REVIEW ARTICLE

Magnesium in aging and aging-related disease

Zhiguo Zou^1†, Qifan Lu^1†, Yifan Wang¹, Xing Gao², Xinye Zhu¹, Xiyuan Lu^1* and Jun Pu^1*

¹Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China; ²Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

Abstract

Magnesium (Mg²⁺) is an essential divalent cation in human body. Its balance is tightly controlled via a balanced interplay among intestinal absorption, storage, and renal excretion, involving multiple transporters across cell membrane that regulate Mg²⁺ influx and efflux. Mg²⁺ is involved in a variety of physiological and pathological processes such as enzymatic reactions, energy metabolism, cell proliferation, apoptosis, oxidative stress, and inflammation. In particular, Mg²⁺ contributes to the molecular hallmarks of aging. Emerging evidence demonstrates that altered Mg²⁺ status has been associated with many aging-related diseases, including cancer, cardiovascular disease, neurodegenerative disease, musculoskeletal function, metabolic syndrome, and COVID-19. In this review, we focus on Mg²⁺ and its association with molecular hallmarks of aging. We also summarize recent findings supporting an important role of Mg²⁺ in aging-related disease including the COVID-19 pandemic.

Keywords: magnesium; magnesium transporters; aging; human disease

 

 

Magnesium (Mg²⁺) is the eighth most common element in the earth’s crust (1). It is involved in various cellular activities, including signal transduction, ion transport, nucleic acid, protein synthesis, genomic stability, energy supply, and metabolic homeostasis (2). Due to its physiological significance, Mg²⁺ balance in human body and intracellular Mg²⁺ homeostasis needs to be tightly controlled via a dynamic interplay between intestinal absorption and renal excretion, involving multiple transporters across cell membrane that regulate Mg²⁺ influx and efflux (1). Mg²⁺ transporters include claudins, transient receptor potential melastatin 7 (TRPM7), TRPM6, solute carrier family 41 (SLC41), ancient conserved domain protein/cyclin M (CNNM), magnesium transporter 1 (MagT1), and mitochondrial RNA splicing 2 (Mrs2) (3, 4). Both hypomagnesemia and hypermagnesemia lead to human diseases. Chronic Mg²⁺ deficiency contributes to an increased risk of a variety of clinical disorders, such as cardiovascular diseases (CVDs), including hypertension and cardiac arrhythmias, stroke, type 2 diabetes, metabolic syndrome, depression, and neuropsychiatric disorders (5).

Aging is a progressive loss of physiological integrity and characterized by an increasing susceptibility to the development of multiple chronic diseases (6). The aging process involves various changes at the cellular, organ, and body levels. In general, aging encompasses multiple modes induced by DNA damage, oxidative stress, drug damage, mitochondrial dysfunction, paracrine secretion, or telomere shortening (7). Aging also leads to an increased incidence of numerous human diseases, such as CVDs, neurodegenerative diseases, immune disorders, respiratory diseases, cancers, and infections (8).

In this present review, we provide an illustrative overview of Mg²⁺ balance in human body and the underlying mechanisms involving various Mg²⁺ transporters. We also discuss the involvement of Mg²⁺ in molecular hallmarks of aging, with a focus on the important role of Mg²⁺ in aging-related human diseases.

Mg²⁺ and human health

Mg²⁺ basics

Mg²⁺ is highly soluble and, therefore, readily available to living organisms (9). As the fourth most abundant cation in the body behind sodium, potassium, and calcium, Mg²⁺ is present in three forms, free, ionized (55–70%), protein-bound (20–30%), and forming complexes with anions such as phosphate, bicarbonate, and citrate (5–15%). In healthy individuals, serum concentration of total Mg²⁺ is maintained tightly within a range between 0.65 and 1.05 mmol/L (1). Bone functions as a large buffer pool contribute to the maintenance of serum Mg²⁺ concentrations (10). Total Mg²⁺ concentration in mammalian cells is in the 17–20 mM range, mostly located in mitochondria, nucleus, and endoplasmic reticulum (11). Within these organelles, Mg²⁺ is bound to phospholipid, proteins, nucleic acids, chromatin, and nucleotides. Cytoplasmic Mg²⁺ is the last and well detectable pool of intracellular Mg²⁺, with the majority complexed with Adenosine Triphosphate (ATP) phosphonucleotides, and phosphometabolites (11, 12). With the application of novel Mg²⁺-selective fluorescent probes and the development of new imaging techniques, cellular Mg²⁺ homeostasis awaits more accurate and dynamic evaluation (13). Mg²⁺ is an essential element for normal life activities, and Mg²⁺ homeostasis is precisely regulated to maintain functional stability of cells.

Mg²⁺ transporters and Mg²⁺ homeostasis

Mg²⁺ is absorbed mainly in the small intestine (mainly in the jejunum and the ileum), stored in bone mineral, and excreted through urine and feces (14). In the small intestine, paracellular absorption is driven by higher luminal Mg²⁺ concentrations (1.0–5.0 mmol/L) and accounts for 80–90% of Mg²⁺ uptake (15). The kidneys regulate serum Mg²⁺ concentrations through excretion and reabsorption. Mg²⁺ excretion follows a circadian rhythm and only 3–5% of serum Mg²⁺ is excreted, and the thick ascending limb of the loop of Henle reabsorbs 60–70% of the filtered Mg²⁺, with about 10% reabsorbed in the distal tubule (3, 16). Under physiological conditions, the tightly regulated balance of Mg²⁺ intestinal uptake, intracellular storage, and renal excretion is achieved through a specialized transport system consisting of Mg²⁺ transporters across biological membranes (Fig. 1).

Fig. 1. Mechanism of Mg²⁺ balance in the body. Mg²⁺ is absorbed mainly in the intestine and excreted through the kidney. Claudin-16, Claudin-19, TRPM6/7, Mrs2, SLC41A1/3, and CNNM2/4 are transporters of Mg²⁺. Receptor tyrosine kinase (RTK) and its ligands such as epidermal growth factor (EGF) influence Mg²⁺ homeostasis by regulating Mg²⁺ transporters.

Biological function of Mg²⁺

Mg²⁺, as a cofactor, has been involved in more than 600 enzymatic reactions and exerts critical effects in a variety of cellular biological activities (11, 17). Mg²⁺ is indispensable for major cellular processes, including energy metabolism, apoptosis, and proliferation. Mg²⁺ acting as an allosteric modulator or as a cofactor in the form of Mg-ATP modulates the activity of enzymes implicated in glycolysis, the Krebs cycle, and the respiratory chain, core processes of energy metabolism (18). Mechanisms whereby Mg²⁺ regulates cell proliferation involve the cell cycle inhibitor p27 and p53, and other negative modulators of cell proliferation such as Jumonji and numblike (18, 19). Evidence for the role of Mg²⁺ in cell apoptosis remains inconclusive. In many experimental models, Mg²⁺ deprivation induced cell death by apoptosis, and dietary Mg²⁺ restriction accelerated apoptosis (18, 20, 21).

X-ray crystal structure analysis reveals that Mg²⁺ specifically binds to the major and minor grooves of DNA (22, 23). Mg²⁺ stabilizes the DNA conformation by electrostatic force or hydrogen bonds and contributes to the secondary and tertiary structure of DNA (24, 25). DNA aggregation study showed that DNA fragments strongly aggregated on Mg²⁺-treated glass and in Mg²⁺ solution in a concentration-dependent manner (26). Thus, the maintenance of intracellular Mg²⁺ at a physiological level is important for DNA stability. Additionally, abnormal Mg²⁺ concentrations can also lead to oxidative stress and damage to the double-stranded structure, thus weakening the DNA stability (27, 28). Moreover, Mg²⁺ is required for a variety of enzymes involved in DNA repair pathways, such as nucleotide excision repair (NER), base excision repair (BER), and mismatch repair (MMR), indicating the important role of Mg²⁺ in maintaining genome stability (29–31).

Both in vitro and in vivo experiments have demonstrated that a decreased level of Mg²⁺ affects the behavior of leukocytes and vascular endothelial cells and activates the production of inflammatory factors in acute inflammation (32). The underlying mechanisms involve the upregulation of stress proteins and Nuclear Factor -kappa B (NF-kB) pathways, and the impairment of Ca²⁺ dynamics (33). Increased reactive oxygen species (ROS) and altered Ca²⁺ dynamics induced by low Mg²⁺ further lead to impaired mitochondrial function (34). In chronic diseases, Mg²⁺ inhibits oxygen free radical production and mast cell degranulation, protects epithelial cells, and alleviates the inflammatory and oxidative damage to cells and blood vessels (35). Moreover, reduced Mg²⁺ has been observed in a variety of diseases, such as CVD, asthma, preeclampsia, osteoporosis, inflammatory bowel disease, mental health disorders, and neurodegenerative disease (36–38).

Mg²⁺ and aging

Aging is a progressive reduction of the body’s physiological and psychological adaptability to the environment, leading to increased vulnerability to death. Studies have linked aging to molecular cross-linking, free radicals-induced damage, changes in immune function, telomere shortening, and the presence of senescence genes in DNA (7, 39). However, there is not a single theory that can completely explain the aging process, indicating that it is a complicated process regulated by multiple factors at the genetic and cellular levels, and by the environment and society. Previous studies have demonstrated several cellular and molecular hallmarks of aging, including telomere attrition, mitochondrial dysfunction, genome instability, epigenetic alterations, a loss of proteostasis, dysregulated nutrient sensing, cellular senescence, stem cell exhaustion, and altered intracellular communication (Fig. 2) (40). In this review, we focus on several hallmarks of aging, which have been closely associated with Mg²⁺.

Fig. 2. The role of Mg²⁺ in cell physiology, aging, and aging-related disease. Mg²⁺ contributes to the regulation of intracellular environment, signaling pathways, cation concentration, and mitochondrial function. Mg²⁺ is critically linked to molecular hallmarks of aging and is involved in the development of aging-related disease.

Mg²⁺ and telomere attrition

Telomere consists of a 6-bp repeat sequence, TTAGGG. It is located at the ends of chromosomes, which shortens gradually with each cell division and ultimately limits cellular proliferative capacity (41). Telomeric chromatin structure and integrity are influenced by Mg²⁺. Telomere (>50%) is localized in the nuclear laminae, and their trailing laminin-binding proteins are dependent on the presence of Mg²⁺ (42). In addition to maintaining the telomere structure, Mg²⁺ also contributes to the regulation of telomerase; the enzyme catalyzes the addition of guanine-rich repetitive sequences to maintain telomeres (43). Telomerase reverse transcriptase (TERT) is the catalytic component of telomerase (44). TERT is known to exerts its biological effects through an interaction with the mammalian target of rapamycin (mTOR) pathway, which is sensitive to changes of Mg²⁺ status (45). Liu et al. found that Mg²⁺ can activate the mTOR signaling, which consequently protects against the age-related decline in muscle regenerative potential and muscle mass (46). Additionally, circadian fluctuation of mTOR is regulated through Mg²⁺ oscillations in a MgATP-sensitive manner (45). Altered circadian rhythms affect the expression of TERT mRNA and accelerate the aging process, and fluctuations in Mg²⁺ are critically implicated in the modulation of cellular clock and play a role in aging-related diseases (47).

Mg²⁺ and mitochondrial dysfunction

Intracellular Mg²⁺ deficiency has been shown to affect coupled respiration, increase ROS production, and inhibit the antioxidant defense systems, including superoxide dismutase (SOD), catalase, and glutathione, leading to the disruption of mitochondrial function (48). A reduction in intracellular Mg²⁺ also disturbs mitochondrial Mg²⁺ homeostasis through modulating mitochondrial RNA splicing 2 (Mrs2), a Mg²⁺ transporter specifically involved in mitochondrial Mg²⁺ influx and promoting mitochondrial Mg²⁺ efflux via the 41st family of solute carrier member 3 (SLC41A3) (49). The regulation of mitochondrial Mg²⁺ by Mrs2 has significantly influenced cellular energy status and cellular vulnerability. Mrs2 knockdown induces loss of electron transport chain complex I, decreases cellular and nuclear ATP levels, depolarizes ΔΨm, and renders cells sensitive to oxidative stress inducers and apoptotic stimuli (48). In line with this, the overexpression of Mrs2 enhances cellular resistance to apoptosis-inducing drugs (50).

SLC41A3 is a novel transporter important for mitochondrial Mg²⁺ efflux, and its mRNA expression was increased under Mg²⁺-deficient conditions (51). Intriguingly, intracellular ATP levels were reduced in cells with SLC41A3 overexpression, indicating that the transporter contributes to mitochondrial ATP production (52). Studies based on obesity models show that during ischemia and hypoxia, the increase of extracellular Mg²⁺ was associated with decreased ATP levels and TRPM7 inhibition, leading to exacerbated cell damage (53, 54). Moreover, reduced intake of Mg²⁺ and consequent low serum Mg²⁺ level induce oxidative stress injury through decreasing antioxidant enzyme activity, activating the inflammatory pathways, lipid peroxidation, and endothelial dysfunction (55). Dietary Mg²⁺ supplementation in a mouse model of premature aging has been shown to enhance the mitochondrial membrane potential and consequently increase H⁺-coupled mitochondrial NADPH and ATP productions, leading to an extended life expectancy (56).

Mg²⁺ in genomic instability and epigenetic alterations

As early as 1976, it was shown that Mg²⁺ in DNA polymerase is essential for the fidelity of DNA replication (57). Acting as an essential cofactor for the DNA damage repair process, Mg²⁺ contributes to the stabilization of the chromatin structure during the cell cycle (58). However, in cells undergoing apoptosis, intracellular levels of free Mg²⁺ are increased, constituting an early event in the process of apoptosis (59). At the protein level, Ca²⁺- and Mg²⁺-dependent endonucleases have been implicated in DNA breaks during apoptosis (60). Furthermore, Mg²⁺ has been linked to epigenetics, and DNA methylation is associated with chromatin compaction and gene silencing.

In the offspring of Mg²⁺-deficient dams, 11β-hydroxysteroid dehydrogenase-2 (Hsd11b2) CpG promoters displayed substantial hypermethylation, contributing to downstream down-regulated gene expression (61). In pregnant rats, Mg²⁺ deficiency induced by a low Mg²⁺ diet is able to affect the methylation of specific cytosines in the hepatic glucocorticoid genes and consequently cause metabolic complications in the neonatal offspring (62). In addition, even a short-term deprivation of dietary Mg²⁺ has been shown to greatly upregulate neutral-sphingomyelinase (N-SMAse) and p53 in cardiomyocytes, which is associated with genomic changes that are important in the development of aging (63).

Mg²⁺ and metabolic disturbances

Many studies have demonstrated metabolic characteristics of aged animals, such as glucose intolerance, insulin resistance, decreased fatty acid oxidation, mitochondrial biosynthesis, and impaired oxidative phosphorylation (64). Mg²⁺ exerts its significant impact on the metabolic state through functioning as a cofactor of critical enzymes in mitochondria, where Mg²⁺ binds to ATP and forms Mg-ATP complex to regulate the glycolytic enzymes (65). Mg²⁺ contributes to the activation of mitochondrial dehydrogenases that are important in energy metabolism, including pyruvate dehydrogenase complex (PDH) (66), isocitrate dehydrogenase (IDH), and 2-oxoglutarate dehydrogenase complex (OGDH), rate-limiting enzymes of the Krebs cycle (67, 68). Mg²⁺ also functions as a second messenger in the regulation of insulin secretion and release, influencing insulin downstream signaling pathways (69–71). Calorie restriction (CR) is known to improve lifespan and age-associated deteriorations by changing metabolic state (72). Studies have found that Mg²⁺ mediates the beneficial effects of CR via R-loops suppressors Rnh1/201 and Pif1, and Mg²⁺ supplementation protects against the accumulation of R-loops (RNA–DNA hybrids), which contributes to genomic instability and lifespan-shortening (73). It has been shown that CR increases intracellular Mg²⁺ by upregulating Mg²⁺ transporter TRPM7, while disruption of the transporter reduces environmental Mg²⁺ levels and compromises CR-induced repression of the lifespan-shortening formation of RNA-DNA hybrids (73).

Mg²⁺, protein stability, and intracellular communication

Low levels of Mg²⁺ have been observed in the brain tissue of patients with neurological disorders, such as migraine, epilepsy, and Parkinson’s and Alzheimer’s diseases (AD). Underlying mechanisms of these diseases might include an abnormal aggregation of extracellular amyloid β-protein (Aβ), tau phosphorylation, and neuroinflammation characterized by increased TNF-α and IL-1β expressions (74). It was observed that at the cellular level and in animal models, Mg²⁺ was able to downregulate TNF-α and IL-1β and reduce the accumulation of amyloid β precursor protein in the brain (75, 76). In addition, Mg²⁺ was documented to promote Aβ clearance, through participating in the proteasomal degradation pathway and decreasing the permeability of blood–brain barrier (77).

Mg²⁺ and its transporters are crucial modulators of the communication between intracellular signaling pathways. The N-methyl-D-aspartate (NMDA) receptor is involved in excitatory neurotransmission, neuroplasticity, neuroexcitotoxicity, and memory and circadian clock rhythm, important process associated with aging (78). Mg²⁺ is able to inhibit NMDA receptors, and a decrease in extracellular Mg²⁺ depolarizes the membrane potential, leading to hyperexcitability (79). The ability of TRPM7 to act as a kinase also suggests that it is able to influence intracellular signaling. Several TRPM7 kinase substrates have been identified, including annexin-1, myosin IIA heavy chain, and calpain, supporting a role for TRPM7 in cell function, such as contraction, dilation, growth, migration, apoptosis, cell adhesion, and anti-inflammatory responses (80–83). In lymphocytes, Mg²⁺ influx through TRPM7 contributes to the functioning of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway, which is critical to prevent axonal overgrowth and induce cellular response to membrane stretch and fluid shear force (2, 84). In addition, the overexpression of SLC41A1, a Na⁺/Mg²⁺ exchanger responsible for Mg²⁺ efflux, was observed to remarkably weaken the phosphorylation of Akt/PKB on Thr308 and Ser473, and ERK1/2 on Thr202/Tyr204 (85).

Mg²⁺ and aging-related diseases

Aging is one of the primary risk factors associated with the development of multiple human diseases, including cancer, CVD, neurodegenerative disease, osteoporosis, musculoskeletal disorders, and COVID-19 (86). The prevalence of these diseases is remarkably increased in the elderly, significantly affecting the life expectancy. For examples, approximately 80 million people in the United States have at least one form of CVD, with almost one-half aged ≥60 years (87). As of today, the majority of new cancers occur in susceptible populations aged 55 years or older, and the incidence is still rapidly increasing as compared to younger adults (88). An epidemiological study in France shows that deaths specifically related to cancer patients aged over 65 account for 75.3% from all cancers (89). Similar epidemiological data are also observed for other aging-related disease. In this review, we will throw light on the critical role of Mg²⁺ in these common human diseases based on recent experimental and epidemiological data.

Mg²⁺ and cancer

It has been shown that elevated intracellular Mg²⁺ concentrations favor tumor proliferation, due to its involvement in the regulation of tumor-associated telomerase and protein phosphatase 1D, a Mg²⁺-dependent enzyme (90). Mg²⁺ deficiency impairs cell migration and growth by inducing cell cycle arrest. Upon Mg²⁺ restriction, cancer cells undergo cell cycle arrest in the G0/G1 through the up-regulation of p27, p21, and p16 (91, 92). Additionally, Mg²⁺ selectively enhanced the stability G-quadruplex of oncogene promoters and consequently impacts transcription of target genes, which provides a new insight on the observation that Mg²⁺ deficiency promotes the occurrence of cancers (93).

In addition to Mg²⁺ itself, Mg²⁺ transporters are also importantly implicated in the development of cancer. Many studies have already shown that the Mg²⁺ transporter TRPM7 exerts important effects on cellular proliferation, survival, cell cycle progression, migration, and invasion in various cell lines of cancer. An aberrant expression of TRPM7 has been observed in different types of cancer, especially pancreatic adenocarcinoma. The TRPM7 expression in the tissue of human pancreatic adenocarcinoma was positively correlated with the primary tumor size, stage, and progression (94). In line with this, the down-regulation of TRPM7 in human pancreatic cancer cells inhibits cell proliferation, effect that could be diminished by Mg²⁺ supplementation (95). In breast cancer tissues, the CNNM3 expression is increased and promotes Mg²⁺ entry into cells through binding to the phosphatase of regenerating liver 2 (PRL-2), consequently contributing to oncogenesis (96).

Mg²⁺ and cardiovascular disease

Mild to moderate Mg²⁺ deficiency associates with an increased risk of atherosclerosis, ischemic heart disease, and congestive heart failure (HF), while severe Mg²⁺ deficiency can cause ventricular arrhythmias that might lead to even sudden cardiac death (97). Mg²⁺ is important in regulating membrane potential and contractility of cardiomyocytes and autoregulatory cells (98). Severe Mg²⁺ loss may induce a prolongation of QT interval and the widening of QRS waves, resulting in ventricular arrhythmias (99). In the vasculature, Mg²⁺ is known to exert vasoprotective effects through regulating vascular tone and cytosolic Ca²⁺ (100). Epidemiological and experimental data show that Mg²⁺ has an inverse association with blood pressure, and the Mg²⁺ supplement may decrease peripheral vascular resistance and blood pressure (101). A meta-analysis of 34 randomized clinical trials involving 2028 participants shows that daily intake of 300 mg Mg²⁺ for 1 month is sufficient to elevate serum Mg²⁺ and reduce blood pressure (102). It is worth noting that TRPM7, acting as a vascular Mg²⁺ regulator, is critically implicated in hypertension. In a mouse model of TRPM7 deficiency, angiotensin II (Ang II)-induced blood pressure elevation was exaggerated, and the deteriorate effects on cardiac remodeling and left ventricular dysfunction were also amplified (103).

Mg²⁺ was found to influence the development of atherosclerosis by regulating the production of prostacyclin and NO (104–106). Low Mg²⁺ status might promote the expression of proinflammatory and prothrombotic factors, such as interleukin-1β (IL-1β), IL-6, and vascular cell adhesion molecule 1 (VCAM-1), important molecules for the progress of atherosclerosis (107). Vascular calcification is one of the main features of atherosclerosis (108). Mg²⁺ regulated by TRPM7 increases the expression of inhibitors of calcification such as matrix Gla protein, osteopontin, and bone morphogenetic protein (BMP7) and reduces the formation of osteogenic VSMCs and vascular calcification (109). Moreover, clinical studies have confirmed that low serum Mg²⁺ levels are found in patients with coronary artery disease (CAD), an atherosclerotic disease that typically affects the heart (110).

Mg²⁺ and neurodegenerative disease

Mg²⁺ abundance in cerebrospinal fluid is higher than that in blood and is positively correlated with cognitive function (2, 111). In an in vitro blood–brain barrier model, TRPM7 and MagT1 are functionally active and involved in the transport of Mg²⁺ (77). Neuronal growth depends on changes of the cytoskeleton in the growth cone (112). High TRPM7 expression was observed in the tips of the growth cone, which mediates Mg²⁺ influx to fulfil the energy requirements of the neuronal network (113). In addition, Mg²⁺ promotes the differentiation of neural stem cells into neurons, and TRPM7 was able to influence astrocyte proliferation and migration by regulating extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) activities (114).

Mg²⁺ deficiency causes emotional memory impairment and worsens the symptoms presented in AD (115). Mg²⁺ protects neuronal function in AD by reducing the TNF-α expression in glial cells with mechanisms involving PI3K/Akt and nuclear factor-kappa B (NF-κB) (76). In an animal model of Parkinson’s disease (PD), the expression level of SLC41A1 was reduced contributing to apomorphine (APO)-induced rotational behavior, while Mg²⁺ supplement significantly improved the behavior (116). Additionally, function loss of Mrs2 transporter important for mitochondrial Mg²⁺ homeostasis was observed in rats with demyelinating mutations. (117). It is believed that the disruption of mitochondrial Mg²⁺ dynamic dysregulates ATP production, leading to abnormal cell metabolism, thus triggering demyelination and neurological dysfunctions (49). Furthermore, neurological diseases such as migraine, seizures, anxiety, depression, and stroke have also been associated with a low Mg²⁺ abundance in serum and cerebrospinal fluid (49, 118, 119). However, further well-designed Randomized Controlled Trial (RCT) studies are still needed to confirm whether Mg²⁺ supplementation can improve the prognosis of these diseases.

Mg²⁺ and musculoskeletal function

Mg²⁺ is important for skeletal muscle energy metabolism as a cofactor for enzymes related to ATP synthesis, and Mg²⁺ deficiency is associated with fibromyalgia, a condition characterized by chronic widespread musculoskeletal pain (120). In healthy older women, daily Mg²⁺ supplementation over 12 weeks significantly improved physical performance assessed by Short-Physical Performance Battery (SPPB) score and a 4-m walking test, suggesting that Mg²⁺ may serve as a complementary treatment for aging-related physical deconditioning (121). In addition, Mg²⁺ enhances the activity of vitamin D and is involved in osteoblast proliferation and bone mineralization, and Mg²⁺ deficiency leads to reduced parathyroid hormone (PTH) synthesis and secretion, causing low Ca²⁺ (122). Therefore, Mg²⁺ supplement might be promising in the prevention of age-related osteoporosis.

Mg²⁺ and abnormal metabolism

Mg²⁺ has been found to modulate the activation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lipoprotein lipase, and lecithin-cholesterol acyltransferase, enzymes critically implicated in lipid metabolism (123). Mg²⁺ is also required to regulate genes that are involved in adipogenesis, lipolysis, and inflammation, such as PPAR-γ (124). Animal studies have shown that Mg²⁺ decreases lipid accumulation in hepatocytes by regulating enzymatic activities and transcriptional genes related to lipid metabolism (125). In type 2 diabetic patients, reduced serum Mg²⁺ levels were observed, and Mg²⁺ is believed to mediate the development of diabetes through insulin resistance (126). The effects of Mg²⁺ on glucose, lipids, and blood pressure suggest a role of Mg²⁺ in metabolic syndrome, and in line with this, Mg²⁺ supplementation was reported to be effective in treating metabolic syndrome in patients with comorbid hypomagnesemia (127).

Mg²⁺ and COVID-19

COVID-19 is one type of zoonotic epidemic exploded in late December in 2019, which shares a high degree of homology with Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) (128). COVID-19 is more prevalent in the elderly, and elderly patients are more likely to develop severe or critical pneumonia, with a high mortality rate (129, 130). Intriguingly, more and more clinical evidence showed that some aspects of COVID-19 pathogenesis are similar with the symptoms presented in Mg²⁺ deficiency (131). It has been demonstrated that up to 60% of critically ill patients in the ICU present with some degree of Mg²⁺ deficiency (132). In addition, people with hypertension, CVD, diabetes, and obesity are at high risk of developing COVID-19 (133). It is well known that these aging-related diseases are all characterized by hypomagnesemia and are associated with low-grade inflammation. Low Mg²⁺ status is believed to stimulate granulocyte oxidative burst, activate endothelial cells, and upregulate the production of cytokines, thus promoting inflammation that might lead to diseases (33). Mg²⁺ also leads to increased plasminogen activator inhibitor-1 (PAI-1) production and the inhibition of fibrinolysis, which may be associated with the elevated D-D dimer observed in COVID-19 (134). Moreover, COVID-19 could directly infect endothelial cells via ACE2 receptor, which induces cytokine storm, thus increasing permeability, vasoconstriction, and fostering thrombogenesis, while Mg²⁺ is significant in maintaining endothelial function and vascular integrity (135, 136). Collectively, a low Mg²⁺ status might accelerate the progression of COVID-19 from mild to serve stages, and Mg²⁺ supplementation might be one of the feasible treatment modalities, especially in severe patients (137).

Conclusion and perspectives

Mg²⁺ is an indispensable cation in human body regulating a variety of physiological and pathological processes. Under normal conditions, intracellular and extracellular Mg²⁺ levels are tightly controlled through a complicated Mg²⁺ transport system, and dynamic Mg²⁺ homeostasis is critical for human health. However, altered Mg²⁺ status also contributes to the molecular hallmarks of the aging process. Emerging evidence indicates that Mg²⁺ plays an important role in multiple aging-related diseases including the COVID-19 pandemic. The modulation of Mg²⁺ status might be a promising therapeutic option for human disease, which deserved further investigation.

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