Marisa Fioravanti

Nutritional Supplements with Oral Amino Acid Mixtures Increases Whole-Body Lean Mass and Insulin Sensitivity in Elderly Subjects with Sarcopenia

Decreases in whole-body lean mass can cause sarcopenia, a disease frequently found in the elderly. This condition is frequently associated with frailty and disability in aging as well as the onset and progression of several geriatric syndromes. Sarcopenia therefore must be managed with multidimensional approaches that include physical training, nutritional support, and metabolic and anabolic treatment. The purpose of our study was to assess the effect of an orally administered special mixture of amino acids (AAs) in elderly subjects with reduced lean body mass and sarcopenia. A randomized, open-label, crossover study was conducted in 41 elderly subjects (age range: 66-84 years) with sarcopenia, assigned to 2 distinct treatments (AAs and placebo). All subjects had normal body weight (body mass index within 19-23). The AA treatment consisted of 70.6 kcal/day (1 kcal = 4.2 kJ) of 8 g of essential AA snacks, given at 10:00 am and 5:00 pm. Lean mass was measured with dual-energy x-ray absorptiometry in leg, arm, and trunk tissues. Significant increases in whole-body lean mass in all areas were seen after 6 months and more consistently after 18 months of oral nutritional supplementation with AAs. Fasting blood glucose, serum insulin, and homeostatic model assessment of insulin resistance (an index of insulin resistance) significantly decreased during AA treatment. Furthermore, a significant reduction in serum tumor necrosis factor-alpha (TNF-alpha) and a significant increase in both insulin-like growth factor-1 (IGF-1) serum concentrations and in the IGF-1/TNF-alpha ratio were also found. No significant adverse effects were observed during AA treatment. These preliminary data indicate that nutritional supplements with the oral AA mixture significantly increased whole-body lean mass in elderly subjects with sarcopenia. The improvement in the amount of whole-body lean mass could be linked to increased insulin sensitivity and anabolic conditions related to IGF-1 availability.

Pineal and pituitary-adrenocortical function in physiological aging and in senile dementia

The simultaneous evaluation of the circadian rhythm of plasma melatonin and ACTH and of serum cortisol and DHEAS represents a clinically reliable tool to appreciate the neuroendocrine changes occurring in physiological and pathological brain aging.A selective impairment of the nocturnal melatonin secretion has been observed in elderly subjects, being significantly related either to the age or to the severity of dementia. A significant increase of serum cortisol levels during evening- and night-times was found in elderly subjects, particularly if demented, when compared to young controls. Besides, both the circadian amplitude of cortisol rhythm and the nocturnal cortisol increase were significantly reduced in relation either to age or to cognitive impairment. By comparison to vascular dementia, patients with Alzheimers disease exhibited the highest cortisol concentrations throughout the 24h. The sensitivity of the hypothalamic-pituitary-adrenal axis to the steroid feedback was significantly impaired in old subjects and particularly in the demented ones. The serum DHEAS levels were significantly lower in elderly subjects and even more in demented patients than in young controls. Consequently, a significant increase of the cortisol/DHEAS molar ratio was evident when going from young controls to healthy elderly subjects and to demented patients. In conclusion, the aging process affects many neuroendocrine functions resulting in subtle but clinically relevant consequences; the occurrence of senile dementia seems to play an additive role.

Neuroendocrine correlates of the aging brain in humans

Physiological brain aging is characterized by important biochemical and structural changes and by the unbalance among the different neurotransmitters and neuromodulators. The study of the circadian organization of neuroendocrine functions may be considered a clinically reliable tool to investigate the changes of the CNS and particularly of the limbic-hypothalamic system occurring in aged people. The circadian rhythms of plasma melatonin, ACTH and cortisol and of oral temperature were studied in 16 clinically healthy women aged 66-90 years and in 14 young controls aged 20-30. In addition, the effect of dexamethasone on the plasma cortisol circadian rhythm and the cortisol response to Synacthen pulse intravenous injection were evaluated. All subjects were studied as inpatients, with the same synchronization to the hospital life schedule. When compared with young controls, elderly subjects exhibited a reduction of the mean level and of the amplitude of the circadian rhythm of oral temperature, an increase of the mean level of ACTH and cortisol rhythms and a selective impairment of melatonin nocturnal secretion. Furthermore, elderly subjects showed a reduced sensitivity to the dexamethasone suppression test, by comparison to young controls. These changes were age-related and they may depend either on CNS modification or on alterations of the hormonal metabolic clearance.

Age-related changes of the adrenal secretory pattern: possible role in pathological brain aging

The biosynthetic dissociation of the adrenocortical secretion occurring with age may have a pathogenetic role in the pathophysiology of brain aging. We studied cortisol and DHEAS secretion in healthy old and young subjects, in senile dementia, in major depression of elderly subjects and in healthy centenarians. A clear age-related decline of DHEAS secretion was well evident in healthy centenarians, and a further decrease in DHEAS concentration was found in old depressed patients and moreover in the demented ones, by comparison with age-matched controls. The circadian profile of serum cortisol was clearly flattened in old subjects, due to the selective increase in the cortisol nocturnal levels, particularly evident in demented subjects; on the other hand, the morning serum cortisol levels were not significantly different among centenarians, young and old controls. The molar ratio between cortisol and DHEAS showed a significant age-related increase; the occurrence of senile dementia and of major depression played an additive role, by comparison to physiological aging. The qualitative and quantitative modifications of the adrenocortical secretion occurring with aging seem mainly dependent on age itself, but the occurrence of pathological conditions may amplify these changes. Since cortisol and DHEAS play opposite effects on the central nervous system, the evaluation of the ratio between cortisol and DHEAS seems to be a good marker of the neuroendocrine features in old subjects.

Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians.

Abstract:  Melatonin secretion is an endogenous synchronizer, and it may possess some anti‐aging properties. Thus we examined melatonin levels in physiological aging, in extreme senescence and in senile dementia. In healthy old (age 66–94 yr) and young subjects (age 23–39 yr) and in demented patients (age 68–91 yr) plasma melatonin was measured by radioimmunoassay in eight serial blood samples. In centenarians (age 100–107 yr) melatonin levels were estimated by assaying urinary 6‐hydroxymelatonin sulfate (aMT6s) in two different urine samples collected from 08:00 to 20:00 hours and from 20:00 to 08:00 hours. These data were compared with the aMT6s excretion of old and young controls. Elderly subjects, demented or not, exhibited a flattened circadian profile of plasma melatonin, because of the suppression of the nocturnal peak. An age‐related decline of the circadian amplitude of the melatonin rhythm occurred in old subjects, especially in demented individuals. Furthermore, the melatonin nocturnal peak was significantly correlated with the severity of the cognitive impairment. aMT6s urinary excretion also declined with age. However, as in young controls, in centenarians the aMT6s excretion was significantly higher at night than during the day. In conclusion, pineal melatonin secretion is affected by age and by the degree of cognitive impairment. In centenarians the maintenance of the circadian organization of melatonin secretion may suggest that the amplitude of the nocturnal peak and/or the persistence of a prevalent nocturnal secretion may be an important marker of biological age and of health status.

Safety of Type 2 Diabetes Treatment With Repaglinide Compared With Glibenclamide in Elderly People: A randomized, open-label, two-period, cross-over trial

The incidence of type 2 diabetes increases with age (1), and elderly people with this disease may be particularly susceptible to hypoglycemia due to long-acting oral antidiabetic drugs (OADs). The American Geriatric Society clinical guidelines on type 2 diabetes treatment in elderly people report that short-acting hypoglycemic agents are preferable to longer-acting agents (chlorpropramide), which are associated with increased risk of hypoglycemia (2). Repaglinide is an insulin secretagogue with a rapid onset and relatively short duration of action (3,4). Several studies have shown repaglinide to be a safe and effective treatment for type 2 diabetes (5–9). However, few data are available on its use in elderly patients and, in particular, on the incidence of hypoglycemic events. The present study assessed the safety of repaglinide versus glibenclamide in this population, in terms of hypoglycemia and adverse events. This was a 24-week, randomized, open-label, two-period, cross-over comparison between mealtime repaglinide and twice-daily glibenclamide. Patients ( n = 90) were aged ≥65 years and had been previously treated with diet or OADs (mean age 74.6 years, HbA1c [A1C] 7.9%). A subgroup of 37 patients aged ≥75 years was evaluated separately. After screening, previous OAD treatment was discontinued and patients were randomized to first receive either repaglinide (Novonorm; …

Overproduction of IFN-γ and TNF-α from Natural Killer (NK) Cells Is Associated with Abnormal NK Reactivity and Cognitive Derangement in Alzheimer's Disease

Abstract: Alterations of natural killer (NK) function can be involved in the neuroimmune mechanism of neurodegeneration in dementia of the Alzheimers type (DAT). NK cell cytotoxicity (NKCC) and the generation and release of IFN‐γ and TNF‐α (spontaneous and modulated by IL‐2) from pure NK cells (CD 16+, CD 56+, CD 3−) were studied together with circulating IFN‐γ and TNF‐α levels and cognitive function in 22 old patients with DAT and 15 healthy old subjects. Higher (p < 0.001) IL‐2 modulated NKCC (with IL‐2 50 U/mL and 100 U/mL) was demonstrated in DAT patients (+35% and +99% from baseline) than in healthy subjects (+6% and +76% from baseline). Increased spontaneous and IL‐2‐induced release of IFN‐γ and TNF‐α from NK cells were found in DAT patients compared to healthy subjects (p < 0.001), whereas no difference of serum IFN‐γ and TNF‐α was demonstrated between DAT and control groups. Significant negative correlations among the spontaneous release of IFN‐γ and TNF‐α from NK and the decrease of the score of cognitive function (MMSE) were found in patients with DAT. In conclusion, alterations of NKCC control and NK‐derived cytokine release in DAT could be involved in the neuroinflammatory mechanism related to the progression of neurodegeneration and dementia.

Whey protein, amino acids, and vitamin D supplementation with physical activity increases fat-free mass and strength, functionality, and quality of life and decreases inflammation in sarcopenic elderly

BACKGROUND Interventions to attenuate the adverse effects of age-related loss of skeletal muscle and function include increased physical activity and nutritional supplementation. OBJECTIVE This study tested the hypothesis that nutritional supplementation with whey protein (22 g), essential amino acids (10.9 g, including 4 g leucine), and vitamin D [2.5 μg (100 IU)] concurrent with regular, controlled physical activity would increase fat-free mass, strength, physical function, and quality of life, and reduce the risk of malnutrition in sarcopenic elderly persons. DESIGN A total of 130 sarcopenic elderly people (53 men and 77 women; mean age: 80.3 y) participated in a 12-wk randomized, double-blind, placebo-controlled supplementation trial. All participants concurrently took part in a controlled physical activity program. We examined body composition with dual-energy X-ray absorptiometry, muscle strength with a handgrip dynamometer, and blood biochemical indexes of nutritional and health status, and evaluated global nutritional status, physical function, and quality of life before and after the 12 wk of intervention. RESULTS Compared with physical activity and placebo, supplementation plus physical activity increased fat-free mass (1.7-kg gain, P < 0.001), relative skeletal muscle mass (P = 0.009), android distribution of fat (P = 0.021), handgrip strength (P = 0.001), standardized summary scores for physical components (P = 0.030), activities of daily living (P = 0.001), mini nutritional assessment (P = 0.003), and insulin-like growth factor I (P = 0.002), and lowered C-reactive protein (P = 0.038). CONCLUSION Supplementation with whey protein, essential amino acids, and vitamin D, in conjunction with age-appropriate exercise, not only boosts fat-free mass and strength but also enhances other aspects that contribute to well-being in sarcopenic elderly. This trial was registered at clinicaltrials.gov as NCT02402608.

Improvement of Blood Glucose Control and Insulin Sensitivity During a Long-Term (60 Weeks) Randomized Study with Amino Acid Dietary Supplements in Elderly Subjects with Type 2 Diabetes Mellitus

A decrease in lean muscular mass causes sarcopenia, a disease frequently found in the elderly population. The reduction of muscle mass may be responsible for reduced insulin sensitivity and decreased glucose uptake, thus increasing the risk for hyperglycemia and insulin-resistance syndrome in elderly subjects with type 2 diabetes mellitus. We therefore wanted to determine the effect of a special mixture of oral amino acids (AAs) on elderly subjects with type 2 diabetes. A randomized, open-label, crossover study was conducted in 34 subjects with diabetes (age range, 65-85 years) assigned to 2 distinct treatments (AAs and placebo). In spite of treatment with oral hypoglycemic drugs or insulin, all subjects were in poor metabolic control (glycated hemoglobin [HbA(1c)] >7%). The subjects studied had normal body weight (ie, body mass index within 19-23). AAs consisted of 70.6 kcal/day (1 kcal = 4.2 kJ) of 8 g of AA snacks, given at 10.00 am and 5.00 pm. Fasting and postprandial (1 hour and 2 hours) blood glucose, serum insulin, and homeostatic model assessment of insulin resistance (an index of insulin resistance) significantly decreased during AA treatment. Furthermore, a significant reduction of HbA(1c) levels was found throughout the study. No significant adverse effects were observed during the active treatment. We suggest that nutritional supplementation with a special mixture of oral AAs is safe and significantly improves metabolic control and insulin sensitivity in poorly controlled elderly subjects with type 2 diabetes. This effect was consistent during the long-term observation period of 60 weeks and was also present after the crossover from AAs to placebo.

Hemorheological changes and overproduction of cytokines from immune cells in mild to moderate dementia of the Alzheimer’s type: adverse effects on cerebromicrovascular system.

An association between hemorheological alterations (i.e., whole-blood and plasma hyperviscosity, reduced erythrocyte deformability, increased red cell aggregation, hyperfibrinogenemia and increased acute-phase protein levels) and the mild stage of senile dementia of the Alzheimers type (DAT) was suggested in the present study. In particular, hyperfibrinogenemia and the increase of erytrhocyte aggregation were correlated with the increased generation and release of TNF-alpha and IFN-gamma (spontaneous release and IL-2-modulated release) from natural killer (NK) lymphocytes (CD16+, CD56+, CD3- cells) of patients with DAT; whereas a normal cytokine release from NK cells was found in healthy old subjects and in patients with vascular dementia (VaD). The in vitro and in vivo administration of the hemorheologic drug pentoxifylline (PTX) significantly reduced spontaneous and IL-2-modulated cytokine overproduction from NK cells (in vitro effects with 500 U/ml and 1000 U/ml/NK cells) and improved all the hemorheological parameters. Taken together, these data suggest that disturbances of cerebrovascular flow and of hemorheology could be considered a negative component related to the pathogenesis and progression of DAT neurodegeneration. The association between hemorheological changes and alterations of TNF-alpha and IFN-gamma release from NK may indicate a potential immunorheologic mechanism associated with cerebrovascular damage in DAT and could suggest the use of vascular protective drugs as support of the main pharmacological and non-pharmacological therapy of AD.