Magnesium homeostasis and aging

ARTICLE

Auteur(s) : Mario Barbagallo, Mario Belvedere, Ligia J Dominguez

Geriatric Unit, Department of Internal Medicine and Emergent Pathologies, University of Palermo, Italy

Aging represents a major risk factor for magnesium (Mg) deficit. Several alterations of Mg status have been identified in the elderly [1-13]. Total body Mg content tends to decrease with age, with bone being the main storage compartment of body Mg. Of the 21-28 g of Mg present in the adult human body, about 55-65% is in the mineral phase in the skeleton, 34-44% in the intracellular space, and only 1% in the extracellular fluid [14]. Although the Mg stored in the bone is not easily exchanged, the age-related reduction of bone mass is associated to a reduction of total body mineral and Mg content (figure 1). Despite its importance, there is still insufficient information available regarding the distribution and turnover of exchangeable Mg in humans. There is a lot of variability in Mg intake, absorption, conservation and excretion. Alterations of Mg metabolism that have been associated to aging include a reduction of Mg intake and intestinal absorption, and an increase of Mg urinary and fecal excretion (figure 1), all these changes indicating a tendency to a Mg deficit with aging.

An age-related decline in the capacity of the intestine to absorb dietary Mg has been suggested but is not well documented. In rats, several results indicate that the apparent Mg absorption is not altered with aging [15], but more recent studies using stable isotopes suggest that Mg absorption decreases moderately with age [16].

Plasma and cellular equilibrium of Mg homeostasis as well as Mg concentrations are tightly regulated [17-19], and changes in plasma Mg can occur only in the presence of a significant long lasting Mg depletion. Although no known hormonal factor is specifically involved in the regulation of Mg metabolism, many hormones are known to affect Mg balance and transport, such as parathyroid hormone (PTH), calcitonin, vitamin D, catecholamines, and insulin. In particular, there is an important link between Mg and calciotropic hormones, since not only PTH and vitamin D may regulate Mg homeostasis, but Mg itself is essential for the normal function of the parathyroid glands, vitamin D metabolism, and to ensure an adequate sensitivity of target tissues to PTH and active vitamin D metabolites [20, 21]. It is thus likely that the modifications with age of these regulating hormones (decrease in vitamin D status and increase in PTH levels) [22, 23] may affect the Mg homeostasis in the elderly, although these aspects have not been completely elucidated. In particular, although vitamin D is an important regulator of calcium transport in the intestine, the importance of vitamin D for Mg absorption remains uncertain. In humans, the results of experiments on the effect of vitamin D and Mg absorption have been conflicting. The effect of vitamin D-stimulated Mg absorption remains uncertain given the increase in urinary excretion of Mg that has been associated with vitamin D administration.

Total plasma Mg concentrations (MgT), in relation to this tight control, are remarkably constant in healthy subjects throughout life and do not tend to change with aging [1, 6] (figure 2). MgT concentration ranges from 0.65 to 0.95 mmol/L. In the serum Mg exists in 3 forms: a protein-bound fraction (25% bound to albumin and 8% bound to globulins), a chelated fraction (12%), and the metabolically active ionized fraction (Mg-ion: 55%) [1, 14, 17, 18]. MgT, probably because of the large part bound to proteins or chelated, is not very sensitive in detecting subclinical Mg deficiencies. Possible changes may depend mainly on age-related diseases, therapies and age-related changes in renal function; 24-hour Mg retention studies have revealed an increased Mg retention in the elderly, suggesting a significant subclinical Mg deficit, not easily detected by total serum Mg [10]. The use of an ion-selective electrode (ISE), Mg-selective electrode to measure the active ionized free Mg (Mg-ion), has been suggested to be of help in detecting some of these subclinical Mg deficits. A close direct relationship was found between Mg-ions and the intracellular Mg measurement [24]. In clinical practice, the measurement of active ionized free Mg in the serum may allow a higher sensitivity than MgT in detecting subclinical Mg deficits in several clinical conditions, including aging. In preliminary data in healthy elderly (> 65 years old) subjects, we found a slight but significant reduction in Mg-ions compared to young controls (< 65 years old), changes not detected by the measurement of total serum Mg (table 1).

Mg in the intracellular compartment also tends to be reduced with aging. Intracellular free Mg (Mgi) has been found to be significantly decreased in healthy elderly (> 65 years old) compared to young controls (< 65 years old) [11, 12]. We have specifically studied the behavior of intracellular Mg content with age, using ³¹P-NMR spectroscopy, in peripheral red blood cells in healthy subjects and have shown a continuous age-dependent fall of intracellular Mg levels in healthy elderly subjects [12], without significant changes in total serum Mg (figures 3, 4). Thus, at least in conditions associated to a subclinical Mg deficit, the initial compartments that seems to be involved are the intracellular compartment and the ionized fraction of serum Mg, while a reduction of the bound and complexed total serum Mg (hypomagnesemia) may appear only at a later stage, in relation to more considerable and long-lasting Mg depletion.

Mechanisms of Mg deficits with age

Analyses from the same NHANES III survey have shown that Mg intake in the older US population is well below the recommended daily allowance (RDA, average of 225 and 166 mg/day vs recommended 420 and 320 mg/day for men and women, respectively) [25]. Among US adults, 68% consume less than the RDA for Mg, 45% consume less than 75% of the RDA, and 19% consume less than 50% of the RDA [31]. In Europe, the Suppléments en Vitamines et Minéraux Antioxidants (SU.VI.MAX) study showed that 77% of women and 72% of men have dietary Mg intakes lower than RDA; 23% of women and 18% of men consumed less than 2/3 of these RDA [26].

Other possible pathogenetic factors that may contribute to a Mg depletion with age (in addition to the inadequate dietary intake) are a decreased Mg absorption and/or an increased urinary Mg loss, and/or multiple drug use. The efficiency of Mg absorption declines with age. Mg is absorbed by both passive and active processes, mostly in the duodenum and in the ileum. A reduction of the absorption of Mg from the intestines in the elderly may be influenced by the reduction of vitamin D metabolism with age [1-3].

Renal active reabsorption of Mg takes place in the loop of Henle, in the proximal convoluted tubule, and is influenced by both the urinary concentration of sodium, and urinary pH. An increase of renal Mg excretion may also contribute to the Mg deficit and is linked to a reduced tubular reabsorption, associated with a reduction of the renal function that is a common condition in the elderly. Drug use (i.e. long-term treatment with loop diuretics, digitalis) and/or pathological conditions associated to aging (i.e. type 2 diabetes mellitus, hyperadrenoglucocorticism, insulin resistance, alcoholism, acute myocardial infarction, stroke, among others) are also associated to secondary Mg deficiencies [2, 3, 5, 6].
Table 1 Ionized (Mg ion) and Total (Mg Tot) Magnesium in the elderly (> 65 y) vs younger (< 65 y) subjects.

Aging, Mg and inflammation

In animals, several studies have shown that Mg deprivation causes excessive production and release of proinflammatory molecules tumor necrosis factor (TNF)-α, IL-1β, IL-6, vascular cell adhesion molecule (VCAM)-1, and plasminogen activator inhibitor (PAI)-1, increased circulating inflammatory cells, and increased hepatic production and release of acute phase proteins (i.e. complement, α2-macroblobulin, fibrinogen) [33-41]. Experimental studies in rats have shown that Mg deficiency induces a chronic impairment of the redox status associated with inflammation, which could contribute to increased oxidized lipids, and may promote hypertension and vascular disorders [38].

In humans, clinical data have shown that low serum Mg levels as well as inadequate dietary Mg are strongly related to low-grade systemic inflammation [31, 42, 43]. Data from the Women’s Health Study, have shown that Mg intake is inversely related to systemic inflammation, measured by serum C-reactive protein (CRP) concentrations, and with the prevalence of the metabolic syndrome in adult women [43]. Using the 1999–2002 NHANES database, King et al. found that dietary Mg intake was inversely related to CRP levels. Among the 70% of the population not taking supplements, Mg intake below the RDA was significantly associated with a higher risk of having elevated CRP [44]. Several other studies have confirmed an inverse relationship among Mg intake, serum Mg and TNF-α, IL-6, and CRP levels [44-46]. In a cross-sectional study, a higher TNF-α concentration was inversely correlated with serum Mg and in multi-variate analysis, those with the lowest serum Mg were 80% more likely to have higher circulating levels of TNF-α [46].

Mg deficiency has been associated, both in experimental animal models and in humans, with increased oxidative stress and decreased antioxidant defense due, at least in part, to increased inflammation parameters [39, 47, 48]. Previous studies have convincingly shown that Mg deficiency results in increased production of oxygen-derived free radicals in various tissues, increased free radical-elicited oxidative tissue damage, increased production of superoxide anion by inflammatory cells, decreased antioxidant enzyme expression and activity, decreased cellular and tissue antioxidant levels, and increased oxygen peroxide production [2, 38, 49, 50]. Mg may also prevent oxygen radical formation by scavenging free radicals and by inhibiting xanthine oxidase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [51]. There is also evidence that magnesium may play a role in the immune response as a co-factor for immunoglobulin (Ig) synthesis, C’3 convertase, immune cell adherence, antibody-dependent cytolysis, IgM lymphocyte binding, macrophage response to lymphokines, and T helper-β cell adherence [52, 53].

Mg and age-related cardiovascular and metabolic diseases

The role of Mg in the regulation of cellular glucose metabolism, insulin action and sensitivity, as well as in the modulation of vascular smooth muscle tone, and blood pressure homeostasis is well established [12, 14, 54, 55]. Chronic Mg deficits have been linked to an increased risk of cardiovascular and metabolic diseases, including hypertension, stroke, atherosclerosis, ischemic heart disease, cardiac arrhythmias, glucose intolerance, insulin resistance, type 2 diabetes mellitus, endothelial dysfunction, vascular remodeling, alterations in lipid metabolism, platelet aggregation/thrombosis, inflammation, oxidative stress, cardiovascular mortality, asthma, chronic fatigue, as well as depression and other neuropsychiatric disorders [56-62], all conditions mostly observed in the elderly population.

At the cellular level, cytosolic free Mg levels are consistently reduced in subjects with type 2 diabetes mellitus. Using gold standard NMR techniques, our group has shown significantly lower steady-state Mgi and reciprocally increased Cai levels in subjects with type 2 diabetes, compared with young non-diabetic subjects [12, 63]. Mgi depletion in diabetes has been shown to be clinically and pathophysiologically significant, since Mgi levels quantitatively and inversely predict the fasting and post glucose levels of hyperinsulinemia, as well as peripheral insulin sensitivity, and both systolic and diastolic blood pressures [12, 14, 54, 55, 63]. A continuous fall in Mg with increasing age was observed in peripheral blood cells. The previously described age-dependent alterations in cytosolic free magnesium levels were indistinguishable from those present in essential hypertension or type 2 diabetes, independently of age. Thus, both type 2 diabetes and hypertension display the same ionic changes (lower intracellular Mg and higher intracellular calcium) at all ages, and might therefore help to explain the age-related increased incidence of these diseases. In addition, the old clinical concept of diabetes being a disease of accelerated vascular aging is literally true, referring to Mg status, since diabetic patients display the same intracellular ionic changes at all ages (figure 4).

In diabetic subjects, both low Mg intake and increased Mg urinary losses have been associated with Mg deficits [54, 55]. Hyperglycemia and hyperinsulinemia may both have a role in the increased urinary Mg excretion contributing to Mg depletion. A depletion of Mg seems to be a cofactor for a further derangement of insulin resistance. A Mg-deficient diet is associated with a significant impairment of insulin-mediated glucose uptake, and to an increased risk of developing glucose intolerance and diabetes [64].

Recent epidemiologic data have shown a significant inverse association between Mg intake and diabetes risk. A deficient Mg status may both be a secondary consequence or may precede and cause insulin resistance and altered glucose tolerance, and even diabetes [62, 65-68].

Inflammation and oxidative stress have been proposed to be the link between Mg deficit and insulin resistance/metabolic syndrome [44-46]. More generally, chronic hypomagnesaemia and conditions commonly associated with Mg deficiency, such as type 2 diabetes mellitus and aging, are all associated with an increase in free radical formation with subsequent damage to cellular processes [1, 2, 44-46]. We have shown that the effects of antioxidant therapies with vitamin E and glutathione to improve insulin sensitivity and whole body glucose disposal are, at least in part, mediated by their action to improve cellular Mg homeostasis [69-71].

Altogether, these data are consistent with a role of Mg deficiency in promoting oxidative stress and inflammation, hence, the development of insulin resistance, vascular remodeling, atherosclerosis, type 2 diabetes and cardio-metabolic syndrome.

Mg and age-related sarcopenia

Mg supplementation (up to 8 mg/kg daily) enhanced muscle strength in young untrained individuals [74]. Similarly, physically active young subjects experienced improved endurance performance and decreased oxygen use during sub-maximal exercise after Mg supplementation [75]. Using data from the InCHIANTI study, a well-characterized representative sample of older men and women, a significant, independent and strong relationship between circulating Mg and muscle performance was found, which was consistent across several muscle parameters for both men and women [76]. These data are consistent: a) with the relation of Mg status to muscle ATP and the role of Mg in energetic metabolism; b) the increased reactive oxygen species (ROS) production in Mg deficiency; and, c) the proinflammatory effect of Mg depletion.

Mg and osteoporosis

Mg and the aging process

Several studies have reported alterations in cell physiology with senescence features during Mg deficiency in different cell types. Mg related alterations may include reduced oxidative stress defense, cell cycle progression, culture growth, cellular viability [36, 50, 81, 83, 84], and activation of proto-oncogene (i.e. c-fos, c-jun) and transcription factor expressions (i.e. NF-κB) [85]. Recent data have shown that Mg deficiency may accelerate cellular senescence in cultured human fibroblasts [86]. Continuous culture of primary fibroblasts in magnesium-deficient media resulted in loss of replicative capacity with an accelerated expression of senescence-associated biomarkers. A marked decrease in the replicative lifespan was seen compared to fibroblast populations cultured in standard Mg media conditions. Human fibroblast populations cultured in Mg-deficient conditions also showed an increased senescence-associated β-galactosidase activity. Additionally, activation of cellular aging (p53 and pRb) pathways by Mg-deficient conditions also increased the expression of proteins associated with cellular senescence, including p16INK4a and p21WAF1. Telomere attrition was found to be accelerated in cell populations from Mg-deficient cultures, suggesting that the long-term consequence of inadequate Mg availability in human fibroblast cultures is an accelerated cellular senescence [86].

Conclusion

The possibility that maintaining an optimal Mg balance throughout life might help in preventing or significantly retarding the inflammation process and manifestations of chronic diseases, is a working hypothesis that needs to be tested in prospective studies.

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