This is a recent review, published in the prestigious journal Nutrients in February 2024, by Ligia J. Dominguez and others from the University of Palermo and the University of Enna in Italy. They systematically reviewed the relationship between magnesium and indicators of aging in the human body, and found that this common mineral can actually slow down the aging rate, which is really surprising!

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Key tips:

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1. Magnesium is the fourth most abundant mineral element in the human body and is closely related to the activity of more than 600 enzymes, affecting a variety of physiological processes.

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2.Magnesium deficiency is very common in the elderly, which is related to many factors such as genes, environment and lifestyle. Insufficient magnesium levels in the body can accelerate the aging process.

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3. Studies have found that magnesium can affect 12 key features of aging, including genomic instability, telomere shortening, and epigenetic changes. Magnesium supplementation is expected to delay aging and improve health expectations.

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Here is a detailed summary of the original article:

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Magnesium deficiency accelerates 12 aging characteristics

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Genomic instability: Magnesium stabilizes the DNA double helix structure and is involved in a variety of DNA repair mechanisms. Magnesium deficiency can lead to accumulation of DNA damage, increased genetic mutations, and accelerated aging.

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Telomere shortening: Telomeres are repeated sequences at the ends of chromosomes that protect the genome from damage. Magnesium stabilizes the end.

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Epigenetic changes: Epigenetic changes in gene expression occur without altering the DNA sequence. Magnesium regulates epigenetic mechanisms such as DNA methylation and histone modification.

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Protein homeostasis imbalance: protein synthesis and degradation within the cell reach a dynamic balance, called protein homeostasis. Magnesium is involved in regulating proteasome and lysosome function, and magnesium deficiency leads to accumulation of misfolded proteins.

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Disturbance of nutritional perception: Insulin /IGF-1 and other signaling pathways perceive cellular nutritional status and regulate metabolism. Magnesium is a cofactor of insulin receptors and downstream kinases, and magnesium deficiency causes insulin resistance.

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Mitochondrial dysfunction: Mitochondria are cellular energy factories, and their DNA and respiratory chains are vulnerable to damage. Magnesium is the second most abundant cation in mitochondria, which is involved in ATP synthesis and antioxidant, and magnesium deficiency aggravates mitochondrial damage.

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Cellular senescence: senescent cells stop dividing, secrete inflammatory factors, and destroy the tissue microenvironment. Magnesium can inhibit cell cycle blocking proteins p53 and p21 and delay cell senescence.

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Stem cell depletion: Stem cells are responsible for tissue regeneration and repair, and their number and function decline with age. Magnesium affects hematopoietic stem cell differentiation, and magnesium deficiency may accelerate stem cell depletion.

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Changes in intercellular communication: cytokines, hormones, etc. mediate intercellular signal exchange. Aging increases the secretion of inflammatory factors. Magnesium inhibits inflammation and improves cell communication.

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Impaired Autophagy: Autophagy is an important pathway for cells to degrade damaged proteins and organelles. Magnesium maintains autophagy function by regulating the activity of autophagy related genes and kinases.

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Intestinal flora disorder: intestinal flora is involved in nutrient metabolism and immune regulation, and microbial imbalance is related to aging. Magnesium regulates gut flora and improves host health.

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Chronic inflammation: Aging is accompanied by chronic low-grade inflammation throughout the body, that is, "inflammatory aging". Magnesium deficiency causes excessive activation of inflammatory signaling pathways such as NF-κB and aggravates the inflammatory response.

According to a large number of epidemiological studies and randomized controlled trials, increasing dietary magnesium intake and supplementing magnesium preparations can reduce age-related chronic inflammation, insulin resistance, cardiovascular disease, etc. Although there is no direct evidence to prove that magnesium can prolong life, indirect evidence shows that magnesium supplementation contributes to healthy aging.

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Although magnesium is relatively safe, people with renal insufficiency should be cautious, and large doses of oral medicine can cause diarrhea. Older adults should prioritize getting enough magnesium from their diets, such as green leafy vegetables, whole grains, nuts, etc. If necessary, follow the doctor's advice to supplement magnesium, and regularly monitor the blood magnesium concentration.

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Detailed experimental evidence and clinical data:

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Experimental evidence of magnesium and genomic stability DNA is the genetic material of life, and its stability is the basis for the normal functioning of cells. The study found that there are magnesium ions between about 50% of the base pairs in the DNA double helix structure, which plays a role in stabilizing the structure. In model organisms such as Escherichia coli and yeast, a low magnesium environment causes a significant increase in DNA replication error rates. Human fibroblast culture experiments also confirmed that low magnesium can cause accelerated telomere shortening and up-regulation of DNA damage response gene expression. Animal experiments showed that the antioxidant defense system was damaged in the liver tissue of magnesium deficient rats, and the level of 8-hydroxy-deoxyguanosine, a marker of DNA oxidative damage, was increased. A study in mice found that drinking magnesium-rich water lengthened telomere length and reduced DNA damage. These results suggest that magnesium is essential for maintaining genomic stability.

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In population studies, serum or erythrocyte magnesium levels have been negatively correlated with various indicators of genomic instability, such as micronucleus frequency, levels of DNA damage products 8-hydroxy-deoxyguanosine, and telomere length. A cross-sectional study of nearly 200 healthy adults found that those with the lowest red blood cell magnesium levels had peripheral blood lymphocyte telomere lengths that were, on average, 11.5% shorter than those with the highest magnesium levels. Another cohort study of 1800 middle-aged and elderly men aged 45-74 years followed for 5 years found that dietary magnesium intake was significantly negatively associated with the degree of DNA damage in peripheral blood lymphocytes at baseline, and that each increase in magnesium intake of 100mg/ day reduced the degree of DNA damage by 5.5% after 5 years. This suggests that magnesium supplementation in humans may also help maintain genomic stability.

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Second, the relationship between magnesium and telomerase activity and cell aging Telomeres are special structures at the end of chromosomes, composed of TTAGGG repeats and telomere-binding proteins, which protect chromosomes from degradation during cell division. But in human cells, telomere length shortens by 50 to 100 base pairs per division, and when the shortening reaches a critical value, the cell enters a state of senescence. Telomerase is a ribonucleoprotease that lengthens the telomere sequence, but is usually poorly expressed or not expressed in adult cells.

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In mouse embryonic fibroblasts (MEF), low magnesium medium decreased telomerase activity by more than 50% and showed cellular senescence features, such as increased β-galactosidase activity and up-regulated expression of cell cycle inhibitors p16 and p21. These aging phenotypes can be reversed after treatment with magnesium or telomerase activators. Similar results were observed in human endothelial cells and fibroblasts. Molecular mechanism studies have found that magnesium may regulate telomere length by affecting the expression and localization of some key proteins in the telomere complex, such as TRF1 and TRF2. In addition, magnesium can also activate signaling pathways such as AKT and ERK, and inhibit cell cycle inhibitors such as p53 and Rb, thereby delaying cell aging.

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Clinical studies also support a link between magnesium and cellular senescence. In more than 100 healthy elderly people, serum magnesium levels were positively correlated with T lymphocyte proliferation and negatively correlated with plasma p16 levels. Another study included 250 elderly people in the community, and found that baseline serum magnesium levels were closely related to changes in physiological aging indicators such as hearing threshold, grip strength, and walking speed, suggesting that magnesium status may affect the overall aging process in the body. A cohort study of more than 2,000 people over the age of 70 compared different serum magnesium levels with the 10-year risk of death and found that the group with the lowest magnesium levels had a 2.2 times greater risk of death than the group with the highest levels. Although these observational studies cannot directly prove cause and effect, they do support a strong association between magnesium and aging from a population perspective.

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The role of magnesium in insulin signaling pathway Insulin is the core regulatory hormone of human blood glucose homeostasis. After insulin binds to its receptor, it causes self-phosphorylation of the receptor, and activates a series of downstream protein kinases such as PI3K and AKT, and finally regulates the expression of genes related to glucose metabolism. Numerous experiments have shown that magnesium plays a key role in almost every step of insulin signaling. 1. In islet beta cells, magnesium forms MgATP complex with ATP to participate in the whole process of insulin synthesis, processing and secretion. In mouse and rat beta cell lines, low-magnesium medium reduced glucose-stimulated insulin secretion by more than 70%. 2. In insulin target cells, tyrosine kinase activity of insulin receptors depends on magnesium ions, and magnesium deficiency leads to insulin receptor phosphorylation and downstream signal transduction obstruction, resulting in insulin resistance. In 3T3-L1 adipocytes and L6 skeletal muscle cells, low-magnesium medium reduced insulin-stimulated glucose uptake by 40% to 60%. 3. Magnesium also participates in the regulation of insulin sensitivity by inhibiting protein phosphatase, regulating integrins expression, affecting GLUT4 transporter activity and other mechanisms. Some animal experiments have shown that moderate dietary supplementation of magnesium improves insulin resistance in obese and type 2 diabetic rats.

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Epidemiological studies also support the close relationship between magnesium and glucose metabolism. The US Nurses' Health Study, which included nearly 70,000 women over the age of 45 followed for more than 20 years, found that those in the highest quintile of dietary magnesium intake had a 27% lower risk of developing type 2 diabetes than those in the lowest quintile. A meta-analysis of 25 cohort studies involving nearly 1 million participants showed that every 100mg/ day increase in dietary magnesium intake was associated with an 8% to 13% reduction in the risk of type 2 diabetes. In people with existing diabetes, reduced serum magnesium levels are also closely related to disease progression and complications. A study of more than 300 patients with type 2 diabetes found that serum magnesium levels were significantly lower in those with coronary heart disease than in those with diabetes alone. In conclusion, a large number of studies have shown that magnesium supplementation may delay aging by improving insulin resistance.

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4. Magnesium deficiency and mitochondrial dysfunction Mitochondria are the main sites of cellular energy metabolism and reactive oxygen species (ROS) production. During the aging process, the efficiency of mitochondrial electron transport chain decreases and ROS production increases, causing mtDNA mutation, membrane lipid peroxidation and other damage, forming a vicious cycle and accelerating cell aging. Studies have found that one-third of magnesium in the body is stored in mitochondria, which is essential for maintaining mitochondrial structure and function. In mouse liver mitochondria, nine of the 13 subunits of adenosine triphosphatase require magnesium as a cofactor. In mouse myocardial mitochondria, low magnesium can significantly decrease the activities of key enzymes in the tricarboxylic acid cycle, such as isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. In rat liver mitochondria, magnesium deficiency can reduce ATP synthesis rate by more than 60%, decrease respiratory control rate, and increase ROS production, resulting in increased mtDNA damage and mutation rate. Magnesium supplementation can reverse these mitochondrial dysfunction. In human skeletal muscle cells and cardiomyocytes, low magnesium can depolarize mitochondrial membrane potential, induce the opening of mitochondrial permeability transition pore (mPTP), trigger the release of cytochrome C, and eventually lead to apoptosis. In human umbilical vein endothelial cells, low magnesium induces a large number of mitochondrial ROS by activating protein kinase C, leading to endothelial dysfunction. A study of more than 100 patients with metabolic syndrome found that serum magnesium levels were positively correlated with mitochondrial respiratory function and negatively correlated with mitochondrial ROS levels. In summary, the above evidence suggests that magnesium is an important factor in maintaining mitochondrial homeostasis, and mitochondrial dysfunction is one of the core mechanisms of aging.

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Fifth, the regulatory role of magnesium on chronic inflammation and immune aging Chronic low-grade inflammation is another important feature of aging. Studies have found that the levels of inflammatory factors such as IL-6 and TNF-α in aging individuals are significantly increased, while the levels of anti-inflammatory cytokines such as IL-10 are decreased, and these chronic inflammatory states caused by aging are known as "inflammaging". Inflammatory aging can cause tissue damage and immune imbalance, which is the pathological basis of many chronic diseases. Experimental studies have shown that magnesium deficiency can induce inflammatory response and immune dysfunction. In mouse macrophage culture, low magnesium can up-regulate NF-κB activity and promote the release of various inflammatory factors. In bronchial epithelial cells of rats, the secretion of IL-6 and IL-8 can be increased by 2 to 3 times by LPS stimulation under low magnesium environment. In human endothelial cells, low magnesium can activate the p38 MAPK signaling pathway, cause the expression of intercellular adhesion molecules to be up-regulated, and aggravate the inflammatory response. In magnesium deficient rats, the levels of TNF-α, CRP and interleukin in circulation and tissues were significantly increased, the immune organs were atrophy, the number and function of T and B lymphocytes were decreased, and immunosuppression was aggravated. Magnesium supplementation can effectively relieve these inflammatory and immune disorders. Clinical studies have also found that low magnesium is closely related to chronic inflammation. A cross-sectional study of more than 5,000 adults in the United States found that serum magnesium concentration was significantly negatively correlated with CRP and white blood cell counts, and CRP and IL-6 levels in the lowest quartile of magnesium levels were 60% and 40% higher than those in the highest quartile. The correlation was even stronger in obese people. Another study of 3,200 people over the age of 65 found that serum magnesium levels were positively correlated with white blood cell telomere length and negatively correlated with CRP and D-dimer levels. A meta-analysis of 25 randomized controlled trials with a total sample size of more than 2,000 people showed that oral magnesium supplementation reduced serum CRP levels by an average of 22%,TNF-α by 15%, and IL-6 by 18%. Therefore, magnesium supplementation may delay body aging through anti-inflammatory effects.

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The regulatory relationship between magnesium and autophagy Autophagy is an important mechanism for cell degradation and removal of damaged proteins and organelles, and is crucial for maintaining the homeostasis of the cellular environment. Studies have shown that autophagy function is gradually weakened during aging, and defects in autophagy can cause protein aggregation, mitochondrial dysfunction, etc., and accelerate cell aging. Magnesium, as a second messenger, is involved in regulating the initiation and process of autophagy. In yeast, magnesium deficiency inhibits the expression of autophagy related genes Atg1 and Atg13 by activating TORC1 signaling pathway. In mammalian cells, low magnesium environment can inhibit the activity of ULK1, Beclin1 and other autophagy initiating proteins, and block the formation of autophagosomes. In human embryonic kidney cells, magnesium ion chelating agent EDTA can inhibit autophagy flow. In vitro experiments have shown that physiological concentrations of magnesium ions can directly bind and activate Atg4, a proteolytic enzyme necessary for autophagosome maturation. Animal studies have also found that moderate dietary supplementation of magnesium can reduce autophagy disorders in neurons and cardiomyocytes, improve cognitive function and cardiac systolic function. Although there is a lack of direct clinical evidence, some observational studies suggest a correlation between magnesium and autophagy. Magnesium levels were positively correlated with the expression of autophagy markers Atg5 and Beclin1 in brain tissue and peripheral blood mononuclear cells of patients with Alzheimer's disease. In patients with type 2 diabetes, serum magnesium concentration is closely related to the expression levels of autophagy related genes LC3 and p62. In conclusion, magnesium is likely to play an important role in resisting aging by regulating autophagy. But its specific mechanism needs to be further studied.

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7. Interaction between Magnesium and intestinal flora Intestinal flora is an important "organ" in the human body, which plays an irreplaceable role in nutritional metabolism, immune regulation, neuroendocrine and other aspects. Recent research has found that changes in the composition and function of the gut microbiota are closely related to aging. For example, the proportion of firmicutes and Bacteroides in the gut of older people decreased significantly, while the proportion of opportunistic pathogens such as enterococcus and Staphylococcus increased. This imbalance of flora can cause damage to the intestinal barrier, promote the release of inflammatory factors, and aggravate chronic inflammation in the whole body.

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As an important nutrient substrate in the gut, magnesium can affect the composition of the flora through a variety of mechanisms. In germ-free mice, drinking water rich in magnesium can significantly increase the number of beneficial bacteria such as bifidobacterium and Bacteroides, and reduce intestinal pH value. In a mouse model of colitis, magnesium supplementation mitigated intestinal flora disturbances and inhibited NF-κB activation in the inflammatory signaling pathway. In healthy human experiments, the proportion of bifidobacteria in feces increased after 8 weeks of magnesium supplementation, and the levels of lipopolysaccharide, D-lactic acid and other bacterial metabolites decreased. Some preclinical studies have also found that magnesium deficiency can disrupt intestinal tight junctions, increase permeability, and create conditions for translocation of enterogenic endotoxins.

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Magnesium can also affect the aging process of the host by regulating bacterial metabolism. For example, magnesium stimulates the production of short-chain fatty acids such as Bifidobacterium, which activates the G-protein-coupled receptor GPR43, which inhibits obesity-related inflammation and insulin resistance. In addition, magnesium can also affect bile acid and tryptophan metabolism, and disorders of these two pathways are closely related to aging and neurodegenerative diseases. In conclusion, magnesium is expected to be a new strategy for delaying aging by reshaping intestinal flora and regulating the bacteria-gut-brain axis, but its long-term effects need to be verified by prospective cohort studies.

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In summary, a large number of experimental and epidemiological evidence shows that magnesium is an important nutrient to resist aging and promote health and longevity. It is involved in the regulation of aging through the following mechanisms:

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Although the effects of magnesium supplementation on human lifespan are currently inconclusive, indirect evidence suggests that magnesium can help delay multiple aging phenotypes and improve health expectations. In the future, prospective cohort studies and randomized controlled trials are needed to further clarify the anti-aging effects of magnesium and its dose-effect relationship, so as to provide evidence-based evidence for the formulation of magnesium supplementation strategies. In addition, the magnesium nutritional status and demand of different populations are not the same, so the formulation of individual magnesium supplement program is also an urgent problem to be solved. It is believed that with the development of aging medicine and nutrition, we will eventually uncover all the mysteries of this magical element magnesium, and use it to fight aging and realize the dream of healthy longevity.

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