Magnesium in Aging, Health, and Diseases

Magnesium ion (Mg) is the divalent intracellular cation most present in the human cell and the second cation after potassium (K). Mg's atomic weight is 24.305 g/mol, and its atomic number is 12. Mg has a crucial role in numerous biological processes, including oxidative phosphorylation, energy production, glycolysis, protein, and nucleic acid synthesis. Mg plays a role in the mitochondrial synthesis of adenosine triphosphate (ATP) to form MgATP.

Cell signaling needs MgATP for protein phosphorylation and activation of cyclic adenosine monophosphate (cAMP), which is involved in a number of biochemical processes. Mg ions participate in the transport of other ions through cell membranes, in muscle contraction, and in controlling neuron excitability. Cellular Mg homeostasis is linked to the cellular metabolism of other ions, i.e., K, sodium (Na), calcium (Ca), via Na+/K+/ATPase, Ca++ activated K channels and other mechanisms.

Magnesium has a key role in cellular homeostasis and organ functioning. Thus, Mg has a physiological role in controlling various key cellular activities and metabolic pathways, including enzyme-substrate, structural, and membrane functions. Mg is a cofactor in over 600 enzymatic reactions and is required for the activity of protein kinases, glycolytic enzymes, all phosphorylation processes, and for all reactions that implicate ATP. Mg ion has a mild Ca antagonist action and is involved in a number of structural functions (multi-enzyme complexes, i.e., G-proteins, proteins and nucleic acids synthesis, N-methyl-D-aspartic acid (NMDA) receptors, mitochondria, polyribosomes, etc.).

In the last decades, the pathophysiological and clinical importance of Mg has been acknowledged,
as well as the possible effects of Mg deficits on several human diseases.

Optimal Mg requirement with food is considered to be 320 mg/day for women and 420 mg/day for men, according to the 2015–2020 Dietary Guidelines for Americans, but higher requirements may be needed in some physiologic conditions such as pregnancy, aging, or during exercise and in some pathological conditions (i.e., infections, type 2 diabetes mellitus (T2DM), etc.).

Many factors may alter Mg balance: high content in the diet of Na, Ca, protein, alcohol, or caffeine, or the use of certain drugs (diuretics, e.g., furosemide; proton-pump inhibitors, e.g., omeprazole, etc.). Mg absorption mainly occurs in the small intestine. To maintain the balance, a healthy person needs to consume around 5–7 mg/kg/day. Mg deposited in the bone is not easily exchanged and any rapid Mg requirement is provided by the Mg present in the intracellular compartment. The kidney helps to control and modulate Mg balance; each day around 120 mg of Mg is eliminated into the urine.

Renal Magnesium (Mg) control is strictly dependent on Mg status, since Mg depletion stimulates Mg reabsorption across the nephron, while Mg urinary excretion is decreased in conditions of body Mg depletion. Diuretics alter renal Mg handling increasing Mg wasting. No hormone is known to be a specific Mg regulator. However, many hormonal factors have an identified effect on Mg homeostasis (i.e., insulin, parathyroid hormone (PTH), calcitonin, catecholamines).

Several changes of magnesium (Mg) metabolism have been reported with aging, including diminished Mg intake, impaired intestinal Mg absorption, and renal Mg wasting.

Mild Mg deficits are generally asymptomatic and clinical signs are usually non-specific or absent. Asthenia, sleep disorders, hyperemotionality, and cognitive disorders are common in the elderly with mild Mg deficit and maybe often confused with age-related symptoms.

Chronic Mg deficits increase the production of free radicals which have been implicated in the development of several chronic age-related disorders. Numerous human diseases have been associated with Mg deficits, including cardiovascular diseases, hypertension and stroke, cardio-metabolic syndrome and type 2 diabetes mellitus, airways constrictive syndromes and asthma, depression, stress-related conditions and psychiatric disorders, Alzheimer’s disease (AD), and other dementia syndromes, muscular diseases (muscle pain, chronic fatigue, and fibromyalgia), bone fragility, and cancer.

Dietary Mg and/or Mg consumed in drinking water (generally more bioavailable than Mg contained in food) or in alternative Mg supplements should be taken into consideration in the correction of Mg deficits. Maintaining an optimal Mg balance all through life may help in the prevention of oxidative stress and chronic conditions associated with aging. This needs to be demonstrated by future studies.

A chronic Mg deficiency is frequently present in older adults.

Low-grade chronic inflammation is frequently present in numerous age-related chronic diseases,
and with the aging process itself.

Since a chronic Mg inadequacy may cause an exaggerated production of inflammatory mediators and ROS, and it may trigger an inflammatory state, our group has previously hypothesized that chronic Mg insufficiency may be one of the mediators helping to explain the link between inflammation and aging-related diseases. It is possible to hypothesize that preserving an optimal Mg balance during the course of life may help to prevent inflammation and related conditions associated with Mg inadequacy and may thus help to lengthen healthy life.

However, while it is advisable to maintain a satisfactory Mg balance with a sufficient dietary intake of Mg, the possible role of Mg supplements is still unclear. Very few long-term longitudinal blind studies on the effects of Mg supplementation have been performed. The possibility that maintaining a satisfactory Mg balance throughout life may become an economic and safe health strategy in the growing aging population is a suggestive hypothesis that needs to be proven by future prospective studies.