy with levofloxacin and ferrostatin-1, an antioxidant ferroptosis inhibitor, effectively reduces inflammatory cytokines, corneal scarring, and Fe³⁺ levels, while restoring the expression of antioxidant regulators²⁶⁶. In diabetic keratopathy, Fer-1 alleviates high-glucose-induced iron overload and ROS production, restores the function of corneal epithelial cells²⁶⁷. For DED, multiple antioxidant strategies show therapeutic potential: AST scavenges ROS and upregulates antioxidant pathways²⁴², SRT1720 activates SIRT1 to inhibit ferroptosis²⁶⁸, and AKR1C1 reduces ferroptosis-induced cell damage and inflammation²⁶⁹. In corneal alkali burn, Fe-Cur CPNs scavenge ROS to inhibit the NF-κB pathway, mitigating corneal neovascularization and promoting epithelial repair²⁷⁰. These antioxidant strategies effectively inhibit ferroptosis and inflammation, synergizing with iron chelators to improve therapeutic outcomes of corneal injuries.

Conclusion and future prospects

Metal ions are integral to numerous biological processes, but their dysregulation, particularly in the aging process, plays a pivotal role in the development and progression of age-related ocular diseases. Imbalances in metal ions such as iron, copper, zinc, and calcium exacerbate oxidative stress, inflammation, and cellular dysfunction, which drive retinal degeneration and diseases like AMD, glaucoma, DR, and cataracts. These dysregulated metal ions are central to the pathophysiology of these conditions, influencing cellular aging, neuronal degeneration, and tissue damage. Understanding the intricate mechanisms by which metal ions contribute to these age-related diseases is essential for developing effective therapeutic strategies.

Recent research has highlighted the therapeutic potential of metal chelators and antioxidants in modulating metal ion homeostasis. These treatments show promise in alleviating metal ion-induced oxidative stress and preventing disease progression. However, further studies are necessary to better understand their long-term effects, safety, and how best to integrate these strategies into clinical practice. Future research should aim to uncover the molecular pathways through which metal ions, particularly iron and copper, exacerbate oxidative stress and inflammation in ocular tissues. This knowledge will help identify more targeted and efficient interventions for age-related ocular diseases.

Moreover, as metal ion dysregulation impacts not only ocular health but also broader systemic processes, it is crucial to explore how these imbalances contribute to other age-related diseases, such as neurodegenerative disorders. Research into the intersection of metal ion homeostasis, aging, and neurodegeneration will enhance our understanding of these processes and inform therapeutic development for both ocular and neurodegenerative diseases. Additionally, the clinical translation of metal ion regulation therapies will require overcoming challenges related to drug delivery, optimal dosing, and patient-specific factors. Personalized treatment approaches, potentially combining metal chelation, antioxidants, and other therapeutic modalities, could offer more effective solutions. The integration of cutting-edge technologies, such as gene therapy, stem cell treatments, and targeted drug delivery systems, presents an exciting frontier in the treatment of age-related ocular diseases. Our team has contributed to this field by investigating the role of metal ions in ocular diseases and exploring senotherapeutics (e.g., Procyanidin C1 and Pyrroloquinoline quinone) as well as rejuvenation strategies in aging retinas and the hematopoietic immune system^271–274. These findings can be integrated with metal ion regulation to develop more comprehensive anti-aging ocular therapies.

In conclusion, metal ions are critical players in aging and ocular diseases, and the emerging therapeutic strategies targeting metal ion dysregulation show considerable promise. However, comprehensive, multi-target approaches that integrate metal ion regulation with other interventions may hold the key to effectively preventing or slowing the progression of age-related ocular diseases and improving the quality of life for aging populations. Continued research is essential to translate these insights into practical, widely applicable therapies.

Author contributions

C.Z.: Writing–review & editing, Writing–original draft, Resources, Project administration, Formal analysis. J.W.: Writing–review & editing, Methodology, Formal analysis, data curation. X.S.: Writing–original draft, data curation. Y.L.: Project administration, Formal analysis. J.H.: Writing–review & editing. X.Z.: Formal analysis, data curation. W.D.: Writing–original draft. Z.L.: data curation. Y.Z.: Resources. Z.X.: Supervision, Project administration. W.S.: Supervision, Project administration. X.L.: Supervision, Project administration, Investigation. Y.Z.: Supervision, Project administration, Investigation.

Data availability

No datasets were generated or analyzed during the current study.

Competing interests

The authors declare no competing interests.