Safety and tolerability of 6-month supplementation with a vitamin D, calcium and leucine-enriched whey protein medical nutrition drink in sarcopenic older adults.

AIMS: Safety and tolerability of prolonged supplementation with a vitamin D, calcium and leucine-enriched whey protein medical nutrition drink (WP-MND) was evaluated in sarcopenic older adults. METHODS: A 13-week double-blinded, randomized, isocaloric placebo-controlled trial (PROVIDE study; n = 380) was extended with a voluntary 13-week open-label extension (OLE). OLE participants were randomized to receive daily 1 or 2 servings of WP-MND (21 g protein, 3 g leucine, 10 µg vitD and 500 mg calcium per serving). Gastro-intestinal tolerability, kidney function and serum levels of calcidiol, parathyroid hormone (PTH) and calcium were evaluated at week 0, 13 and 26. RESULTS AND DISCUSSION: In response to the high daily protein intake (median1.5; IQR: 1.3, 1.7 g/kg BW/day), the estimated glomerular filtration rate (eGFR) increased in the test group during the RCT (p = 0.013). The same trend was observed for those participants with moderate chronic kidney disease. During OLE no eGFR change was observed in any of the groups. Serum calcidiol and calcium reached a plateau after 13-week WP-MND supplementation. As expected, PTH significantly changed in the opposite direction, decreasing during RCT in the test group (T vs C: p < 0.001) and during OLE in former control groups. During RCT, 20/366 participants with normal baseline calcidiol reached levels ≥ 100 nmol/L (T: n = 18; C: n = 2) and 6 developed albumin-corrected calcium levels > 2.55 mmol/L (T: n = 3; C: n = 3), without associated adverse events. CONCLUSION: A 6 months intervention with up to 2 servings of WP-MND did neither result in kidney function deterioration nor symptoms of vitamin D or calcium toxicity. The product was overall well tolerated.

Thirteen weeks of supplementation of vitamin D and leucine-enriched whey protein nutritional supplement attenuates chronic low-grade inflammation in sarcopenic older adults: the PROVIDE study.

BACKGROUND: A chronic low-grade inflammatory profile (CLIP) is associated with sarcopenia in older adults. Protein and Vitamin (Vit)D have immune-modulatory potential, but evidence for effects of nutritional supplementation on CLIP is limited. AIM: To investigate whether 13 weeks of nutritional supplementation of VitD and leucine-enriched whey protein affected CLIP in subjects enrolled in the PROVIDE-study, as a secondary analysis. METHODS: Sarcopenic adults (low skeletal muscle mass) aged ≥ 65 years with mobility limitations (Short Physical Performance Battery 4-9) and a body mass index of 20-30 kg/m2 were randomly allocated to two daily servings of active (n = 137, including 20 g of whey protein, 3 g of leucine and 800 IU VitD) or isocaloric control product (n = 151) for a double-blind period of 13 weeks. At baseline and after 13 weeks, circulating interleukin (IL)-8, IL-1 receptor antagonist (RA), soluble tumor-necrosis-factor receptor (sTNFR)1, IL-6, high-sensitivity C-reactive protein, pre-albumin and 25-hydroxyvitamin(OH)D were measured. Data-analysis included repeated measures analysis of covariance (corrected for dietary VitD intake) and linear regression. RESULTS: IL-6 and IL-1Ra serum levels showed overall increases after 13 weeks (p = 0.006 and p < 0.001, respectively). For IL-6 a significant time × treatment interaction (p = 0.046) was observed, with no significant change over time in the active group (p = 0.155) compared to control (significant increase p = 0.012). IL-8 showed an overall significant decrease (p = 0.03). The change in pre-albumin was a significant predictor for changes in IL-6 after 13 weeks. CONCLUSIONS: We conclude that 13 weeks of nutritional supplementation with VitD and leucine-enriched whey protein may attenuate the progression of CLIP in older sarcopenic persons with mobility limitations.

Sufficient levels of 25-hydroxyvitamin D and protein intake required to increase muscle mass in sarcopenic older adults - The PROVIDE study.

BACKGROUND: Inadequate nutritional intake and altered response of aging muscles to anabolic stimuli from nutrients contribute to the development of sarcopenia. Nutritional interventions show inconsistent results in sarcopenic older adults, which might be influenced by their basal nutritional status. OBJECTIVE: To test if baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations and dietary protein intake influenced changes in muscle mass and function in older adults who received nutritional intervention. METHODS AND DESIGN: Post-hoc analysis was performed in the PROVIDE study that was a randomized controlled, double blind trial among 380 sarcopenic older adults. This study showed that those who received a vitamin D and leucine-enriched whey protein medical nutrition drink for 13 weeks gained more appendicular muscle mass (aMM), and improved lower-extremity function as assessed by the chair stand test compared with controls. To define low and high groups, a baseline serum concentration of 50 nmol/L 25(OH)D and baseline dietary protein intake of 1.0 g/kg/d were used as cut offs. RESULTS: At baseline, participants with lower 25(OH)D concentrations showed lower muscle mass, strength and function compared with participants with a high 25(OH)D, while the group with lower protein intake (g/kg/day) had more muscle mass at baseline compared with the participants with higher protein intake. Participants with higher baseline 25(OH)D concentrations and dietary protein intake had, independent of other determinants, greater gain in appendicular muscle mass, skeletal muscle index (aMM/h2), and relative appendicular muscle mass (aMM/body weight × 100%) in response to the nutritional intervention. There was no effect modification of baseline 25(OH)D status or protein intake on change in chair-stand test. CONCLUSIONS: Sufficient baseline levels of 25(OH)D and protein intake may be required to increase muscle mass as a result of intervention with a vitamin D and protein supplement in sarcopenic older adults. This suggests that current cut-offs in the recommendations for vitamin D and protein intake could be considered the "minimum" for adults with sarcopenia to respond adequately to nutrition strategies aimed at attenuating muscle loss.

Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport.

Brown and beige adipocytes combust nutrients for thermogenesis and through their metabolic activity decrease pro-atherogenic remnant lipoproteins in hyperlipidemic mice. However, whether the activation of thermogenic adipocytes affects the metabolism and anti-atherogenic properties of high-density lipoproteins (HDL) is unknown. Here, we report a reduction in atherosclerosis in response to pharmacological stimulation of thermogenesis linked to increased HDL levels in APOE*3-Leiden.CETP mice. Both cold-induced and pharmacological thermogenic activation enhances HDL remodelling, which is associated with specific lipidomic changes in mouse and human HDL. Furthermore, thermogenic stimulation promotes HDL-cholesterol clearance and increases macrophage-to-faeces reverse cholesterol transport in mice. Mechanistically, we show that intravascular lipolysis by adipocyte lipoprotein lipase and hepatic uptake of HDL by scavenger receptor B-I are the driving forces of HDL-cholesterol disposal in liver. Our findings corroborate the notion that high metabolic activity of thermogenic adipocytes confers atheroprotective properties via increased systemic cholesterol flux through the HDL compartment.

High Prevalence of Physical Frailty Among Community-Dwelling Malnourished Older Adults-A Systematic Review and Meta-Analysis.

BACKGROUND: Malnutrition and frailty are two geriatric syndromes that significantly affect independent living and health in community-dwelling older adults. Although the pathophysiology of malnutrition and physical frailty share common pathways, it is unknown to what extent these syndromes overlap and how they relate to each other. METHODS: A systematic review was performed resulting in a selection of 28 studies that assessed both malnutrition and frailty in community-dwelling older adults. Furthermore, a meta-analysis was performed on 10 studies that used Mini- Nutritional Assessment and the Fried frailty phenotype to estimate the prevalence of malnutrition within physical frailty and vice versa. RESULTS: In the systematic review, 25 of the 28 studies used the Mini-Nutritional Assessment (long or short form) for malnutrition screening. For frailty assessment, 23 of the 28 studies focused on the physical frailty phenotype, of which 19 followed the original Fried phenotype. Fifteen studies analyzed the association between malnutrition and frailty, which was significant in 12 of these. The meta-analysis included 10 studies with a total of 5447 older adults. In this pooled population of community-dwelling older adults [mean (standard deviation) age: 77.2 (6.7) years], 2.3% was characterized as malnourished and 19.1% as physically frail. The prevalence of malnutrition was significantly associated with the prevalence of physical frailty (P < .0001). However, the syndromes were not interchangeable: 68% of the malnourished older adults was physically frail, whereas only 8.4% of the physical frail population was malnourished. CONCLUSIONS: The systematic review and meta-analysis revealed that malnutrition and physical frailty in community-dwelling older adults are related, but not interchangeable geriatric syndromes. Two out of 3 malnourished older adults were physically frail, whereas close to 10% of the physically frail older adults was identified as malnourished.

Nutritional status, body composition, and quality of life in community-dwelling sarcopenic and non-sarcopenic older adults: A case-control study.

BACKGROUND & AIM: Sarcopenia, the age-related decrease in muscle mass, strength, and function, is a main cause of reduced mobility, increased falls, fractures and nursing home admissions. Cross-sectional and prospective studies indicate that sarcopenia may be influenced in part by reversible factors like nutritional intake. The aim of this study was to compare functional and nutritional status, body composition, and quality of life of older adults between age and sex-matched older adults with and without sarcopenia. METHODS: In a multi-centre setting, non-sarcopenic older adults (n = 66, mean ± SD: 71 ± 4 y), i.e. Short Physical Performance Battery (SPPB): 11-12 and normal skeletal muscle mass index, were recruited to match 1:1 by age and sex to previously recruited adults with sarcopenia: SPPB 4-9 and low skeletal muscle mass index. Health-related quality of life, self-reported physical activity levels and dietary intakes were measured using the EQ-5D scale and index, Physical Activity Scale for the Elderly (PASE), and 3-day prospective diet records, respectively. Concentrations of 25-OH-vitamin D, α-tocopherol (adjusted for cholesterol), folate, and vitamin B-12 were assessed in serum samples. RESULTS: In addition to the defined components of sarcopenia, i.e. muscle mass, strength and function, reported physical activity levels and health-related quality of life were lower in the sarcopenic adults (p < 0.001). For similar energy intakes (mean ± SD: sarcopenic, 1710 ± 418; non-sarcopenic, 1745 ± 513, p = 0.50), the sarcopenic group consumed less protein/kg (-6%), vitamin D (-38%), vitamin B-12 (-22%), magnesium (-6%), phosphorus (-5%), and selenium (-2%) (all p < 0.05) compared to the non-sarcopenic controls. The serum concentration of vitamin B-12 was 15% lower in the sarcopenic group (p = 0.015), and all other nutrient concentrations were similar between groups. CONCLUSIONS: In non-malnourished older adults with and without sarcopenia, we observed that sarcopenia substantially impacted self-reported quality of life and physical activity levels. Differences in nutrient concentrations and dietary intakes were identified, which might be related to the differences in muscle mass, strength and function between the two groups. This study provides information to help strengthen the characterization of this geriatric syndrome sarcopenia and indicates potential target areas for nutritional interventions.

Effects of a vitamin D and leucine-enriched whey protein nutritional supplement on measures of sarcopenia in older adults, the PROVIDE study: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Age-related losses of muscle mass, strength, and function (sarcopenia) pose significant threats to physical performance, independence, and quality of life. Nutritional supplementation could positively influence aspects of sarcopenia and thereby prevent mobility disability. OBJECTIVE: To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of sarcopenia. DESIGN: A multicenter, randomized, controlled, double-blind, 2 parallel-group trial among 380 sarcopenic primarily independent-living older adults with Short Physical Performance Battery (SPPB; 0-12) scores between 4 and 9, and a low skeletal muscle mass index. The active group (n = 184) received a vitamin D and leucine-enriched whey protein nutritional supplement to consume twice daily for 13 weeks. The control group (n = 196) received an iso-caloric control product to consume twice daily for 13 weeks. Primary outcomes of handgrip strength and SPPB score, and secondary outcomes of chair-stand test, gait speed, balance score, and appendicular muscle mass (by DXA) were measured at baseline, week 7, and week 13 of the intervention. RESULTS: Handgrip strength and SPPB improved in both groups without significant between-group differences. The active group improved more in the chair-stand test compared with the control group, between-group effect (95% confidence interval): -1.01 seconds (-1.77 to -0.19), P = .018. The active group gained more appendicular muscle mass than the control group, between-group effect: 0.17 kg (0.004-0.338), P = .045. CONCLUSIONS: This 13-week intervention of a vitamin D and leucine-enriched whey protein oral nutritional supplement resulted in improvements in muscle mass and lower-extremity function among sarcopenic older adults. This study shows proof-of-principle that specific nutritional supplementation alone might benefit geriatric patients, especially relevant for those who are unable to exercise. These results warrant further investigations into the role of a specific nutritional supplement as part of a multimodal approach to prevent adverse outcomes among older adults at risk for disability.

Beta-adrenergic receptor blockade does not inhibit cold-induced thermogenesis in humans: possible involvement of brown adipose tissue.

CONTEXT: Recently, brown adipose tissue (BAT) gained interest as a possible target for cold-induced thermogenesis, and therefore a target for treatment of obesity in adult humans. However, mitochondrial uncoupling takes place not only in BAT but also in skeletal muscle tissue. Both tissues may be involved in cold-induced thermogenesis, which is presumably regulated by the sympathetic nervous system. OBJECTIVE: Here we studied whether blockade of ß-adrenergic receptors using propranolol diminishes cold-induced thermogenesis and mitochondrial uncoupling in skeletal muscle tissue. DESIGN: Ten lean subjects participated in this study and stayed twice (control and ß-blockade using propranolol) for 84 h in a respiration chamber-the first 36 h for baseline measurements, followed by 48 h of mild cold exposure (16 C). Energy expenditure was measured continuously. After 36 and 84 h, muscle biopsies were taken in which mitochondrial uncoupling was studied. RESULTS: Energy expenditure increased upon mild cold exposure (+5.0 ± 1.2 W; P < 0.005), i.e. cold-induced thermogenesis. However, contrary to our hypothesis, this cold-induced thermogenesis was not diminished after ß-blockade (+4.7 ± 2.1 W for blockade vs. +5.1 ± 1.4 W for control; P = 0.59 for interaction cold blockade). Skeletal muscle mitochondrial uncoupling was significantly related to cold-induced thermogenesis in the control situation (R(2) = 0.650; P < 0.01). There was no such relation during ß-blockade. CONCLUSIONS: Our results suggest that skeletal muscle mitochondrial uncoupling may be involved in cold-induced thermogenesis and that this may be regulated by ß(2)-receptors. When the ß(1)- and ß(2)-receptors are blocked, a ß(3)-regulated process like mitochondrial uncoupling in BAT might take over the role of skeletal muscle mitochondrial uncoupling.

Cold-induced adaptive thermogenesis in lean and obese.

On entering a cold environment, people react by increasing insulation and energy expenditure (EE). However, large interindividual differences exist in the relative contribution of each mechanism. Short-term studies revealed that obese subjects increase EE (i.e., adaptive thermogenesis) less than lean subjects, which might have implications for the predisposition to obesity. In this study, we validate the differences in adaptive thermogenesis between lean and obese upon midterm mild cold exposure. Therefore, 10 lean and 10 obese subjects were exposed for 48 h to mild cold (16 degrees C) in a respiration chamber. The preceding 36 h they stayed in the same chamber at a neutral temperature (22 degrees C) for the baseline measurements. EE, physical activity, skin temperature, and core temperature have been measured for the last 24 h of both parts. Mean daytime EE increased significantly in the lean subjects (P < 0.01), but not in the obese. Physical activity decreased significantly in the lean (P < 0.01) and the obese (P < 0.001) subjects. The change in EE was related to the change in physical activity in both groups (respectively R(2) = 0.673, P < 0.01 and R(2) = 0.454, P < 0.05). Upon mild cold exposure, lean subjects decreased proximal skin temperature less, but distal skin temperature more than obese. In conclusion, the interindividual differences in cold-induced thermogenesis were related to changes in physical activity in both lean and obese, pointing at the existence of individual variation in physical activity to compensate for cold-induced thermogenesis. Furthermore, although a large part of the lean subjects counteracted the cold by increasing EE, most obese subjects changed temperature distribution, and therefore, increased insulation.

Cold- and overfeeding-induced changes in the human skeletal muscle proteome.

Adaptive thermogenesis, the increase in energy expenditure in response to diet or cold exposure, shows large interindividual differences. The objective of this study was to investigate the proteins in human muscle tissue that relate to this variation. Therefore, we studied correlations between changes in expressions of proteins and increases in energy expenditure. This, in proteomic research, innovative application of widely used statistical approaches optimized the information yield in this study. The metabolic responses to cold and overfeeding in 9 lean adult male subjects were measured in a respiration chamber in a baseline condition, during three days of cold exposure and during three days of overfeeding. After each respiration chamber measurement a muscle biopsy was taken, from which proteins were isolated and separated using 2D gel-electrophoresis. Ninety-five spots that were significantly changed were analyzed using MALDI-TOF/TOF mass spectrometry. Of these proteins, 52 have been identified. Remarkably, many of the identified proteins that changed in expression significantly after overfeeding and after cold exposure are part of the glycolytic pathway. However, the identified proteins are not considered to be rate limiting. After overfeeding, the abundance of these glycolytic proteins increased. Upon cold exposure, differences in glycolytic protein concentrations related significantly to the interindividual differences in cold-induced adaptive thermogenesis. Moreover, increased abundance of ATP synthase subunits suggested an increased ATP-production. This shows that upon cold exposure ATP utilizing processes might be involved that were not apparent in the baseline situation. The results of this study stress the importance of changes in glycolytic proteins in both cold- and overfeeding-induced adaptive thermogenesis.

Human skeletal muscle mitochondrial uncoupling is associated with cold induced adaptive thermogenesis.

BACKGROUND: Mild cold exposure and overfeeding are known to elevate energy expenditure in mammals, including humans. This process is called adaptive thermogenesis. In small animals, adaptive thermogenesis is mainly caused by mitochondrial uncoupling in brown adipose tissue and regulated via the sympathetic nervous system. In humans, skeletal muscle is a candidate tissue, known to account for a large part of the epinephrine-induced increase in energy expenditure. However, mitochondrial uncoupling in skeletal muscle has not extensively been studied in relation to adaptive thermogenesis in humans. Therefore we hypothesized that cold-induced adaptive thermogenesis in humans is accompanied by an increase in mitochondrial uncoupling in skeletal muscle. METHODOLOGY/PRINCIPAL FINDINGS: The metabolic response to mild cold exposure in 11 lean, male subjects was measured in a respiration chamber at baseline and mild cold exposure. Skeletal muscle mitochondrial uncoupling (state 4) was measured in muscle biopsies taken at the end of the respiration chamber stays. Mild cold exposure caused a significant increase in 24h energy expenditure of 2.8% (0.32 MJ/day, range of -0.21 to 1.66 MJ/day, p<0.05). The individual increases in energy expenditure correlated to state 4 respiration (p<0.02, R(2) = 0.50). CONCLUSIONS/SIGNIFICANCE: This study for the first time shows that in humans, skeletal muscle has the intrinsic capacity for cold induced adaptive thermogenesis via mitochondrial uncoupling under physiological conditions. This opens possibilities for mitochondrial uncoupling as an alternative therapeutic target in the treatment of obesity.

Individual thermogenic responses to mild cold and overfeeding are closely related.

CONTEXT: Adaptive thermogenesis is defined as the increase in energy expenditure in response to overfeeding or cold. Large interindividual differences in adaptive thermogenesis have been described. OBJECTIVE: Because there are indications for a common underlying mechanism, we studied in humans whether the increase in thermogenesis during short-term overfeeding (3 d) is related to mild cold-induced thermogenesis. INTERVENTIONS: Thirteen lean male subjects have been exposed to three experimental conditions in respiration chambers: baseline (36 h in energy balance at thermoneutrality, 22 C), overfeeding (84 h at 160% of energy balance, 22 C), and mild cold (84 h in energy balance, 16 C). MAIN OUTCOME MEASURES: During the interventions, total daily energy expenditure (TDEE), physical activity, skin temperatures, and core temperature were measured. After each condition, fasting plasma norepinephrine concentration was measured. RESULTS: Overfeeding caused significant increases in TDEE (0.77 MJ/d, P < 0.001). During cold exposure TDEE increased significantly (0.59 MJ/d, P < 0.005), whereas physical activity decreased. The changes in TDEE during both overfeeding and mild cold exposure showed considerable interindividual variation (respectively, -0.11 to 1.61 MJ/d and -0.19 to 1.58 MJ/d). The individual changes in energy expenditure during mild cold exposure and overfeeding were highly correlated (P < 0.005). Fasting norepinephrine plasma concentrations correlated significantly to energy expenditure in both situations (P < 0.05). CONCLUSIONS: These results suggest that both overfeeding-induced and mild cold-induced adaptive thermogenesis share common regulating mechanisms. This indicates that cold exposure could be used as a biomarker for the individual thermogenic response to excess energy intake.