Iron Overload and Cellular Aging: The Critical Interplay Between Iron and Copper in mTOR Signaling and Oxidative Stress

Introduction

Iron and copper, while fundamental to our diet, play pivotal roles far beyond basic nutrition. They are integral to our overall health and have profound impacts on the aging process. While the importance of iron in oxygen transport and energy production is well recognized, its potential to cause oxidative stress and stimulate the mTOR pathway—both of which can accelerate aging—is less appreciated. Similarly, copper is crucial not only for its role in enzyme activation and energy production but also for its ability to regulate iron levels, thus influencing aging processes.

This review examines how imbalances in iron and copper metabolism can accelerate aging, with a focus on oxidative stress, mitochondrial dysfunction, and mTOR dysregulation. We also address the challenges posed by iron toxicity, a condition often misdiagnosed as iron deficiency, which can exacerbate health issues due to unrecognized excess iron.

Additionally, we explore how copper's influence over iron metabolism can mitigate some of these aging processes. We analyze how copper's regulatory influence on iron can mitigate these adverse effects by reducing iron levels, thus inhibiting mTOR activity and decreasing reactive oxygen species (ROS) production and inflammation.

By understanding these mechanisms, we aim to deepen the appreciation of the profound impacts these minerals have on our health and develop targeted strategies to address age-related health concerns, thereby promoting a path to healthier aging.

The Essential Role of Dietary Iron in Overall Health

Before exploring iron’s impact on aging, it is important to understand its fundamental roles in a healthy state. Iron plays an essential role in maintaining our health, primarily by forming a crucial component of hemoglobin, the protein in red blood cells responsible for oxygen transport from the lungs to body tissues. This vital function ensures all body tissues have the oxygen they need to function effectively. Additionally, iron contributes to myoglobin production, a muscle cell protein that regulates oxygen storage and release. [1]

Beyond its critical roles in oxygen transportation and storage, iron is integral to numerous other cellular functions, including growth, neurological development, and hormone synthesis. It also supports the health of connective tissues and ensures smooth cellular operations, underpinning various bodily functions from movement to cognition. [2]

Iron's importance extends to the immune system as well. It aids in developing and maturing immune cells essential for defending the body against pathogens. During an infection, the body employs a strategy known as 'nutritional immunity,' limiting iron availability to pathogens by sequestering it in storage proteins such as ferritin. This helps prevent pathogens from accessing the iron they need to thrive, aiding in infection control. [3]

Dietarily, iron is consumed in two primary forms: heme and non-heme. Non-heme iron is found in plants and fortified foods, while heme iron is crucial for hemoglobin's oxygen-carrying capacity in meats, seafood, and poultry. The body utilizes heme iron more efficiently than non-heme iron, highlighting the importance of dietary balance to ensure adequate iron intake. [2]

The Role of Copper in Human Physiology

Before exploring the interactions between copper and iron and their effects on aging, it is essential to grasp copper's foundational role in human physiology. As an essential trace element, copper must be consumed adequately through the diet to support vital bodily functions. However, it presents a paradox: while indispensable for health, copper can become toxic in excessive amounts.

Copper is crucial for synthesizing several proteins essential for our bodies to operate correctly. Insufficient copper intake can lead to significant health issues, such as bone problems in infants and an increased risk of osteoporosis in adults. Osteoporosis is a condition that results in weakened bones, which become fragile and more susceptible to fractures. This bone-weakening disease is characterized by decreased bone density and increased porosity, particularly affecting the hips, spine, and wrists. Additionally, copper deficiency is associated with a compromised immune system and an increased likelihood of infections. [7] [8]

One key question is how copper facilitates its various roles within the body. The answer lies in its involvement with enzymes, which are biological proteins that act as catalysts to accelerate physiological processes, ensuring they proceed at rates conducive to survival. Copper is integral to the activation of many enzymes.

For instance, cytochrome c oxidase, which depends on copper, is crucial for energy production in the mitochondria—the cells' powerhouses. Another enzyme, lysyl oxidase, requires copper to synthesize strong connective tissues such as tendons and ligaments. Additionally, copper is involved in the activity of dopamine β-hydroxylase, an enzyme essential for dopamine synthesis, a neurotransmitter that influences mood and movement. [8]

Moreover, as we will discuss in more detail later in this review, copper plays a significant role in iron metabolism—this is critical to reducing the inflammatory and mTOR stimulatory effects of iron. It is a critical component of ceruloplasmin, an enzyme that modifies iron into a form that can bind to transferrin for body-wide transport. Copper also helps regulate the release of iron from cells, maintaining a balance of iron levels within the body. The function of ceruloplasmin to transport, convert, and regulate iron highlights the importance of copper in iron metabolism. [8]

Copper is indispensable in our physiology and is required to produce vital proteins and activate enzymes crucial for numerous bodily functions. While a copper deficiency can lead to serious health problems such as bone deterioration and cardiovascular issues, excessive copper can be toxic. Copper's pivotal role in enzyme activation, especially those related to energy production, connective tissue formation, and neurological functions, and its critical involvement in iron metabolism underscores its essential nature in maintaining overall health and balance within the body.

The Interplay of Copper and Iron

Before we explore the role of excess iron levels in cellular aging, it is important to understand the role of copper in maintaining appropriate iron levels. This relationship has significant implications for aging.

The interplay of copper and iron metabolism is intricate and begins as these minerals are absorbed in the duodenum, the first part of the small intestine. Iron binds to transferrin, a protein that transports it through the bloodstream to the liver. Iron can be stored as ferritin in the liver or released back into circulation, primarily destined for the bone marrow to aid in red blood cell synthesis. This synthesis is crucial as red blood cells transport oxygen from the lungs to tissues throughout the body. [9]

Copper, when absorbed, is also transported to the liver, but it travels bound to different proteins such as albumin or α2-macroglobulin. Within the liver, copper may either be incorporated into ceruloplasmin, a copper-containing enzyme, or excreted into bile to assist digestion. The role of ceruloplasmin is particularly significant in iron metabolism; it acts as a facilitator for releasing iron from tissues, enhancing its availability for essential processes such as hemoglobin formation. This enzyme ensures that copper and iron work in concert within the body, optimizing the production and function of red blood cells. [9]

Beyond dietary sources, iron is also recycled from old cells and tissues. This recycling process primarily occurs through the actions of reticuloendothelial macrophages, which recover iron from aged red blood cells. The liver plays a central role in regulating this iron balance with the hormone hepcidin, which controls iron absorption from the intestine and the release from macrophages and liver stores. Iron is not actively excreted from the body; it is lost incidentally through shedding skin and intestinal cells and minor bleeding. [9]

The synergistic relationship between copper and iron is essential for maintaining several bodily functions. After absorption, copper's binding to ceruloplasmin or its entry into bile facilitates the digestion and metabolic processes. Simultaneously, iron's binding to transferrin and its eventual use in the bone marrow for red blood cell production highlights the dependency on copper-mediated mechanisms. Together, these processes illustrate the body's efficiency in managing and utilizing iron and copper to sustain essential functions and overall metabolic balance. [9]

Implications of Iron and Copper Metabolism in Aging

Iron and copper are essential minerals that play significant roles in aging due to their involvement in cellular and metabolic functions. Let’s first review how iron levels, in excess, impact important longevity pathways. We will review the role of iron in creating oxidative stress and its role in stimulating the mTOR pathway.

Iron's Role in Generating Oxidative Stress

Iron contributes to aging at least partially through the generation of reactive oxygen species (ROS). ROS are unstable molecules containing oxygen, produced as byproducts of metabolic processes. While crucial for specific cellular signaling pathways, these molecules can cause substantial damage if not appropriately regulated. Iron can catalyze the formation of ROS, mainly when it reacts with hydrogen peroxide, another type of ROS. This reaction can lead to oxidative stress, where excessive ROS damages cells, lipids, proteins, and DNA. [10]

Oxidative damage to DNA can lead to mutations and genomic instability, a hallmark of aging and cancer [19]. Proteins, when oxidatively modified, may lose their functional integrity, leading to the accumulation of dysfunctional proteins that can aggregate, interfering with cellular processes.

Oxidative stress reflects an imbalance between ROS production and the body's ability to detoxify these reactive products and repair the damage. This imbalance can accelerate the aging process and contribute to the development of age-related diseases. For instance, lipid peroxidation, a specific type of damage where ROS oxidizes lipids in cell membranes, leads to cell dysfunction and death, impacting overall health and longevity. [10]

ROS and Mitochondrial Health

Moreover, mitochondria, the energy powerhouses of cells, are central to ROS production. According to the free radical theory of aging, the accumulation of oxidative damage in mitochondria is a primary contributor to aging. Studies suggest that iron accumulation in mitochondria, due to decreased regulation by proteins such as frataxin, exacerbates mitochondrial dysfunction. This dysfunction is a critical factor in cellular aging and related pathologies. [11]

ROS and Inflammation

ROS levels can initiate and propagate inflammatory responses. This initiation often occurs through the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a critical transcription factor in the inflammatory pathway.

When cells are under oxidative stress due to high levels of ROS, NF-κB is activated. Once activated it upregulates the expression of various pro-inflammatory cytokines, chemokines, and adhesion molecules. These molecules are pivotal in amplifying inflammatory processes, recruiting immune cells to the site of stress or injury, and further amplifying the inflammatory response.

The relationship between ROS and inflammation creates a cycle where oxidative stress leads to inflammation, and inflammation, in turn, induces further ROS production. For example, activated immune cells, such as macrophages and neutrophils, produce more ROS as a part of the respiratory burst, an antimicrobial response mechanism. This additional ROS production can exacerbate oxidative stress, leading to further cellular damage and contributing to the aging process.

Moreover, chronic inflammation itself is a recognized contributor to aging and a variety of age-related diseases, such as arthritis, diabetes, cardiovascular diseases, and neurodegenerative disorders [20]. The persistent presence of inflammatory signals and the continuous release of ROS can lead to a state known as inflammaging — a chronic, low-grade inflammation that is associated with aging.

Iron, ROS, and Systemic Aging

The systemic accumulation of iron and the associated increase in ROS have been linked to several age-related conditions, including neurodegenerative diseases like Alzheimer's and Parkinson’s, where iron deposition in the brain is a common feature [21]. While iron is indispensable in the context of oxygen transport and other metabolic processes, its role in ROS production highlights a dual nature where its essential functions can also lead to harmful effects when levels get too high.

Iron and Heightened mTOR Signaling

We’ve established how iron plays a critical role in oxygen transport and energy metabolism. However, its involvement in signaling pathways, particularly the mammalian target of rapamycin (mTOR) pathway, has significant implications for cellular aging and dysfunction.

When we eat a diet with excess nutrients, our bodies respond by ramping up a pathway called mTOR. The mTOR pathway is responsible for regulating cell growth and replication. You can think of mTOR as the air-traffic controller for cellular growth. When a cell is exposed to growth stimuli or an excess of nutrients, mTOR coordinates cellular protein synthesis and cell growth.

Conversely, when nutrients are scarce, mTOR coordinates the cell's autophagy machinery to recycle cellular debris and convert it into cellular energy to compensate for the lack of nutrients. This process of autophagy is the cell's built-in programming to preserve energy in states of nutrient deprivation while simultaneously creating a cellular 'deep cleaning' phenomenon.

As we get older, mTOR may stay active all the time—opening the door to out-of-control cell growth that can lead to cancer and closing the door on cell repair. When mTOR is overactive, cell growth becomes excessive, and cell output becomes toxic to the tissue. The defining characteristic of these dysfunctional cells is that they grow excessively large, over-excrete toxic proteins, chemicals, and inflammatory molecules, and cause excessive tissue growth by releasing excessive growth factors and mitogens (molecules that cause cells to replicate). This overactivity accelerates the formation of unhealthy tissue and age-related chronic diseases. When patients take rapamycin for geroprotective reasons, they specifically target the inhibition of mTOR to decelerate this process.

Research indicates that iron can, directly and indirectly, activate mTORC1, the complex associated with mTOR responsible for sensing amino acids and cellular energy levels. Iron's role in the activation of mTORC1 is partly attributed to its interaction with REDD1, a protein that inhibits mTORC1 under stress conditions such as hypoxia. When iron is abundant, REDD1 is degraded, thereby alleviating its inhibitory effect on mTORC1, leading to increased mTOR signaling [22].

Furthermore, iron-sulfur clusters, essential cofactors for a variety of cellular enzymes, also play a role. These clusters are critical for mitochondrial function and help in the regulation of cellular energy balance, which in turn influences mTOR activity. An overload of iron disrupts the normal function of these clusters, leading to mitochondrial dysfunction and increased oxidative stress, which further stimulates mTOR signaling [23]. Altogether we see stimulating mTOR activity, which has a number of implications for aging.

Implications of Iron in Induced mTOR Stimulation for Cellular Dysfunction and Aging

The overactivation of mTOR by excess iron leads to several cellular changes that are characteristic of aging. These include increased protein synthesis, inhibition of autophagy, and cellular senescence. Autophagy, a process for degrading and recycling cellular components, is particularly affected. mTOR is a known inhibitor of autophagy; thus, its stimulation by iron can lead to decreased autophagic activity, contributing to the accumulation of damaged proteins and organelles, a hallmark of aging cells [24].

We can see how iron abundance stimulates ROS production, inflammation, and mTOR activity. Now let’s revisit the role of copper in the aging process. In particular, let’s re-examine how copper can potentially regulate iron levels, reduce oxidative stress, and its role in promoting mitochondrial health.

Copper's Role in Aging

Like iron, copper's influence on aging is critical, primarily due to its role in enzymatic reactions that mitigate oxidative damage. Copper is vital for the function of several enzymes, including superoxide dismutase (SOD1), which neutralizes one of the most damaging ROS, superoxide. Inadequate copper intake can limit the body's capacity to defend against oxidative damage, contributing to accelerated aging and various age-related conditions. [12]

The Lesser-Known Connections of Iron and Copper in Aging and Metabolic Health

While iron and copper are often thought of primarily in terms of their roles in oxygen transport and enzyme function, they actually play crucial roles in metabolic health that directly impact aging. These trace minerals are involved in subtle yet critical biochemical pathways that influence energy metabolism and glucose control. These actions are key to preventing conditions like diabetes. [15]

Iron is essential for creating ATP (adenosine triphosphate), which you can think of as the currency of energy within cells. This process mainly occurs in the mitochondria, the power plants of our cells, where enzymes that depend on iron convert the energy from our food into usable ATP. If there's not enough iron, our body can't produce as much ATP, leading to symptoms like fatigue and reduced physical performance, which are especially pronounced in older adults.

Furthermore, iron is important in the metabolism of glucose, the sugar that serves as a primary energy source. However, having too much or too little iron can disrupt how our body handles glucose, which could lead to insulin resistance—an issue that increases the risk of developing type 2 diabetes. This risk is partly due to iron overload causing oxidative stress, a condition where there is an imbalance between free radicals (damaging molecules) and antioxidants in the body, which can damage cells and reduce the efficiency of the pancreas. [15]

Copper, like iron, is integral to our metabolic health but works through different mechanisms. It is critical for activating certain enzymes needed for both energy production and protecting cells from oxidative damage. These enzymes not only help in the synthesis of ATP but also play a role in defending the body against the cellular wear and tear that contributes to aging. Copper’s influence extends to how our body regulates glucose levels as it affects the secretion and activity of insulin, the hormone responsible for controlling blood sugar levels. A lack of copper can lead to inadequate insulin function, which can disturb normal glucose metabolism and contribute to metabolic issues commonly seen in aging populations. [15]

Interactions Between Copper and Iron Metabolism: Implications for mTOR Activity and Cellular Aging

Copper and iron metabolism are closely intertwined, with copper playing a critical role in regulating iron levels. One of the key proteins in iron metabolism is ceruloplasmin, a copper-containing enzyme that is essential for the efficient export of iron from cells to the plasma [25].

Ceruloplasmin facilitates the conversion of iron from its insoluble ferrous form (Fe^2+) to the soluble ferric form (Fe^3+), which is necessary for its binding to transferrin, the main iron transport protein in the blood. In conditions where copper levels are elevated, the activity of ceruloplasmin is enhanced, leading to increased iron mobilization and a decrease in cellular iron stores.

Moreover, copper can also compete with iron for absorption in the gastrointestinal tract. Increased dietary copper can lead to decreased iron absorption due to competitive inhibition at shared transport channels, further reducing systemic iron levels.

The reduction of iron levels within cells has significant implications for the activity of the mTOR pathway. As previously mentioned, iron is a critical cofactor for several enzymes involved in mitochondrial function and energy metabolism, which are key regulators of mTOR activity. Lowered iron availability leads to reduced production of ATP, resulting in decreased energy status within the cell. This energy deficit can inhibit the activity of mTORC1, which is sensitive to cellular energy levels [26].

The interaction between copper and iron has profound effects on cellular function through the modulation of mTOR activity. By reducing iron levels, copper indirectly contributes to the downregulation of mTOR, which can have beneficial effects, such as enhanced autophagy and reduced cellular senescence, potentially slowing down the aging process and decreasing the risk of age-related diseases.

Monitoring Iron and Copper Biomarkers

Monitoring and managing the levels of iron and copper, along with associated markers like Total Iron-Binding Capacity (TIBC), transferrin saturation, and ferritin, is critical for maintaining metabolic health and mitigating the effects of aging. TIBC measures the blood's capacity to bind iron with transferrin, the main protein in the blood that binds iron and transports it throughout the body. An increase in TIBC can indicate the body's increased demand for iron, often due to a deficiency, while a decrease suggests iron overload, where less capacity is needed because of excessive iron.

Transferrin saturation shows the percentage of transferrin molecules that are currently bound with iron. This marker helps assess the status of iron transport within the body. High transferrin saturation levels can indicate an iron overload, which can lead to oxidative stress—a condition that produces harmful free radicals known to damage cells, proteins, and DNA. This oxidative stress is a significant contributor to chronic inflammation, a root cause of many metabolic disorders, including insulin resistance and type 2 diabetes.

Furthermore, ferritin, which stores iron in the body, serves as an acute-phase reactant that can increase in response to inflammation. Elevated ferritin levels can thus be indicative of both iron overload and an active inflammatory process. Chronic inflammation is closely linked to metabolic syndrome, a cluster of conditions that heighten the risk of heart disease and diabetes. The syndrome itself is characterized by increased waist circumference, elevated triglycerides, reduced HDL cholesterol, elevated blood pressure, and higher fasting glucose levels—all factors that can be exacerbated by dysregulated iron metabolism.

Regular assessments of these iron-related biomarkers, particularly in individuals experiencing chronic inflammation or those at risk for metabolic syndrome, are crucial. By monitoring these levels, healthcare providers can intervene with lifestyle adjustments or medications to manage iron and copper balance, reducing inflammation and improving overall metabolic health. These interventions are key to optimizing health outcomes and promoting longevity. [16]

The Concern of Iron Overload

As we have discussed, iron is a fundamental element in the human body. But despite its vital roles, the presence of iron in amounts exceeding physiological needs can lead to toxicity. This condition is not only frequently overlooked but is also often misdiagnosed as iron deficiency. The misdiagnosis and general lack of awareness regarding iron excess can delay appropriate treatment and exacerbate health issues. [17]

Research by leading iron biologists suggests that humans typically accumulate about 1 mg of iron each day of their life. Over the span of 60 years, this results in a total accumulation of approximately 21,900 mg of iron. To put this into perspective, 21,900 mg of iron is roughly the equivalent contained in 87 units of blood, or 43.5 liters. Considering that an average human body contains only about 6 liters of blood—each unit containing 250 mg of iron in 500 ml—the potential for systemic overload becomes apparent. This accumulation highlights a critical oversight in current medical understanding and public health policy. [17]

The connection between iron overload and a range of severe health conditions is well-supported by scientific research. Disorders such as Alzheimer’s disease, Parkinson’s disease, autism, arthritis, cardiovascular diseases, cancer, arrhythmias, depression, chronic fatigue syndrome, fibromyalgia, hair loss, hypothyroidism, liver cirrhosis, glaucoma, and even accelerated aging have all been associated with high levels of iron in the body. Unfortunately, these links are often either misunderstood or ignored across various medical disciplines, leading to suboptimal clinical outcomes. [18]

The detrimental effects of iron overload are mediated through several key mechanisms, including the overstimulation of the mTOR pathway, increased production of reactive oxygen species (ROS), and the promotion of inflammation. Each of these factors plays a significant role in the pathogenesis of the aforementioned conditions:

1. Overstimulation of mTOR: Excessive iron can hyperactivate the mTOR signaling pathway, which is crucial for cell growth and survival but, when dysregulated, contributes to pathological processes including cellular senescence and tumorigenesis. For instance, in cancer and neurodegenerative diseases like Alzheimer’s and Parkinson’s, aberrant mTOR activity exacerbates disease progression by impairing normal cellular functions and promoting detrimental cellular states.

2. Increased ROS production: Iron catalyzes the formation of highly reactive hydroxyl radicals through the Fenton reaction, leading to oxidative stress. This oxidative stress damages cellular components such as DNA, proteins, and lipids, contributing to the onset and progression of diseases like arthritis, cardiovascular diseases, and liver cirrhosis. In neurological disorders, the oxidative damage can exacerbate neuronal degeneration and dysfunction.

3. Promotion of inflammation: The inflammatory response induced by iron-driven oxidative stress is a critical factor in diseases such as arthritis and cardiovascular diseases. Chronic inflammation, driven by continuous oxidative stress, leads to a deleterious cycle that perpetuates tissue damage and disease progression.

Furthermore, the dynamics of iron accumulation are complicated by its interaction with other minerals, notably copper. Studies have demonstrated that iron accumulates more rapidly in the presence of a copper deficiency. This deficiency impairs the uptake of bioavailable copper, exacerbating the problem of iron overload. Copper is essential for the proper functioning of enzymes that regulate iron export from cells, and a deficiency can lead to increased cellular iron, further fueling the pathological processes driven by mTOR activation, ROS, and inflammation. [18]

The balance of iron in the body is a delicate matter. While essential in moderate amounts, excess iron poses significant health risks, compounded by common misdiagnoses and a lack of awareness in the medical community. Addressing this issue requires a concerted effort to refine diagnostic criteria, improve public and professional understanding, and adjust therapeutic approaches considering the intricate interplay between iron and other minerals like copper.

Conclusion

The intricate roles of iron and copper in human health extend far beyond their basic nutritional functions, influencing critical aspects of metabolic health and the aging process. These essential minerals are integral not only to energy production, immune function, and neurological health but also play profound roles in metabolic stability and cellular aging dynamics. Iron, crucial for ATP synthesis and glucose metabolism, interacts significantly with mTOR pathways and reactive oxygen species (ROS) generation. Copper, vital for activating enzymes in energy production and antioxidant defense, also affects iron levels by regulating ceruloplasmin and iron absorption, thereby influencing insulin secretion and glucose regulation.

The relationship between iron-induced ROS and cellular dysfunction is especially noteworthy. Excessive iron catalyzes the production of ROS, leading to oxidative stress which can trigger inflammatory responses, further exacerbating cellular aging and contributing to diseases such as diabetes by impairing pancreatic beta-cell function. Conversely, copper’s role in reducing iron levels can mitigate these effects by decreasing mTOR activity, which in turn supports autophagy and reduces cellular senescence.

Maintaining a delicate balance of these minerals is crucial, as imbalances can lead to significant metabolic and cellular disturbances. Excess iron, for example, not only induces oxidative stress but also stimulates inflammatory pathways, contributing to aging and associated metabolic disorders. Similarly, copper deficiency can compromise metabolic functions and exacerbate health issues.

Through a deeper understanding of the complex interactions between iron and copper, and their effects on processes like mTOR signaling, ROS generation, and inflammation, we can develop targeted strategies to mitigate age-related declines and promote healthier aging. By optimizing iron and copper levels and ensuring their balanced metabolism, we can enhance metabolic stability, reduce the risk of age-related diseases, and improve overall well-being throughout the aging process. This holistic approach underscores the significance of trace minerals in aging and metabolic health, highlighting potential therapeutic avenues to address age-associated challenges.