Exogenous ketone esters as a potential therapeutic for treatment of sarcopenic obesity.

Identifying effective treatment(s) for sarcopenia and sarcopenic obesity is of paramount importance as the global population advances in age and obesity continues to be a worldwide concern. Evidence has shown that a ketogenic diet can be beneficial for the preservation of muscle quality and function in older adults, but long-term adherence is low due in part to the high-fat (≥80%), very low carbohydrate (<5%) composition of the diet. When provided in adequate amounts, exogenous ketone esters (KEs) can increase circulating ketones to concentrations that exceed those observed during prolonged fasting or starvation without significant alterations in the diet. Ketone esters first emerged in the mid-1990s and their use in preclinical and clinical research has escalated within the past 10-15 years. We present findings from a narrative review of the existing literature for a proposed hypothesis on the effects of exogenous ketones as a therapeutic for preservation of skeletal muscle and function within the context of sarcopenic obesity and future directions for exploration. Much of the reviewed literature herein examines the mechanisms of the ketone diester (R,S-1,3-butanediol diacetoacetate) on skeletal muscle mass, muscle protein synthesis, and epigenetic regulation in murine models. Additional studies are needed to further examine the key regulatory factors producing these effects in skeletal muscle, examine convergent and divergent effects among different ketone ester formulations, and establish optimal frequency and dosing regimens to translate these findings into humans.

Sarcopenic Obesity in Liver Cirrhosis: Possible Mechanism and Clinical Impact.

The picture of chronic liver diseases (CLDs) has changed considerably in recent years. One of them is the increase of non-alcoholic fatty liver disease. More and more CLD patients, even those with liver cirrhosis (LC), tend to be presenting with obesity these days. The annual rate of muscle loss increases with worsening liver reserve, and thus LC patients are more likely to complicate with sarcopenia. LC is also characterized by protein-energy malnutrition (PEM). Since the PEM in LC can be invariable, the patients probably present with sarcopenic obesity (Sa-O), which involves both sarcopenia and obesity. Currently, there is no mention of Sa-O in the guidelines; however, the rapidly increasing prevalence and poorer clinical consequences of Sa-O are recognized as an important public health problem, and the diagnostic value of Sa-O is expected to increase in the future. Sa-O involves a complex interplay of physiological mechanisms, including increased inflammatory cytokines, oxidative stress, insulin resistance, hormonal disorders, and decline of physical activity. The pathogenesis of Sa-O in LC is diverse, with a lot of perturbations in the muscle-liver-adipose tissue axis. Here, we overview the current knowledge of Sa-O, especially focusing on LC.

Combined administration of lauric acid and glucose improved cancer-derived cardiac atrophy in a mouse cachexia model.

Cancer-derived myocardial damage is an important cause of death in cancer patients. However, the development of dietary interventions for treating such damage has not been advanced. Here, we investigated the effect of dietary intervention with lauric acid (LAA) and glucose, which was effective against skeletal muscle sarcopenia in a mouse cachexia model, on myocardial damage. Treatment of H9c2 rat cardiomyoblasts with lauric acid promoted mitochondrial respiration and increased ATP production by Seahorse flux analysis, but did not increase oxidative stress. Glycolysis was also promoted by LAA. In contrast, mitochondrial respiration and ATP production were suppressed, and oxidative stress was increased in an in vitro cachexia model in which cardiomyoblasts were treated with mouse cachexia ascites. Ascites-treated H9c2 cells with concurrent treatment with LAA and high glucose showed that mitochondrial respiration and glycolysis were promoted more than that of the control, and ATP was restored to the level of the control. Oxidative stress was also reduced by the combined treatment. In the mouse cachexia model, myocardiac atrophy and decreased levels of a marker of muscle maturity, SDS-soluble MYL1, were observed. When LAA in CE-2 diet was orally administered alone, no significant rescue was observed in the cancer-derived myocardial disorder. In contrast, combined oral administration of LAA and glucose recovered myocardial atrophy and MYL1 to levels observed in the control without increase in the cancer weight. Therefore, it is suggested that dietary intervention using a combination of LAA and glucose for cancer cachexia might improve cancer-derived myocardial damage.

Simultaneous Pharmacokinetic Analysis of Nitrate and its Reduced Metabolite, Nitrite, Following Ingestion of Inorganic Nitrate in a Mixed Patient Population.

PURPOSE: The pharmacokinetic properties of plasma NO3- and its reduced metabolite, NO2-, have been separately described, but there has been no reported attempt to simultaneously model their pharmacokinetics following NO3- ingestion. This report describes development of such a model from retrospective analyses of concentrations largely obtained from primary endpoint efficacy trials. METHODS: Linear and non-linear mixed effects analyses were used to statistically define concentration dependency on time, dose, as well as patient and study variables, and to integrate NO3- and NO2- concentrations from studies conducted at different times, locations, patient groups, and several studies in which sample range was limited to a few hours. Published pharmacokinetic studies for both substances were used to supplement model development. RESULTS: A population pharmacokinetic model relating NO3- and NO2- concentrations was developed. The model incorporated endogenous levels of the two entities, and determined these were not influenced by exogenous NO3- delivery. Covariate analysis revealed intersubject variability in NO3- exposure was partially described by body weight differences influencing volume of distribution. The model was applied to visualize exposure versus response (muscle contraction performance) in individual patients. CONCLUSIONS: Extension of the present first-generation model, to ultimately optimize NO3- dose versus pharmacological effects, is warranted.

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.

The Role of Nutrition in Attenuating Age-Related Skeletal Muscle Atrophy.

The elderly population is increasing rapidly worldwide, and we are faced with the significant challenge for maintaining or improving physical activity, independence, and quality of life. Sarcopenia, the age-related decline of skeletal muscle mass, is characterized by loss of muscle quantity and quality resulting to a gradual slowing of movement, a decrease in strength and power, elevated risk of fall-related injury, and often frailty. Supplemental, hormonal, and pharmacological approaches have been attempted to attenuate sarcopenia but these have not achieved outstanding results. In this review, we summarize the current knowledge of nutrition-based therapies for counteracting sarcopenia.

Beta-hydroxy-beta-methylbutyrate and sarcopenia: from biological plausibility to clinical evidence.

PURPOSE OF REVIEW: Given the role of leucine as a major regulator of muscle protein turnover, the consumption of protein sources enhanced with this essential amino acid, or its metabolite beta-hydroxy-beta-methylbutyrate (HMB), is assumed to give the greatest benefit in terms of maintenance of muscle mass and function during aging. The aim of this review is to discuss recent literature about HMB metabolism, its pharmacokinetics compared with the metabolite leucine, effectiveness of HMB to improve outcomes in older adults, and novel approaches for HMB use. RECENT FINDINGS: Overall, this review article highlights the potential relationship between HMB dietary supplementation and parameters related to maintenance of muscle mass and strength in older people. However, there are limitations in the studies conducted so far, including low number of participants per study group, heterogeneity of study designs, methodologies, and outcomes. The combination of HMB with other amino acids or supplements limits the ability to determine the direct impact of HMB alone. SUMMARY: It is proposed that HMB may be utilized to protect or rebuild muscle mass in older people with reduced lean body mass.

Nutrition and sarcopenia: A review of the evidence of nutritional influences.

Prevention of age related decline in muscle mass and strength is a key strategy to keeping physical capacity in older age and allowing independent living. To emerge preventive strategies, a better understanding is required of life style factors that impacts on sarcopenia. However, since muscle mass and strength in later life depend on both the rate of muscle loss and the peak achieved in early life, attempts to prevent sarcopenia also require considering diet through the life course and the potential benefits of early interventions. Optimizing diet and nutrition status during the life may be an important strategy to preventing sarcopenia and enhancing physical ability in older age.

Sarcopenia and swallowing disorders in older people.

Aging is accompanied by several changes which may affect swallowing function. The beginning of these changes, termed presbyphagia, still captures a preserved swallowing function, although burdened by the consequences of the physiological aging process. Several stressors (including diseases and medications) can easily trigger the disruption of this (increasingly weak) equilibrium and lead to overt dysphagia. It is noteworthy that the swallowing dysfunction may be aggravated by the sarcopenic process, characterizing the so-called "sarcopenic dysphagia", potentially responsible for several health-related negative outcomes. The assessment and management of sarcopenic dysphagia largely rely on the evaluation and integrated treatment of both constituting conditions (i.e., sarcopenia and dysphagia). The management of dysphagia requires a multidimensional approach and can be designed as either compensatory (aimed at producing immediate benefit for the patient through postural adjustments, swallowing maneuvers, and diet modifications) or rehabilitative. Interestingly, some evidence suggests that resistance training traditionally applied to tackle the lower extremity in sarcopenia may be simultaneously beneficial for sarcopenic dysphagia. If these preliminary results (discussed in the present review article) will be confirmed, the systemic beneficial effects of physical exercise will be indirectly demonstrated. This will also support the need of promoting healthy lifestyle in all sarcopenic individuals (thus potentially at risk of dysphagia).

Dietary strategies for mitigating osteosarcopenia in older adults: a narrative review.

The synchronic loss of bone mineral density and decrease in muscle mass, strength, and function defines the scenario of osteosarcopenia, which is associated with an increased risk of falls and fractures in older adults. An important role in preventing muscle and bone loss is played by nutritional factors, in particular the intake of proteins, calcium, magnesium and vitamin D. This review summarizes the available literature concerning the influence of protein intake and supplementation (vitamin D, Ca, Mg, branched-chain amino acids) on the decline of musculoskeletal integrity in healthy older adults. Furthermore, in this paper, we attempted to give some suggestions to build up adequate nutritional and dietary strategies against the age-related loss of muscle and bone mass.

Bioelectric Impedance Vector Analysis (BIVA) in Breast Cancer Patients: A Tool for Research and Clinical Practice.

Background and objectives: Body composition assessment can provide information associated with breast cancer patients' (BCP) prognosis, that can lead interventions to improve survival outcomes. The aim of this study was to evaluate the effect of an individualized nutrition intervention program on breast cancer patients using bioelectrical impedance vector analysis (BIVA). Materials and Methods: This is a pretest-posttest study in recently diagnosed nonmetastatic BCP undergoing antineoplastic treatment, free of co-morbidities and dietary supplementation. Body composition was assessed at baseline and 6 months after an individualized nutrition intervention program, by dual-energy X-ray absorptiometry and BIVA. According to BIVA, each participant was located in the bivariate tolerance ellipses for Mexican population (50%, 75%, and 95%). In clinical practice, the 50% and 75% ellipses are considered within normality ranges. Results: Nine nonmetastatic BCP completed the intervention and were included in the analysis. After the intervention, they decreased by 5.8 kg of body weight (IQR, 3-6; p < 0.05), 3.8 kg of fat mass (IQR, 0.1-4.2; p < 0.05), and 1.4 kg of fat-free mass (IQR, -0.1 to 4; p < 0.05) while appendicular skeletal muscle mass remained unchanged (-0.2 kg, IQR, -0.8 to 2.3; p = 0.4). Using BIVA at baseline, five participants were among the 50% and 75% ellipses, mainly located in the area corresponding to edema and low lean tissue, two in the cachexia quadrant and two in the athletic quadrant (≥95% ellipse). After 6 months of intervention, six out of nine participants were in the athletic quadrant and eight of nine BCP were above the 5° phase angle cut-off point. One patient initially presented cachexia (≥95% ellipse); at postintervention her vector changed to the 50% ellipse. Conclusions: An individualized nutrition intervention program designed for nonmetastatic BCP was effective to improve the nutritional status of BCP as assessed by BIVA, therefore BIVA can be a useful tool to monitor changes in nonmetastatic BCP body composition in research and clinical practice.

Recent advances in pharmacological, hormonal, and nutritional intervention for sarcopenia.

Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and often frailty. This review focuses on the recent advances of pharmacological, hormonal, and nutritional approaches for attenuating sarcopenia. The article is composed of the data reported in many basic and some clinical studies for mammalian muscles. Resistance training combined with amino acid-containing supplements is the gold standard to prevent sarcopenia. Supplementation with proteins (amino acids) only did not influence sarcopenic symptoms. A myostatin-inhibiting strategy is the most important candidate to prevent sarcopenia in humans. Milder caloric restriction (CR, 15-25%) would also be effective for age-related muscle atrophy in humans. Supplementation with ursolic acid and ghrelin is an intriguing candidate to combat sarcopenia, although further systematic and fundamental research is needed on this treatment.

Nutritional interventions in sarcopenia: where do we stand?

PURPOSE OF REVIEW: To document recent evidence regarding the role of nutrition as an intervention for sarcopenia. RECENT FINDINGS: A review of seven randomized controlled trials (RCTs) on beta-hydroxy-beta-methylbutyrate (HMB) alone on muscle loss in 147 adults showed greater muscle mass gain in the intervention group, but no benefit in muscle strength and physical performance measures. Three other review articles examined nutrition and exercise as combined intervention, and suggest enhancement of benefits of exercise by nutrition supplements (energy, protein, vitamin D). Four trials reported on nutrition alone as intervention, mainly consisting of whey protein, leucine, HMB and vitamin D, with variable results on muscle mass and function. Four trials examined the combined effects of nutrition combined with exercise, showing improvements in muscle mass and function. SUMMARY: To date, evidence suggests that nutrition intervention alone does have benefit, and certainly enhances the impact of exercise. Nutrients include high-quality protein, leucine, HMB and vitamin D. Long-lasting impact may depend on baseline nutritional status, baseline severity of sarcopenia, and long-lasting adherence to the intervention regime. Future large-scale multicentered RCTs using standardized protocols may provide evidence for formulating guidelines on nutritional intervention for sarcopenia. There is a paucity of data for nursing home populations.

Fast digestive proteins and sarcopenia of aging.

PURPOSE OF REVIEW: The speed of dietary protein digestion influences postprandial amino acid availability which is crucial for improving altered anabolic response of skeletal muscle one feature of sarcopenia during aging. RECENT FINDINGS: By analogy with carbohydrate and in reference to their absorption rate, dietary proteins can be classified as 'fast' or 'slow' proteins depending on matrix food structure and technological processes, which can influence amino acids availability and their subsequent metabolic actions. 'Fast' digestive proteins have been shown to stimulate muscle protein synthesis and to improve muscle function in several recent studies involving older patients. These new aspects may be applied for improving health through preservation or restoration of muscle protein mass and function in clinical situations (obesity, rheumatoid arthritis and cancer cachexia). SUMMARY: Using fast digestive proteins is of major interest to overcome 'anabolic resistance' of aging for limiting sarcopenia. Fast proteins' action on muscle anabolism may be stimulated by other nutrients like vitamin D or omega 3 fatty acids or by combination with exercise. The beneficial impact of the 'fast' protein concept beyond the amount of dietary protein on muscle preservation is a promising therapeutic perspective to improve mobility and quality of life of older patients affected with chronic disease.

Systematic review and meta-analysis of the effect of protein and amino acid supplements in older adults with acute or chronic conditions.

The loss of lean body mass, muscle strength and physical function causes significant problems in older adults. Protein and amino acid supplements can preserve muscle strength but the effect on function is variable. We conducted a systematic literature review and meta-analysis to investigate the effect of protein and amino acid supplementation on fat-free mass, muscle strength and physical function in malnourished, frail, sarcopenic, dependent or elderly with acute or chronic conditions, with or without rehabilitation exercise. Databases searched included Medline, BIOSIS, CINAHL, Cochrane Library, EBM Reviews, Embase, Pre-Medline, ProQuest, PubMed and Scopus. Retrieved articles were assessed by two reviewers using the Cochrane Risk of Bias (ROB) Tool. In all, thirty nine randomised controlled trails (n 4274) were included. The studies used a range of protein or essential amino acid (EAA) supplements in a variety of settings, including hospital, community and long-term care. Only seven studies had low ROB and no effect of supplementation was found on any outcomes. Analysis of all thirty-nine studies suggest protein and EAA supplements may improve fat-free mass, muscle strength and physical function (standardised mean difference 0·21-0·27, all P<0·005), but significant heterogeneity and ROB was evident. Predetermined subgroup analysis found undernourished elderly benefitted most; EAA were the most effective supplements and small beneficial effects were seen without rehabilitation exercise. The high heterogeneity and few studies with low ROB limits the conclusions and more high quality studies are needed to determine the best nutritional strategies for the maintenance of strength and function with increasing age.

A randomised controlled intervention study investigating the efficacy of carotenoid-rich fruits and vegetables and extra-virgin olive oil on attenuating sarcopenic symptomology in overweight and obese older adults during energy intake restriction: protocol paper.

BACKGROUND: Weight loss interventions have not been advocated for overweight/obese older adults due to potential loss of skeletal muscle and strength impacting on physical function with potential loss of independence. Carotenoids and polyphenols are inversely associated with sarcopenic symptomology. This paper reports the protocol of a study evaluating the efficacy of a high-protein, energy restricted diet rich in carotenoids and polyphenols on body composition, muscle strength, physical performance and quality of life in overweight and obese older adults. METHODS: This randomised controlled clinical trial will recruit community-dwelling, healthy overweight and obese older adults (≥60 years) for a 12-week weight loss intervention. Seventy-three participants will be recruited and randomized to an energy restricted (~30% restriction), isocaloric diet (30% protein; 30% carbohydrate; 40% fat) enriched with either: a) 375 g/d of high carotenoid vegetables, 300 g/d high carotenoid fruit, and 40-60 ml extra-virgin olive oil (EVOO); or b) 375 g/d of lower carotenoid vegetables, 300 g/d lower carotenoid fruit, and 40-60 ml Polyunsaturated fatty acid (PUFA) based oil. All participants will receive individual dietary counselling each fortnight for the duration of the study and will be asked to maintain their habitual level of physical activity throughout the study. The primary outcome will be appendicular skeletal muscle (ASM) assessed by dual energy X-ray absorptiometry (DXA). Secondary outcomes will include body weight, fat-free mass (FFM), fat mass (FM), muscle strength (Isometric hand-grip strength), physical performance (Short Physical Performance Battery), physical activity (International Physical Activity Questionnaire) and health related quality of life (SF-36). Outcomes will be measured at baseline and at week 12. DISCUSSION: The results of this study will provide a novel insight relating to the potential influence of high carotenoid and polyphenol intakes on attenuation of ASM during dietary energy-restricted weight loss in overweight and obese older adults. TRIAL REGISTRATION: The trial was registered on the Australia New Zealand Clinical Trials Register ( ACTRN12616001400459 ); Trial registration date: 10th October, 2016.

Nutritional strategies to reduce falls risk in older people.

A literature review found an association between increased falls risk and malnutrition, sarcopenia, vitamin D deficiency and dehydration. Strategies to identify, prevent and treat these conditions can help to reduce falls risk in at-risk groups such as frail, older people. Nurses can reduce falls risk in older people by raising awareness of risk factors and embedding nutritional strategies in local falls reduction strategies.

Dietary protein supplementation in the elderly for limiting muscle mass loss.

Supplementation with whey and other dietary protein, mainly associated with exercise training, has been proposed to be beneficial for the elderly to gain and maintain lean body mass and improve health parameters. The main objective of this review is to examine the evidence provided by the scientific literature indicating benefit from such supplementation and to define the likely best strategy of protein uptake for optimal objectified results in the elderly. Overall, it appears that an intake of approximately 0.4 g protein/kg BW per meal thus representing 1.2-1.6 g protein/kg BW/day may be recommended taking into account potential anabolic resistance. The losses of the skeletal muscle mass contribute to lower the capacity to perform activities in daily living, emphasizing that an optimal protein consumption may represent an important parameter to preserve independence and contribute to health status. However, it is worth noting that the maximal intake of protein with no adverse effect is not known, and that high levels of protein intake is associated with increased transfer of protein to the colon with potential deleterious effects. Thus, it is important to examine in each individual case the benefit that can be expected from supplementation with whey protein, taking into account the usual protein dietary intake.

Sarcopenia in Patients with Chronic Liver Disease: Can It Be Altered by Diet and Exercise?

Sarcopenia, a loss of muscle mass, is being increasingly recognized to have a deleterious effect on outcomes in patients with chronic liver disease. Factors related to diet and the inflammatory nature of chronic liver disease contribute to the occurrence of sarcopenia in these patients. Sarcopenia adversely influences quality of life, performance, morbidity, success of transplantation, and even mortality. Specific deficiencies in macronutrients (protein, polyunsaturated fatty acids) and micronutrients (vitamins C, D, and E, carotenoids, and selenium) have been linked to sarcopenia. Lessons learned from nutritional therapy in geriatric patient populations may provide strategies to manage sarcopenia in patients with liver disease. Combining diet modification and nutrient supplementation with an organized program of exercise may help ameliorate or even reverse the effects of sarcopenia on an already complex disease process.

Evaluation of adherence by elderly nursing home patients to regular consumption of apple compote enriched with protein and soluble fiber.

BACKGROUND: An increase in daily doses of protein and fiber for the elderly is relevant in preventing sarcopenia and preserving intestinal balance. However, such intake of supplements is often compromised by the lack of adherence among the elderly. OBJECTIVES: The main objective was to evaluate the perception of the hedonic qualities of compote enriched with NUTRALYS(®) pea protein, NUTRALYS(®)W hydrolyzed wheat gluten and NUTRIOSE(®) soluble fiber and the changes in that perception due to repeated consumption. The secondary objectives were to evaluate the evolution in the quantity of compote eaten, satisfaction with consumption and any changes in fatigue, digestive comfort and digestive tolerance when eating compote every other day for 3 weeks. METHOD: An observational study was conducted in nursing homes on volunteers aged 70-90 years. The compote was proposed as a lunchtime dessert every two days for a period of three consecutive weeks. All criteria were evaluated at days D0 and/or D1, D7, D15 and D21, except for the amount of compote eaten, evaluated after each meal at which it was served. RESULTS: When first tasted, the compote was judged 'rather pleasant' to 'very pleasant' by 91.6 % and this rating held up at 79.2 % (p = 0.1797) after 1 week, 83.3 % (p = 0.3173) after 2 weeks and 79.2 % (p = 0.2568) after 3 weeks. Average consumption of compote was stable and varied between a maximum of 79.5 % of the total quantity at inclusion to a minimum of 61.5 % recorded on D17. The other parameters did not change significantly. CONCLUSION: Pea protein, hydrolyzed wheat gluten and soluble fiber seem to provide an appropriate form of protein and fiber supplementation in the diets of elderly people in nursing homes.