Mario Belvedere

Magnesium homeostasis and aging

Aging is very often associated with magnesium (Mg) deficit. Total plasma magnesium concentrations are remarkably constant in healthy subjects throughout life, while total body Mg and Mg in the intracellular compartment tend to decrease with age. Dietary Mg deficiencies are common in the elderly population. Other frequent causes of Mg deficits in the elderly include reduced Mg intestinal absorption, reduced Mg bone stores, and excess urinary loss. Secondary Mg deficit in aging may result from different conditions and diseases often observed in the elderly (i.e. insulin resistance and/or type 2 diabetes mellitus) and drugs (i.e. use of hypermagnesuric diuretics). Chronic Mg deficits have been linked to an increased risk of numerous preclinical and clinical outcomes, mostly observed in the elderly population, 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. Both aging and Mg deficiency have been associated to excessive production of oxygen-derived free radicals and low-grade inflammation. Chronic inflammation and oxidative stress are also present in several age-related diseases, such as many vascular and metabolic conditions, as well as frailty, muscle loss and sarcopenia, and altered immune responses, among others. Mg deficit associated to aging may be at least one of the pathophysiological links that may help to explain the interactions between inflammation and oxidative stress with the aging process and many age-related diseases.

Oral magnesium supplementation improves vascular function in elderly diabetic patients.

Magnesium (Mg) ions directly influence vascular tone and responsiveness and are cofactors for acetylcholine-induced endothelium-dependent relaxation. Alterations in extracellular Mg are able to modify the formation and release of nitric oxide (NO), altering arterial smooth muscle tone. Previous in vivo studies in humans have shown that parenteral or oral Mg supplementation increase endothelial-dependent vasodilation. The aim of the present study was to evaluate the effects of Mg oral supplementation on endothelial function in elderly diabetic and hypertensive subjects. Sixty elderly (≥ 65 years) diabetic patients were recruited (mean age: 71.1 ± 6.1 years; M/F: 35/25). Endothelial function, evaluated by non-invasive flow-mediated dilatation of the brachial artery, as well as anthropometric and laboratory data, including ionized Mg (Mg-ion), were measured in all patients before and after one-month. Thirty patients underwent oral Mg supplementation with 4.5 g/day of Mg pidolate (368 mg/day of Mg ion), while the rest were used as a control group. The usual management of diabetes and hypertension was not changed during the month of study participation for all the patients. In the group of patients that underwent Mg supplementation, Mg-ion concentration significantly increased from 0.42 ± 0.05 mmol/L to 0.49 ± 0.06 mmol/L; p < 0.05. Mg intervention resulted in a significant improvement of the post-ischemic endothelial-dependent flow-mediated dilation (from 3.3 ± 3.6% to 8.4 ± 3.9%; p < 0.05). No significant differences were found, either in ion-Mg or endothelial function, in the control group. In conclusion, the present study suggests that oral Mg improves endothelial function in diabetic elderly subjects.

Physiology of the aging bone and mechanisms of action of bisphosphonates

Fragility fractures, a major public health concern, are expected to further increase due to aging of the world populations because age remains a cardinal, independent determinant of fracture risk. With aging the balance between bone formation and resorption during the remodeling process becomes negative, with increased resorption and reduced formation. Bisphosphonates (BPs) are widely prescribed anti-resorptive agents that inhibit osteoclasts attachment to bone matrix and enhance osteoclast apoptosis. BPs can be divided into nitrogen-containing (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). Both classes induce apoptosis but they evoke it differently. Several studies have examined the molecular mechanisms underlying BPs’ effects on osteoclasts and bone remodeling. N-BPs (alendronate, risedronate, zoledronate) inhibit the intracellular mevalonate pathway and protein isoprenylation, via the enzyme farnesyl pyrophosphate synthase. N-BPs act by competition, binding to the natural substrate-binding site of the enzyme. The less potent non-N-BPs (etidronate, clodronate), do not inhibit the mevalonate pathway and protein isoprenylation, but are metabolized intracellularly to metabolites, which are cytotoxic analogs of ATP. N-BPs represent the first choice treatment for diseases associated with excessive bone resorption, such as fragility fractures (due to postmenopausal-, male, glucocorticoid- and transplant-induced osteoporosis), Paget’s disease of bone, and bone metastasis. Better understanding of BPs’ effects on osteoblasts/osteocytes (e.g., preventing apoptosis) and differential distribution may further help explain anti-fracture benefit and bone quality effects. Lower affinity BPs (e.g., risedronate) may allow better access to osteocyte network. Effects of BPs on bone senescence, cancer cells apoptosis and prevention of cardiovascular calcifications may open new avenues for biogerontological research.

Age, homocysteine, and oxidative stress: relation to hypertension and type 2 diabetes mellitus.

Objectives: Hyperhomocysteinemia and oxidative stress are independent risk factors for cardiovascular events, which occur more frequently in old age. We evaluated these parameters in relation to age and the presence of hypertension and type 2 diabetes mellitus. Methods: Two hundred eighty-two subjects (female/male: 142/140; 141 were >65 years and 141 were <65 years; mean age 73.9 ± 6.6 years and 52.5 ± 8.2 years, respectively) were randomly recruited from those attending our institution. Blood pressure, anthropometric parameters, oxidative stress parameters (reactive oxygen species [ROS] and malondialdehyde [MDA]), and homocysteine levels were evaluated in participants. Results: Homocysteine (2.9 ± 0.06 vs. 2.3 ± 0.03 µmol/L, p < 0.001) and oxidative stress (ROS: 10.8 ± 0.3 vs. 8.1 ± 0.3 mmol/L, p < 0.001; MDA: 1.62 ± 0.05 vs. 1.21 ± 0.05 nmol/mL, p < 0.001) were significantly higher in older vs. younger subjects without hypertension or diabetes. However, homocysteine and MDA were not significantly different in older vs. younger hypertensive subjects (homocysteine: 3.0 ± 0.03 vs. 2.9 ± 0.04 µmol/L, p  =  NS; MDA: 1.7 ± 0.07 vs. 1.4 ± 0.06 nmol/mL, p  =  NS) and in older vs. younger diabetic hypertensive subjects (homocysteine: 3.02 ± 0.05 vs. 2.9 ± 0.05 µmol/L, p  =  NS; ROS: 10.7 ± 0.7 vs. 9.7 ± 0.8 mmol/L, p  =  NS; MDA: 1.6 ± 0.10 vs. 1.5 ± 0.12 nmol/mL, p  =  NS). Conclusions: Aging is accompanied by elevated homocysteine and oxidative stress levels similar to those observed in younger subjects with hypertension or diabetes mellitus, independent of age. Hence, these conditions appear to accelerate the age-dependent increase in homocysteine and oxidative stress.

Combination of intensive cognitive rehabilitation and donepezil therapy in Alzheimer's disease (AD)

Acetylcholinesterase inhibitors (AchEIs) are extensively used in Alzheimers disease (AD) while reality orientation therapy (ROT) is a cognitive rehabilitation indicated for mentally deteriorated patients. We aimed to evaluate the efficacy of the combination of donepezil with an intensive ROT with active participation of the caregiver. Patients with AD (n=100, mean age 78.4±4.3 years) initiated treatment with donepezil, 5mg/day; 62 of them underwent a 3-week, daily ROT and physical reactivation training with the caregiver (Group A); 38 participants received only donepezil therapy (Group B). All subjects were tested for cognitive and functional abilities at baseline, at the end of the training program, and after 2 months of follow-up. There was a significant improvement in mini-mental state examination (MMSE) score (p<0.001) and the AD assessment scale-cognitive (ADAS-Cog) subscale (p<0.001), without changes in impaired activity of daily living (ADL) and instrumental ADL (IADL) after intensive ROT training in Group A. MMSE was maintained after 2 months in-home ROT continuation. There were no significant changes in MMSE in drug-only treated patients (Group B) after 3 weeks, with a non-significant tendency to improvement in ADAS-Cog. Our results suggest benefit of an intensive ROT program in dementia patients receiving donepezil that seems to be maintained as far as ROT is continued by the caregiver.

Altered ionized magnesium levels in mild-to-moderate Alzheimer's disease

Magnesium deficiency is present in several chronic, age-related diseases, including cardiovascular, metabolic and neurodegenerative diseases. Alzheimers disease (AD) is the most common cause of dementia. The aim of the present study was to study magnesium homeostasis in patients with mild to moderate AD. One hundred and one elderly (≥65 years) patients were consecutively recruited (mean age: 73.4±0.8 years; M/F: 42/59). In all patients, a comprehensive geriatric assessment was performed including cognitive and functional status. Admission criteria for the AD group (diagnosed according to the DSM-IV and the NINCDS-ADRDA criteria) included: mild to moderate cognitive impairment (MMSE score: 11-24/30, corrected for age and education). Blood samples were analyzed for serum total magnesium (Mg-tot) and serum ionized magnesium (Mg-ion). AD patients had significantly lower MMSE scores (20.5±0.7 vs 27.9±0.2; p<0.001), and for the physical function tests. Mg-ion was significantly lower in the AD group as compared to age-matched control adults without AD (0.50±0.01 mmol/L vs 0.53±0.01 mmol/L; p<0.01). No significant differences were found in Mg-tot between the two groups (1.91±0.03 mEq/L vs 1.95±0.03 mEq/L; p=NS). For all subjects, Mg-ion levels were significantly and directly related only to cognitive function (Mg-ion/MMSE r=0.24 p<0.05), while no significant correlations were found in this group of patients between magnesium and ADL or IADL. Our results show the presence of subclinical alterations in Mg-ion in patients with mild to moderate AD.

Serum ionized magnesium in diabetic older persons

OBJECTIVE Several alterations of magnesium metabolism have been associated with type 2 diabetes pathophysiology, a condition particularly frequent in older persons. We aimed to evaluate serum total (Mg-tot) and serum ionized magnesium (Mg-ion) in older persons with type 2 diabetes in order to explore clinically applicable methods for the detection of magnesium deficit. MATERIAL/METHODS Mg-tot and Mg-ion were measured in 105 fasting subjects with type 2 diabetes (mean age: 71.1±0.8 years; M/F: 45/60) and in 100 age-matched non-diabetic control persons (mean age: 72.2±0.8 years; M/F: 42/58). RESULTS Mg-ion concentrations were significantly lower in diabetic persons compared with controls (0.49±0.05 mmol/L vs. 0.55±0.05 mmol/L; p<0.001). Mg-tot was also slightly but significantly lower in diabetic patients (0.82±0.007 mmol/L vs. 0.84±0.006 mmol/L; p<0.05). There was an almost complete overlap in the values of Mg-tot in older diabetic patients and controls; conversely, 44.8% of diabetic patients had Mg-ion values below 0.47 mmol/L, while none of the controls did. After adjustment for age, sex, BMI, and triglycerides, Mg-tot was significantly associated with FBG in all the participants (p<0.05) and Mg-ion was significantly associated with FBG in all the participants (p<0.01) and with HbA1c in diabetic participants (p<0.001). CONCLUSIONS Alterations of magnesium serum concentrations are common in type 2 diabetic older adults; Mg-ion evaluation may help to identify subclinical magnesium depletion (i.e. in patients with normal Mg-tot); the close independent associations of Mg-tot and Mg-ion with FBG and with HbA1c reinforce the possible link between magnesium homeostasis and altered glucose metabolism.

AZITHROMYCIN IN AN OLDER WOMAN WITH DIABETIC GASTROPARESIS

Diabetic neuropathy is a common chronic complication of diabetes and cause of significant morbidity and mortality, because it may involve the autonomous and peripheral nervous systems. Autonomic diabetic neuropathy is a challenging chronic complication of long-standing diabetes manifested with hypotension, syncope, gastroparesis, diarrhea, constipation, bladder dysfunction, sexual dysfunction, cardiac arrest, and/or sudden death. We present a case of diabetic gastroparesis in an older woman. The patient was an 83-year-old woman with a 40-year history of type 2 diabetes who was admitted with hypoglycemia, malnutrition, persistent vomiting, and obstinate constipation. After several unsuccessful attempts with different therapies, we administered intravenous azithromycin (500 mg/day). After 3 days of treatment, vomiting was resolved and the patient evacuated normal feces, with notable improvement in the general conditions and metabolic control. Because diabetic gastroparesis frequently is difficult to manage clinically and there are few beneficial therapeutic choices available at present, the macrolide antibiotic azithromycin, which has strong prokinetic properties, may be a useful option in the treatment of this complex condition.

MAGNESIUM METABOLISM IN INSULIN RESISTANCE, METABOLIC SYNDROME, AND TYPE 2 DIABETES MELLITUS

Magnesium plays a key role in regulating insulin action, insulin-mediated glucose uptake, and vascular tone. Intracellular magnesium depletion may result in a defective tyrosine—kinase activity at the insulin receptor level, in a postreceptorial impairment in insulin action, and clinically in a worsening of insulin resistance. Intra- and extracellular alterations of magnesium metabolism have been identified in clinical states characterized by insulin resistance, such as metabolic syndrome, hypertension, altered glucose tolerance, type 2 diabetes, and aging. Several studies, from our and other’s groups, have confi rmed the clinical relevance of alterations of magnesium homeostasis in these conditions and have highlighted the importance of an accurate definition of the magnesium status. While measurements of total serum magnesium levels have been proven inadequate for this purpose because important magnesium depletions are required before total serum level decreases, two technologies, 31P nuclear magnetic resonance (31P-NMR) spectroscopy and magnesium-specifi c ion-selective electrodes, that, respectively, measure intracellular and extracellular free levels of magnesium, have a higher sensitivity in detecting magnesium deficits. A number of evidences have confirmed that magnesium supplementation is indicated in conditions associated with magnesium deficit, although well-designed therapeutic trials with oral magnesium supplements to study the beneficial effects in metabolic syndrome and in type 2 diabetes are needed.

Magnesium and Alzheimer’s Disease: Implications for Diet and Nutrition

Environmental factors, including nutrition and metal elements, are implicated in the pathophysiology of Alzheimer’s disease (AD). Several in vitro and in vivo data indicate a role for magnesium (Mg) in many biological and clinical aspects of AD. Mg deficiency, aside from having a negative impact on the energy production pathways required by the mitochondria to generate adenosine triphosphate, also affects many biochemical mechanisms vital for neuronal properties and synaptic plasticity, including the response of N-methyl-d-aspartate receptors to excitatory amino acids, stability, and viscosity of the cell membrane. Mg also has an action as a mild calcium antagonist, and as an antioxidant against free-radical damage of the mitochondria. Total and ionized Mg levels in plasma, as well as Mg concentrations in various tissues, were found to be decreased in AD patients and negatively associated with clinical deterioration. Chronic Mg deficiency results in excessive production of oxygen-derived free radicals and low-grade inflammation, these also being possible pathogenic factors in AD. Moreover, Mg was shown to have a role in the processing of amyloid-beta precursor protein, which plays a central role in the pathogenesis of AD. Whether Mg supplementation may help in preventing cognitive decline in the elderly remains to be demonstrated.Environmental factors, including nutrition and metal elements, are implicated in the pathophysiology of Alzheimer’s disease (AD). Several in vitro and in vivo data indicate a role for magnesium (Mg) in many biological and clinical aspects of AD. Mg deficiency, aside from having a negative impact on the energy production pathways required by the mitochondria to generate adenosine triphosphate, also affects many biochemical mechanisms vital for neuronal properties and synaptic plasticity, including the response of N-methyl- d -aspartate receptors to excitatory amino acids, stability, and viscosity of the cell membrane. Mg also has an action as a mild calcium antagonist, and as an antioxidant against free-radical damage of the mitochondria. Total and ionized Mg levels in plasma, as well as Mg concentrations in various tissues, were found to be decreased in AD patients and negatively associated with clinical deterioration. Chronic Mg deficiency results in excessive production of oxygen-derived free radicals and low-grade inflammation, these also being possible pathogenic factors in AD. Moreover, Mg was shown to have a role in the processing of amyloid-beta precursor protein, which plays a central role in the pathogenesis of AD. Whether Mg supplementation may help in preventing cognitive decline in the elderly remains to be demonstrated.