Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence

The provision of sufficient amounts of dietary proteins is central to muscle health as it ensures the supply of essential amino acids and stimulates protein synthesis. Older persons, in particular, are at high risk of insufficient protein ingestion. Furthermore, the current recommended dietary allowance for protein (0.8 g/kg/day) might be inadequate for maintaining muscle health in older adults, probably as a consequence of “anabolic resistance” in aged muscle. Older individuals therefore need to ingest a greater quantity of protein to maintain muscle function. The quality of protein ingested is also essential to promoting muscle health. Given the role of leucine as the master dietary regulator of muscle protein turnover, the ingestion of protein sources enriched with this essential amino acid, or its metabolite β-hydroxy β-methylbutyrate, is thought to offer the greatest benefit in terms of preservation of muscle mass and function in old age.

Related papers:

title: Protein and energy supplementation in elderly people at risk from malnutrition.
abstract: Evidence for the effectiveness of nutritional supplements containing protein and energy, often prescribed for older people, is limited. Malnutrition is more common in this age group and deterioration of nutritional status can occur during illness. It is important to establish whether supplementing the diet is an effective way of improving outcomes for older people at risk from malnutrition.



This review examined trials for improvement in nutritional status and clinical outcomes when extra protein and energy were provided, usually as commercial 'sip-feeds'.


SEARCH STRATEGY
We searched The Cochrane Library, MEDLINE, EMBASE, Healthstar, CINAHL, BIOSIS, CAB abstracts. We also hand searched nutrition journals and reference lists and contacted 'sip-feed' manufacturers.



Randomised and quasi-randomised controlled trials of oral protein and energy supplementation in older people, with the exception of groups recovering from cancer treatment or in critical care.



Two reviewers independently assessed trials prior to inclusion and independently extracted data and assessed trial quality. Authors of trials were contacted for further information as necessary.



Sixty-two trials with 10,187 randomised participants have been included in the review. Maximum duration of intervention was 18 months. Most included trials had poor study quality. The pooled weighted mean difference (WMD) for percentage weight change showed a benefit of supplementation of 2.2% (95% confidence interval (CI) 1.8 to 2.5) from 42 trials. There was no significant reduction in mortality in the supplemented compared with control groups (relative risk (RR) 0.92, CI 0.81 to 1.04) from 42 trials. Mortality results were statistically significant when limited to trials in which participants (N = 2461) were defined as undernourished (RR 0.79, 95% CI 0.64 to 0.97).The risk of complications was reduced in 24 trials (RR 0.86, 95% CI 0.75 to 0.99). Few trials were able to suggest any functional benefit from supplementation. The WMD for length of stay from 12 trials also showed no statistically significant effect (-0.8 days, 95% CI -2.8 to 1.3). Adverse effects included nausea or diarrhoea.



Supplementation produces a small but consistent weight gain in older people. Mortality may be reduced in older people who are undernourished. There may also be a beneficial effect on complications which needs to be confirmed. However, this updated review found no evidence of improvement in functional benefit or reduction in length of hospital stay with supplements. Additional data from large-scale multi-centre trials are still required.

title: Perioperative oral nutritional supplements in normally or mildly undernourished geriatric patients submitted to surgery for hip fracture: a randomized clinical trial.
abstract: Oral nutritional supplements have been recommended after orthopedic surgery in geriatric patients. This has been shown to be effective even in normally nourished or mildly undernourished geriatric patients. Whether perioperative administration of these products is also effective and suitable is not known.



Randomized, controlled, open, paralleled two-arms clinical trial, comparing energy-protein supplements (40 g of protein and 400 kcal per day), with no intervention in normally nourished or mildly undernourished patients. Outcomes were serum proteins, body mass index, postoperative complications among others.



60 Elderly patients were included. Patients in the intervention group (n = 30) ingested 52.2 ± 12.1% of the prescribed supplements per day for 5.8 ± 1.8 days before surgery and until hospital discharge. There was a significant change in serum albumin at follow-up (F = 22.536, P < 0.001), and between the two groups (F = 5.763, P = 0.002), favouring the intervention. The same was observed for serum prealbumin (F = 6.654, P = 0.001 within subjects, F = 2.865, P = 0.045 for interaction). Logistic regression showed that only supplemented proteins per day (OR[95%CI] = 0.925[0.869-0.985]) were associated with less postoperative complications (R(2) = 0.323, χ(2) = 11.541, P = 0.003).



Perioperative supplements in geriatric patients with hip fracture submitted to surgery showed better recovery of plasma proteins. Higher daily protein intakes were associated with less postoperative complications.

title: Effects of protein-rich supplementation and nandrolone on bone tissue after a hip fracture.
abstract: Osteoporosis is a major health problem worldwide. Low weight is a major risk factor for low bone mass and fractures. The aim of this study was to investigate the effects on bone tissue of protein-rich supplementation alone or in combination with nandrolone decanoate in lean elderly women after a hip fracture.



Sixty elderly women with BMI <24 kg/m(2) admitted to hospital due to a femoral neck fracture were randomised to a control group, to receive a protein-rich formula or to receive the same formula with an addition of nandrolone decanoate for 6 months. All patients received additional calcium and vitamin D. The effects after 6 and 12 months were measured by means of bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA), and with biochemical bone markers. Osteocalcin and C-terminal telopeptide of collagen-1 (CTX) were used to estimate bone formation and bone resorption, respectively.



The analyses showed an increase in total body BMD at 6 and 12 months in patients who received protein-rich supplementation. Nandrolone decanoate did not appear to have any additional effect on BMD. Osteocalcin increased in all groups while no significant changes were found for CTX.



The overall results of the study indicated that protein-rich supplementation given to lean elderly female hip fracture patients increased the total body BMD.

title: Nutritional supplementation for hip fracture aftercare in older people.
abstract: Older people with hip fractures are often malnourished at the time of fracture, and subsequently have poor food intake. This is an update of a Cochrane review first published in 2000, and previously updated in 2010.



To review the effects (benefits and harms) of nutritional interventions in older people recovering from hip fracture.



We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, CENTRAL, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Embase, CAB Abstracts, CINAHL, trial registers and reference lists. The search was last run in November 2015.



Randomised and quasi-randomised controlled trials of nutritional interventions for people aged over 65 years with hip fracture where the interventions were started within the first month after hip fracture.



Two review authors independently selected trials, extracted data and assessed risk of bias. Where possible, we pooled data for primary outcomes which were: all cause mortality; morbidity; postoperative complications (e.g. wound infections, pressure sores, deep venous thromboses, respiratory and urinary infections, cardiovascular events); and 'unfavourable outcome' defined as the number of trial participants who died plus the number of survivors with complications. We also pooled data for adverse events such as diarrhoea.



We included 41 trials involving 3881 participants. Outcome data were limited and risk of bias assessment showed that trials were often methodologically flawed, with less than half of trials at low risk of bias for allocation concealment, incomplete outcome data, or selective reporting of outcomes. The available evidence was judged of either low or very low quality indicating that we were uncertain or very uncertain about the estimates.Eighteen trials evaluated oral multinutrient feeds that provided non-protein energy, protein, vitamins and minerals. There was low-quality evidence that oral feeds had little effect on mortality (24/486 versus 31/481; risk ratio (RR) 0.81 favouring supplementation, 95% confidence interval (CI) 0.49 to 1.32; 15 trials). Thirteen trials evaluated the effect of oral multinutrient feeds on complications (e.g. pressure sore, infection, venous thrombosis, pulmonary embolism, confusion). There was low-quality evidence that the number of participants with complications may be reduced with oral multinutrient feeds (123/370 versus 157/367; RR 0.71, 95% CI 0.59 to 0.86; 11 trials). Based on very low-quality evidence from six studies (334 participants), oral supplements may result in lower numbers with 'unfavourable outcome' (death or complications): RR 0.67, 95% CI 0.51 to 0.89. There was very low-quality evidence for six studies (442 participants) that oral supplementation did not result in an increased incidence of vomiting and diarrhoea (RR 0.99, 95% CI 0.47 to 2.05).Only very low-quality evidence was available from the four trials examining nasogastric multinutrient feeding. Pooled data from three heterogeneous trials showed no evidence of an effect of supplementation on mortality (14/142 versus 14/138; RR 0.99, 95% CI 0.50 to 1.97). One trial (18 participants) found no difference in complications. None reported on unfavourable outcome. Nasogastric feeding was poorly tolerated. One study reported no cases of aspiration pneumonia.There is very low-quality evidence from one trial (57 participants, mainly men) of no evidence for an effect of tube feeding followed by oral supplementation on mortality or complications. Tube feeding, however, was poorly tolerated.There is very low-quality evidence from one trial (80 participants) that a combination of intravenous feeding and oral supplements may not affect mortality but could reduce complications. However, this expensive intervention is usually reserved for people with non-functioning gastrointestinal tracts, which is unlikely in this trial.Four trials tested increasing protein intake in an oral feed. These provided low-quality evidence for no clear effect of increased protein intake on mortality (30/181 versus 21/180; RR 1.42, 95% CI 0.85 to 2.37; 4 trials) or number of participants with complications but very low-quality and contradictory evidence of a reduction in unfavourable outcomes (66/113 versus 82/110; RR 0.78, 95% CI 0.65 to 0.95; 2 trials). There was no evidence of an effect on adverse events such as diarrhoea.Trials testing intravenous vitamin B1 and other water soluble vitamins, oral 1-alpha-hydroxycholecalciferol (vitamin D), high dose bolus vitamin D, different oral doses or sources of vitamin D, intravenous or oral iron, ornithine alpha-ketoglutarate versus an isonitrogenous peptide supplement, taurine versus placebo, and a supplement with vitamins, minerals and amino acids, provided low- or very low-quality evidence of no clear effect on mortality or complications, where reported.Based on low-quality evidence, one trial evaluating the use of dietetic assistants to help with feeding indicated that this intervention may reduce mortality (19/145 versus 36/157; RR 0.57, 95% CI 0.34 to 0.95) but not the number of participants with complications (79/130 versus 84/125).



There is low-quality evidence that oral multinutrient supplements started before or soon after surgery may prevent complications within the first 12 months after hip fracture, but that they have no clear effect on mortality. There is very low-quality evidence that oral supplements may reduce 'unfavourable outcome' (death or complications) and that they do not result in an increased incidence of vomiting and diarrhoea. Adequately sized randomised trials with robust methodology are required. In particular, the role of dietetic assistants, and peripheral venous feeding or nasogastric feeding in very malnourished people require further evaluation.

title: Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE Study Group.
abstract: New evidence shows that older adults need more dietary protein than do younger adults to support good health, promote recovery from illness, and maintain functionality. Older people need to make up for age-related changes in protein metabolism, such as high splanchnic extraction and declining anabolic responses to ingested protein. They also need more protein to offset inflammatory and catabolic conditions associated with chronic and acute diseases that occur commonly with aging. With the goal of developing updated, evidence-based recommendations for optimal protein intake by older people, the European Union Geriatric Medicine Society (EUGMS), in cooperation with other scientific organizations, appointed an international study group to review dietary protein needs with aging (PROT-AGE Study Group). To help older people (>65 years) maintain and regain lean body mass and function, the PROT-AGE study group recommends average daily intake at least in the range of 1.0 to 1.2 g protein per kilogram of body weight per day. Both endurance- and resistance-type exercises are recommended at individualized levels that are safe and tolerated, and higher protein intake (ie, ≥ 1.2 g/kg body weight/d) is advised for those who are exercising and otherwise active. Most older adults who have acute or chronic diseases need even more dietary protein (ie, 1.2-1.5 g/kg body weight/d). Older people with severe kidney disease (ie, estimated GFR <30 mL/min/1.73 m(2)), but who are not on dialysis, are an exception to this rule; these individuals may need to limit protein intake. Protein quality, timing of ingestion, and intake of other nutritional supplements may be relevant, but evidence is not yet sufficient to support specific recommendations. Older people are vulnerable to losses in physical function capacity, and such losses predict loss of independence, falls, and even mortality. Thus, future studies aimed at pinpointing optimal protein intake in specific populations of older people need to include measures of physical function.

title: Current nutritional recommendations and novel dietary strategies to manage sarcopenia.
abstract: Sarcopenia, the loss of skeletal muscle mass and function that occurs with aging, is associated with increased risk for several adverse health outcomes, including frailty, disability, falls, loss of independent living, and mortality. At present, no pharmacological treatment exists that is able to definitely halt the progression of sarcopenia. Likewise, no pharmacological remedies are yet available to prevent the onset of age-related muscle wasting. In this scenario, the combination of nutritional interventions and physical exercise appears to be the most effective strategy presently available for the management of sarcopenia. The purposes of this review are to summarize the current knowledge on the role of nutrition as a countermeasure for sarcopenia, illustrate the mechanisms of action of relevant dietary agents on the aging muscle, and introduce novel nutritional strategies that may help preserve muscle mass and function into old age. Issues related to the identification of the optimal timing of nutritional interventions in the context of primary and secondary prevention are also discussed. Finally, the prospect of elaborating personalized dietary and physical exercise recommendations through the implementation of integrated, high-throughput analytic approaches is illustrated.

title: Association of anorexia with sarcopenia in a community-dwelling elderly population: results from the ilSIRENTE study
abstract: ObjectiveThere is increasing evidence that anorexia of aging can cause physical and mental impairment. The aim of the present study was to evaluate the relationship between anorexia and sarcopenia in elderly persons aged 80 years or older.MethodsData are from the baseline evaluation of 354 subjects enrolled in the ilSIRENTE study. The ilSIRENTE study is a prospective cohort study performed in the mountain community living in the Sirente geographic area (L’Aquila, Abruzzo) in Central Italy. We defined anorexia as the presence of loss of appetite and/or lower food intake. According to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, diagnosis of sarcopenia required the documentation of low muscle mass plus the documentation of either low muscle strength or low physical performance. The relationship between anorexia and sarcopenia was estimated by deriving odds ratios from the multiple logistic regression models considering sarcopenia as the dependent variable.ResultsNearly 21 % of the study sample showed symptoms of anorexia. Using the EWGSOP-suggested algorithm, 103 subjects (29.1 %) with sarcopenia were identified. Thirty-four (46.6 %) participants were affected by sarcopenia among subjects with anorexia compared to 69 subjects [24.6 %] without anorexia (p < 0.001). After adjusting for potential confounders including age, gender, functional and cognitive impairment, physical activity, urinary incontinence, comorbidity, congestive heart failure, COPD, depression, anti-cholinergic drugs, and TNF-α plasmatic levels, participants with anorexia had a higher risk of sarcopenia compared with non-anorexic subjects (HR 1.88, 95 % CI 1.01–3.51).ConclusionsAnorexia is common among community-dwelling older subjects in Italy. Our results suggest that among old–old subjects, anorexia is independently associated with sarcopenia.

title: Anorexia of Aging: A Modifiable Risk Factor for Frailty
abstract: Anorexia of aging, defined as a loss of appetite and/or reduced food intake, affects a significant number of elderly people and is far more prevalent among frail individuals. Anorexia recognizes a multifactorial origin characterized by various combinations of medical, environmental and social factors. Given the interconnection between weight loss, sarcopenia and frailty, anorexia is a powerful, independent predictor of poor quality of life, morbidity and mortality in older persons. One of the most important goals in the management of older, frail people is to optimize their nutritional status. To achieve this objective it is important to identify subjects at risk of anorexia and to provide multi-stimulus interventions that ensure an adequate amount of food to limit and/or reverse weight loss and functional decline. Here, we provide a brief overview on the relevance of anorexia in the context of sarcopenia and frailty. Major pathways supposedly involved in the pathogenesis of anorexia are also illustrated. Finally, the importance of treating anorexia to achieve health benefits in frail elders is highlighted.

title: Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and Body Composition (Health ABC) Study.
abstract: Dietary surveys suggest that many older, community-dwelling adults consume insufficient dietary protein, which may contribute to the age-related loss of lean mass (LM).



The objective of the study was to determine the association between dietary protein and changes in total LM and nonbone appendicular LM (aLM) in older, community-dwelling men and women.



Dietary protein intake was assessed by using an interviewer-administered 108-item food-frequency questionnaire in men and women aged 70-79 y who were participating in the Health, Aging, and Body Composition study (n=2066). Changes in LM and aLM over 3 y were measured by using dual-energy X-ray absorptiometry. The association between protein intake and 3-y changes in LM and aLM was examined by using multiple linear regression analysis adjusted for potential confounders.



After adjustment for potential confounders, energy-adjusted protein intake was associated with 3-y changes in LM [beta (SE): 8.76 (3.00), P=0.004] and aLM [beta (SE): 5.31 (1.64), P=0.001]. Participants in the highest quintile of protein intake lost approximately 40% less LM and aLM than did those in the lowest quintile of protein intake (x+/-SE: -0.501+/-0.106 kg compared with -0.883+/-0.104 kg for LM; -0.400+/-0.058 kg compared with -0.661+/-0.057 kg for aLM; P for trend<0.01). The associations were attenuated slightly after adjustment for change in fat mass, but the results remained significant.



Dietary protein may be a modifiable risk factor for sarcopenia in older adults and should be studied further to determine its effects on preserving LM in this population.

title: Nutritional status after short-term dietary supplementation in hospitalized malnourished geriatric patients.
abstract: To examine the evolution of different parameters of the nutritional status after short-term oral protein-energy supplementation in moderately malnourished geriatric patients.



Seventeen hospitalized malnourished elderly patients and 12 healthy adults received dietary supplements for 10 days. A group of six malnourished elderly subjects served as controls. Spontaneous oral intakes, biological and biophysical markers of the nutritional status were measured. Fat-free mass (FFM) was assessed using Dual energy X-ray absorptiometry (DXA), bio-impedance analysis (BIA) and anthropometry.



In elderly subjects, the supplementation significantly increased both dietary intake (energy +32%, protein +65%) and FFM (+1.3 kg, P<0.001) as assessed using DXA. BIA and anthropometric data correlated with DXA measurements in the elderly (BIA: r=0.68--0.80, anthropometry: r=0.80--0.89), but failed to reflect accurately the changes measured in FFM. Supplementation had no notable effect on biological markers in any of the groups. IGF-I and hand-grip strength were not significantly influenced by the supplementation despite trends towards an improvement.



Monitoring short-term changes in nutritional status in malnourished elderly individuals is a problem in routine clinical management. Our data put in the limelight the changes in IGF-I values related to dietary supplementation, and, chiefly, suggest a prime role for the assessment of dietary intake and FFM, as assessed by DXA, as indicators of short-term efficacy of refeeding. Nevertheless larger studies are necessary to confirm the clinical and prognostic significance of the changes.

title: Readmission and mortality in malnourished, older, hospitalized adults treated with a specialized oral nutritional supplement: A randomized clinical trial.
abstract: Hospitalized, malnourished older adults have a high risk of readmission and mortality.



Evaluation of a high-protein oral nutritional supplement (HP-HMB) containing beta-hydroxy-beta-methylbutyrate on postdischarge outcomes of nonelective readmission and mortality in malnourished, hospitalized older adults.



Multicenter, randomized, placebo-controlled, double-blind trial.



Inpatient and posthospital discharge.



Older (≥65 years), malnourished (Subjective Global Assessment [SGA] class B or C) adults hospitalized for congestive heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease.



Standard-of-care plus HP-HMB (n = 328) or a placebo supplement (n = 324), 2 servings/day.



Primary composite endpoint was 90-day postdischarge incidence of death or nonelective readmission. Other endpoints included 30- and 60-day postdischarge incidence of death or readmission, length of stay (LOS), SGA class, body weight, and activities of daily living (ADL).



The primary composite endpoint was similar between HP-HMB (26.8%) and placebo (31.1%). No between-group differences were observed for 90-day readmission rate, but 90-day mortality was significantly lower with HP-HMB relative to placebo (4.8% vs. 9.7%; relative risk 0.49, 95% confidence interval [CI], 0.27 to 0.90; p = 0.018). The number-needed-to-treat to prevent 1 death was 20.3 (95% CI: 10.9, 121.4). Compared with placebo, HP-HMB resulted in improved odds of better nutritional status (SGA class, OR, 2.04, 95% CI: 1.28, 3.25, p = 0.009) at day 90, and an increase in body weight at day 30 (p = 0.035). LOS and ADL were similar between treatments.



Limited generalizability; patients represent a selected hospitalized population.



Although no effects were observed for the primary composite endpoint, compared with placebo HP-HMB decreased mortality and improved indices of nutritional status during the 90-day observation period.

title: Role of dietary protein in the sarcopenia of aging.
abstract: Sarcopenia is a complex, multifactorial process facilitated by a combination of factors including the adoption of a more sedentary lifestyle and a less than optimal diet. Increasing evidence points to a blunted anabolic response after a mixed nutrient meal as a likely explanation for chronic age-related muscle loss. There is currently insufficient longer-term research with defined health outcomes to specify an optimal value for protein ingestion in elderly individuals. However, there is general agreement that moderately increasing daily protein intake beyond 0.8 g x kg(-1) x d(-1) may enhance muscle protein anabolism and provide a means of reducing the progressive loss of muscle mass with age. The beneficial effects of resistance exercise in aging populations are unequivocal. However, research has not identified a synergistic effect of protein supplementation and resistance exercise in aging populations. There is little evidence that links high protein intakes to increased risk for impaired kidney function in healthy individuals. However, renal function decreases with age, and high protein intake is contraindicated in individuals with renal disease. Assessment of renal function is recommended for older individuals before they adopt a higher-protein diet.

title: Regulation of muscle protein by amino acids.
abstract: Amino acid availability is a potent regulator of muscle protein synthesis (MPS). We have performed a series of studies using stable isotope methodology and the arteriovenous balance approach to quantify many aspects of the response of MPS, breakdown, and the balance between synthesis and breakdown to changes in the availability of amino acids. A constant intake of amino acids stimulates MPS in a dose-dependent manner until concentrations are approximately doubled, after which further increases in concentration are ineffective. MPS rises more rapidly after bolus ingestion to a peak rate of MPS higher than during constant intake, but the response is transient. A reduction in amino acid availability below basal levels inhibits MPS. Ingestion of nonessential amino acids is not needed to stimulate MPS. When carbohydrate alone is ingested there is minimal effect on MPS, but there is an interactive effect with amino acid ingestion, meaning the response to amino acids plus glucose is more than the sum of their individual effects. Finally, acute anabolic responses in net MPS correspond quantitatively to differences in 24-h net muscle balances.

title: Alterations of protein turnover underlying disuse atrophy in human skeletal muscle.
abstract: Unloading-induced atrophy is a relatively uncomplicated form of muscle loss, dependent almost solely on the loss of mechanical input, whereas in disease states associated with inflammation (cancer cachexia, AIDS, burns, sepsis, and uremia), there is a procatabolic hormonal and cytokine environment. It is therefore predictable that muscle loss mainly due to disuse alone would be governed by mechanisms somewhat differently from those in inflammatory states. We suggest that in vivo measurements made in human subjects using arterial-venous balance, tracer dilution, and tracer incorporation are dynamic and thus robust by comparison with static measurements of mRNA abundance and protein expression and/or phosphorylation in human muscle. In addition, measurements made with cultured cells or in animal models, all of which have often been used to infer alterations of protein turnover, appear to be different from results obtained in immobilized human muscle in vivo. In vivo measurements of human muscle protein turnover in disuse show that the primary variable that changes facilitating the loss of muscle mass is protein synthesis, which is reduced in both the postabsorptive and postprandial states; muscle proteolysis itself appears not to be elevated. The depressed postprandial protein synthetic response (a phenomenon we term "anabolic resistance") may even be accompanied by a diminished suppression of proteolysis. We therefore propose that most of the loss of muscle mass during disuse atrophy can be accounted for by a depression in the rate of protein synthesis. Thus the normal diurnal fasted-to-fed cycle of protein balance is disrupted and, by default, proteolysis becomes dominant but is not enhanced.

title: Skeletal muscle autophagy and protein breakdown following resistance exercise are similar in younger and older adults.
abstract: The loss of skeletal muscle mass and strength during aging, sarcopenia, increases the risk for falls and dependency. Resistance exercise (RE) training is effective at improving muscle mass and strength in older adults; however, aging is associated with reduced training-induced hypertrophy. Recent research has illustrated an impaired muscle protein synthetic response following an acute bout of RE in older adults but much less is known regarding the effect of acute RE on muscle protein breakdown (MPB). We hypothesize that the ubiquitin proteasome system and the autophagosomal-lysosomal system may regulate the overall rate of MPB during postexercise recovery.



Muscle biopsies of the vastus lateralis were sampled from 16 older (age = 70±2 years) and 16 younger (age = 27±2 years) participants at baseline and at 3, 6, and 24 hours following an acute bout of RE. In conjunction with stable isotopic techniques to measure MPB, we utilized immunoblotting and RT-PCR to examine protein and mRNA expression for key signaling molecules in both the ubiquitin proteasome system and the autophagosomal-lysosomal system.



MuRF1 mRNA expression increased, whereas GABARAP mRNA decreased after RE in both younger and older adults (p < .05). The LC3B-II/LC3B-I protein ratio decreased in both groups after RE (p < .05), but MPB was not different 24 hour post-RE in either group (p > .05).



Aging does not influence skeletal MPB, autophagy, or the ubiquitin proteasome system following an acute bout of RE. Therefore, targeting the muscle protein synthesis response to exercise may hold more promise in the prevention of sarcopenia.

title: Maximizing muscle protein anabolism: the role of protein quality
abstract: protein synthesis (MPS) and muscle protein breakdown are simultaneous ongoing processes. Here, we examine evidence for how protein quality can affect exercise-induced muscle protein anabolism or protein balance (MPS minus muscle protein breakdown). Evidence is highlighted showing differences in the responses of MPS, and muscle protein accretion, with ingestion of milk-based and soy-based proteins in young and elderly persons. Recent findingsProtein consumption, and the accompanying hyperaminoacidemia, stimulates an increase in MPS and a small suppression of muscle protein breakdown. Beyond the feeding-induced rise in MPS, small incremental addition of new muscle protein mass occurs following intense resistance exercise which over time (i.e. resistance training) leads to muscle hypertrophy. Athletes make use of the paradigm of resistance training and eating to maximize the gains in their skeletal muscle mass. Importantly, however, metabolically active skeletal muscle can offset the morbidities associated with the sarcopenia of aging such as type II diabetes, decline in aerobic fitness and the reduction in metabolic rate that can lead to fat mass accumulation. SummaryRecent evidence suggests that consumption of different proteins can affect the amplitude and possibly duration of MPS increases after feeding and this effect interacts and is possibly accentuated with resistance exercise.

title: Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine.
abstract: Numerous reports established that in skeletal muscle the indispensable branched-chain amino acid leucine is unique in its ability to initiate signal transduction pathways that modulate translation initiation. Oral administration of leucine stimulates protein synthesis in association with hyperphosphorylation of the translational repressor, eukaryotic initiation factor (eIF) 4E binding protein 1 (4E-BP1), resulting in enhanced availability of the mRNA cap-binding protein eIF4E, for binding eIF4G and forming the active eIF4F complex. In addition, leucine enhances phosphorylation of the 70-kDa ribosomal protein S6 kinase (S6K1). These results suggest that leucine upregulates protein synthesis in skeletal muscle by enhancing both the activity and synthesis of proteins involved in mRNA translation. The stimulatory effects of leucine on translation initiation are mediated in part through the protein kinase mammalian target of rapamycin (mTOR), where both insulin signaling and leucine signaling converge to promote a maximal response.

title: The Skeletal Muscle Anabolic Response to Plant- versus Animal-Based Protein Consumption.
abstract: Clinical and consumer market interest is increasingly directed toward the use of plant-based proteins as dietary components aimed at preserving or increasing skeletal muscle mass. However, recent evidence suggests that the ingestion of the plant-based proteins in soy and wheat results in a lower muscle protein synthetic response when compared with several animal-based proteins. The possible lower anabolic properties of plant-based protein sources may be attributed to the lower digestibility of plant-based sources, in addition to greater splanchnic extraction and subsequent urea synthesis of plant protein-derived amino acids compared with animal-based proteins. The latter may be related to the relative lack of specific essential amino acids in plant- as opposed to animal-based proteins. Furthermore, most plant proteins have a relatively low leucine content, which may further reduce their anabolic properties when compared with animal proteins. However, few studies have actually assessed the postprandial muscle protein synthetic response to the ingestion of plant proteins, with soy and wheat protein being the primary sources studied. Despite the proposed lower anabolic properties of plant vs. animal proteins, various strategies may be applied to augment the anabolic properties of plant proteins. These may include the following: 1) fortification of plant-based protein sources with the amino acids methionine, lysine, and/or leucine; 2) selective breeding of plant sources to improve amino acid profiles; 3) consumption of greater amounts of plant-based protein sources; or 4) ingesting multiple protein sources to provide a more balanced amino acid profile. However, the efficacy of such dietary strategies on postprandial muscle protein synthesis remains to be studied. Future research comparing the anabolic properties of a variety of plant-based proteins should define the preferred protein sources to be used in nutritional interventions to support skeletal muscle mass gain or maintenance in both healthy and clinical populations.

title: Myofibrillar protein synthesis following ingestion of soy protein isolate at rest and after resistance exercise in elderly men
abstract: BackgroundIncreased amino acid availability stimulates muscle protein synthesis, however, aged muscle appears less responsive to the anabolic effects of amino acids when compared to the young. We aimed to compare changes in myofibrillar protein synthesis (MPS) in elderly men at rest and after resistance exercise following ingestion of different doses of soy protein and compare the responses to those we previously observed with ingestion of whey protein isolate.MethodsThirty elderly men (age 71 ± 5 y) completed a bout of unilateral knee-extensor resistance exercise prior to ingesting no protein (0 g), or either 20 g or 40 g of soy protein isolate (0, S20, and S40 respectively). We compared these responses to previous responses from similar aged men who had ingested 20 g and 40 g of whey protein isolate (W20 and W40). A primed constant infusion of L-[1-13 C]leucine and L-[ring-13 C6]phenylalanine and skeletal muscle biopsies were used to measure whole-body leucine oxidation and MPS over 4 h post-protein consumption in both exercised and non-exercised legs.ResultsWhole-body leucine oxidation increased with protein ingestion and was significantly greater for S20 vs. W20 (P = 0.003). Rates of MPS for S20 were less than W20 (P = 0.02) and not different from 0 g (P = 0.41) in both exercised and non-exercised leg muscles. For S40, MPS was also reduced compared with W40 under both rested and post-exercise conditions (both P < 0.005); however S40 increased MPS greater than 0 g under post-exercise conditions (P = 0.04).ConclusionsThe relationship between protein intake and MPS is both dose and protein source-dependent, with isolated soy showing a reduced ability, as compared to isolated whey protein, to stimulate MPS under both rested and post-exercise conditions. These differences may relate to the lower postprandial leucinemia and greater rates of amino acid oxidation following ingestion of soy versus whey protein.

title: Nutrient-rich meat proteins in offsetting age-related muscle loss.
abstract: From a health perspective, an underappreciated consequence of the normal aging process is the impacts that the gradual loss of skeletal muscle mass, termed sarcopenia, has on health beyond an effect on locomotion. Sarcopenia, refers to the loss of muscle mass, and associated muscle weakness, which occurs in aging and is thought to proceed at a rate of approximately 1% loss per year. However, periods of inactivity due to illness or recovery from orthopedic procedures such as hip or knee replacement are times of accelerated sarcopenic muscle loss from which it may be more difficult for older persons to recover. Some of the consequences of age-related sarcopenia are easy to appreciate such as weakness and, eventually, reduced mobility; however, other lesser recognized consequences include, due to the metabolic role the skeletal muscle plays, an increased risk for poor glucose control and a predisposition toward weight gain. What we currently know is that two stimuli can counter this age related muscle loss and these are physical activity, specifically resistance exercise (weightlifting), and nutrition. The focus of this paper is on the types of dietary protein that people might reasonably consume to offset sarcopenic muscle loss.

title: Fast-digestive protein supplement for ten days overcomes muscle anabolic resistance in healthy elderly men.
abstract: Adequate protein intake is crucial to maintain muscle protein content in elderly subjects, but quality of dietary proteins should be considered. The aim was to determine whether soluble milk protein offers an original strategy to increase muscle anabolism in elderly subjects via a synergistic effect of fast-digesting proteins together with a unique essential AA content.



We investigated the effect of a 10-day adequate-protein (AP) or high-protein (HP) diet together with the protein source as caseins (CAS) or soluble milk proteins (PRO) on specific muscle protein fractional synthesis rates (FSRs) in healthy elderly men (71.8 ± 2.4 yr, n = 31). The isotopic study consisted of two periods of 4 h each: a post-absorptive and a postprandial period. The fed state was defined by consumption of either 15 g or 30 g of PRO or CAS, given fractionally every 20 min for 4 h. Soluble milk proteins are produced using a membrane process directly from pasteurized milk.



Specific muscle protein FSRs were measured during both postabsorptive and postprandial period using a continuous infusion of l-[1-(13)C]leucine.



FSR of sarcoplasmic muscle proteins and actin did not increase significantly in the postprandial state compared to postabsorptive state, whereas myosin FSR rate was increased by feeding whatever the protein source in HP groups (0.024 ± 0.005 vs 0.053 ± 0.011% h(-1), P < 0.05 and 0.026 ± 0.004 vs 0.050 ± 0.005% h(-1), P < 0.004 for PRO HP and CAS HP) but only with the PRO meal in the AP groups (0.031 ± 0.003 vs 0.062 ± 0.009% h(-1), P < 0.03 for PRO AP). Mitochondrial muscle protein FSR was also increased by feeding, irrespective of the protein quantity, but only in PRO meal groups (P < 0.02).



Fast-digesting soluble milk proteins improved postprandial muscle protein synthesis, especially mitochondrial muscle proteins and myosin fractional synthesis rates, in elderly subjects.

title: Anabolic Resistance of Muscle Protein Synthesis with Aging
abstract: Aging has been associated with a reduced muscle protein synthetic response to protein intake, termed “anabolic resistance.” Physical activity performed before protein intake increases the use of protein-derived amino acids for postprandial muscle protein accretion in senescent muscle. Thus, the level of habitual physical activity may be fundamental to maintain the anabolic responsiveness to protein intake with aging.

title: Disuse impairs the muscle protein synthetic response to protein ingestion in healthy men.
abstract: Disuse leads to rapid skeletal muscle atrophy, which brings about numerous negative health consequences. Muscle disuse atrophy is, at least in part, attributed to a decline in basal (postabsorptive) muscle protein synthesis rates. However, it remains to be determined whether muscle disuse also impairs the muscle protein synthetic response to dietary protein ingestion.



We assessed muscle protein synthesis rates after protein ingestion before and after a period of disuse in humans.



Twelve healthy young (24 ± 1 year) men underwent a 14-day period of one-legged knee immobilization by way of a full leg cast. Before and after the immobilization period, quadriceps cross-sectional area, muscle strength, skeletal muscle protein synthesis rates, and associated im (intramuscular) molecular signaling were assessed. Continuous infusions of l-[ring-²H₅]phenylalanine were applied to assess mixed-muscle protein fractional synthetic rates after the ingestion of 20 g dietary protein.



Immobilization led to an 8.4% ± 2.8% (P < .001) and 22.9% ± 2.6% (P < .001) decrease in quadriceps muscle cross-sectional area and strength, respectively. Immobilization resulted in a 31% ± 12% reduction in postprandial muscle protein synthesis rates (from 0.046% ± 0.004% to 0.032% ± 0.006% per hour; P < .05). These findings were observed without any discernible changes in the skeletal muscle phosphorylation status of mammalian target of rapamycin or p70 ribosomal protein S6 kinase.



A short period of muscle disuse impairs the muscle protein synthetic response to dietary protein intake in vivo in healthy young men. Thus, anabolic resistance to protein ingestion contributes significantly to the loss of muscle mass that is observed during disuse.

title: Immobilization induces anabolic resistance in human myofibrillar protein synthesis with low and high dose amino acid infusion
abstract: We tested the hypothesis that increasing blood amino acid (AA) availability would counter the physical inactivity‐induced reduction in muscle protein synthesis. We determined how 14 days of unilateral knee immobilization affected quadriceps myofibrillar protein synthesis (MPS) in young healthy subjects (10 men, 2 women, 21 ± 1 years; 80.2 ± 4.0 kg, mean ±s.e.m.) in the post‐absorptive state and after infusing AA (10% Primene) at low or high doses (43 and 261 mg kg−1 h−1). Muscle cross‐sectional area (MRI) and peak isometric torque declined in the immobilized leg (−5.0 ± 1.2% and −25 ± 3%, respectively, both P < 0.005), but were unchanged (all P > 0.6) in the non‐immobilized leg. Immobilization induced a 27% decline in the rate of post‐absorptive MPS (immobilized, 0.027 ± 0.003: non‐immobilized, 0.037 ± 0.003% h−1; P < 0.001). Regardless of dose, AA infusion stimulated a greater rise in MPS in the non‐immobilized legs; at 4 h MPS was greater by +54 ± 12% with low dose and +68 ± 17% with high dose AA infusion (both P < 0.001). There was some evidence of delayed responsiveness of phosphorylation of Akt to high doses of AA and p70S6k at both doses but no marked differences in that of mTOR, GSK3β or eEF2. Phosphorylation of focal adhesion kinase (Tyr576/577) was reduced (P < 0.05) with immobilization. We observed no change in polyubiquitinated protein content after immobilization. We confirm that 14 days of immobilization reduces MPS in the post‐absorptive state and this diminution is reduced but not abolished by increased provision of AA, even at high rates. The immobilization‐induced decline in post‐absorptive MPS with the ‘anabolic resistance’ to amino acids can account for much of immobilization‐induced muscle atrophy.

title: Two weeks of reduced activity decreases leg lean mass and induces "anabolic resistance" of myofibrillar protein synthesis in healthy elderly.
abstract: Alterations in muscle protein metabolism underlie age-related muscle atrophy. During periods of muscle disuse, muscle protein synthesis is blunted, and muscle atrophy occurs in young and old. The impact of a short reduction in physical activity on muscle protein metabolism in older adults is unknown.



The aim of this study was to investigate the impact of 14 days of reduced daily steps on fasted and fed-state rates of myofibrillar protein synthesis (MPS) to provide insight into the mechanisms for changes in muscle mass and markers of metabolic health.



Before and after 14 days of reduced daily step-count, 10 healthy older adults (age, 72 ± 1 y) underwent measures of insulin sensitivity, muscle strength, physical function, and body composition. Using a primed constant infusion of L-[ring-(13)C6]phenylalanine with serial muscle biopsies, basal, postabsorptive, and postprandial rates of MPS were determined before and after the 14-day intervention.



Daily step-count was reduced by approximately 76% to 1413 ± 110 steps per day. Leg fat-free mass was reduced by approximately 3.9% (P < .001). Postabsorptive insulin resistance was increased by approximately 12%, and postprandial insulin sensitivity was reduced by approximately 43% after step reduction (P < .005). Concentrations of TNF-α and C-reactive protein were increased by approximately 12 and 25%, respectively, after step reduction (P < .05). Postprandial rates of MPS were reduced by approximately 26% after the intervention (P = .028), with no difference in postabsorptive rates.



The present study demonstrates that 14 days of reduced steps in older adults induces small but measurable reductions in muscle mass that appear to be underpinned by reductions in postprandial MPS and are accompanied by impairments in insulin sensitivity and systemic inflammatory markers and postprandial MPS.

title: Alcohol Ingestion Impairs Maximal Post-Exercise Rates of Myofibrillar Protein Synthesis following a Single Bout of Concurrent Training
abstract: The culture in many team sports involves consumption of large amounts of alcohol after training/competition. The effect of such a practice on recovery processes underlying protein turnover in human skeletal muscle are unknown. We determined the effect of alcohol intake on rates of myofibrillar protein synthesis (MPS) following strenuous exercise with carbohydrate (CHO) or protein ingestion.  In a randomized cross-over design, 8 physically active males completed three experimental trials comprising resistance exercise (8×5 reps leg extension, 80% 1 repetition maximum) followed by continuous (30 min, 63% peak power output (PPO)) and high intensity interval (10×30 s, 110% PPO) cycling. Immediately, and 4 h post-exercise, subjects consumed either 500 mL of whey protein (25 g; PRO), alcohol (1.5 g·kg body mass−1, 12±2 standard drinks) co-ingested with protein (ALC-PRO), or an energy-matched quantity of carbohydrate also with alcohol (25 g maltodextrin; ALC-CHO). Subjects also consumed a CHO meal (1.5 g CHO·kg body mass−1) 2 h post-exercise. Muscle biopsies were taken at rest, 2 and 8 h post-exercise.  Blood alcohol concentration was elevated above baseline with ALC-CHO and ALC-PRO throughout recovery (P<0.05). Phosphorylation of mTORSer2448 2 h after exercise was higher with PRO compared to ALC-PRO and ALC-CHO (P<0.05), while p70S6K phosphorylation was higher 2 h post-exercise with ALC-PRO and PRO compared to ALC-CHO (P<0.05). Rates of MPS increased above rest for all conditions (∼29–109%, P<0.05). However, compared to PRO, there was a hierarchical reduction in MPS with ALC-PRO (24%, P<0.05) and with ALC-CHO (37%, P<0.05).  We provide novel data demonstrating that alcohol consumption reduces rates of MPS following a bout of concurrent exercise, even when co-ingested with protein. We conclude that alcohol ingestion suppresses the anabolic response in skeletal muscle and may therefore impair recovery and adaptation to training and/or subsequent performance.

title: Impaired protein metabolism: interlinks between obesity, insulin resistance and inflammation
abstract: Metabolic and structural changes in skeletal muscle that accompany obesity are often associated with the development of insulin resistance. The first events in the pathogenesis of this disorder are considered as an accumulation of lipids within skeletal muscle due to blunted muscle capacity to oxidize fatty acids. Fat infiltration is also associated with muscle fibre typology modification, decrease in muscle mass and impairments in muscle strength. Thus, as a result of obesity, mobility and quality of life are affected, and this is in part due to quantitative and qualitative impairments in skeletal muscle. In addition, the insulin resistance related to obesity results not only in defective insulin‐stimulated glucose disposal but has also detrimental consequences on protein metabolism at the skeletal muscle level and whole‐body level. This review highlights the involvement of fat accumulation and insulin resistance in metabolic disorders occurring in skeletal muscle during the development of obesity, and the impairments in the regulation of protein metabolism and protein turnover in the links between obesity, metabolic inflammation and insulin resistance.

title: Sarcopenia and diabetes: two sides of the same coin.
abstract: on muscle mass, strength, and functional capacity in an older population. The authors demonstrated that skeletal muscle mass, leg muscle strength, and functional capacity are reduced in older patients with type 2 diabetes, when compared with age-matched normoglycemic controls. This study contributes significantly to improving our knowledge about the relationship between diabetes and sarcopenia, an area that remains substantially poorly studied. So far, few observational studies have reported lower muscle strength among older men with type 2 diabetes compared with healthy controls. Interestingly, Park and colleagues 2 showed that older subjects with type 2 diabetes have a 30% greater decline over 3 years in leg muscle strength compared with healthy age-matched controls. Furthermore, the impairment in muscle strength observed among older subjects with diabetes has been correlated with intramuscular fat storage, which is almost 3

title: Muscle protein anabolism in type 2 diabetes
abstract: Purpose of reviewProtein anabolism is abnormal in human type 2 diabetes (T2DM). We review studies of anabolic stimuli that identify potential causes. If uncorrected, and combined with aging effects, they will compromise muscle function and mass. Knowing causes can guide studies of preventive and treatment measures. Recent findingsT2DM accelerates age-related decreases in muscle mass. This could be related to insulin resistance of whole-body protein anabolism demonstrated in hyperglycemic obese men. In contrast, their protein anabolic response to hyperaminoacidemia suggested that ample amino acid administration, especially branched chain amino acids might overcome such insulin resistance. One study of chronic leucine supplementation in elderly T2DM patients did not increase muscle mass. However, they lacked sarcopenia and had adequate dietary protein intake, so may be atypical. Exercise induced similar increases in muscle protein synthesis, mass and strength in healthy and T2DM patients suggesting that physical activity might also overcome insulin resistance of protein anabolism. SummaryMuscle protein anabolism in T2DM is resistant to the action of insulin but perhaps not to amino acid supply or exercise. Whether leucine supplementation improves muscle mass and function in persons with T2DM (especially elderly) with reduced protein intake or muscle mass needs to be determined.

title: Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle
abstract: The nature of the deficit underlying age‐related muscle wasting remains controversial. To test whether it could be due to a poor anabolic response to dietary amino acids, we measured the rates of myofibrillar and sarcoplasmic muscle protein synthesis (MPS) in 44 healthy young and old men, of similar body build, after ingesting different amounts of essential amino acids (EAA). Basal rates of MPS were indistinguishable, but the elderly showed less anabolic sensitivity and responsiveness of MPS to EAA, possibly due to decreased intramuscular expression, and activation (phosphorylation) after EAA, of amino acid sensing/signaling proteins (mammalian target of rapamycin, mTOR; p70 S6 kinase, or p70S6k; eukaryotic initiation factor [eIF]4BP‐1; and eIF2B). The effects were independent of insulin signaling since plasma insulin was clamped at basal values. Associated with the anabolic deficits were marked increases in NFκB, the inflammation‐associated transcription factor. These results demonstrate first, EAA stimulate MPS independently of increased insulin availability; second, in the elderly, a deficit in MPS in the basal state is unlikely; and third, the decreased sensitivity and responsiveness of MPS to EAA, associated with decrements in the expression and activation of components of anabolic signaling pathways, are probably major contributors to the failure of muscle maintenance in the elderly. Countermeasures to maximize muscle maintenance should target these deficits.

title: Dietary protein recommendations and the prevention of sarcopenia
abstract: draw attention to recent work on the role of protein and the amount of protein needed with each meal to preserve skeletal muscle mass in ageing. Recent findingsAgeing does not inevitably reduce the anabolic response to a high-quality protein meal. Ingestion of approximately 25–30 g of protein per meal maximally stimulates muscle protein synthesis in both young and older individuals. However, muscle protein synthesis is blunted in elderly when protein and carbohydrate are coingested or when the quantity of protein is less than approximately 20 g per meal. Supplementing regular mixed-nutrient meals with leucine may also enhance the muscle protein synthetic response in elders. SummaryOn the basis of recent work, we propose a novel and specific dietary approach to prevent or slow down muscle loss with ageing. Rather than recommending a large, global increase in the recommended dietary allowance (RDA) for protein for all elderly individuals, clinicians should stress the importance of ingesting a sufficient amount of protein with each meal. To maximize muscle protein synthesis while being cognizant of total energy intake, we propose a dietary plan that includes 25–30 g of high quality protein per meal.

title: Interplay of stress and physical inactivity on muscle loss: Nutritional countermeasures.
abstract: Inactivity-mediated protein catabolism occurs in many circumstances ranging from catastrophic events such as severe illness or injury, to unique environments such as spaceflight/microgravity, to more insidious causes such as physical frailty and the progression of aging. Nevertheless, regardless of the etiology, the consequences of inactivity are readily observable and debilitating. Mechanistically, the loss of lean body mass during inactivity is the result of a chronic imbalance between muscle protein synthesis and breakdown. When inactivity is accompanied by the stress of trauma or disease, the rate of muscle protein catabolism can increase several fold. Bed rest studies in healthy volunteers provide a unique opportunity to examine the mechanisms contributing to muscle loss and evaluate strategies for intervention that may slow muscle catabolism and promote anabolism. The prerequisite for muscle protein synthesis and the most readily adaptable stimulus is dietary-derived amino acids. This review focuses on the role of amino acid supplementation in the maintenance of skeletal muscle mass during age-related and clinically mandated inactivity.

title: Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia.
abstract: Sarcopenia, the age-associated loss of skeletal muscle mass and function, has considerable societal consequences for the development of frailty, disability, and health care planning. A group of geriatricians and scientists from academia and industry met in Rome, Italy, on November 18, 2009, to arrive at a consensus definition of sarcopenia. The current consensus definition was approved unanimously by the meeting participants and is as follows: Sarcopenia is defined as the age-associated loss of skeletal muscle mass and function. The causes of sarcopenia are multifactorial and can include disuse, altered endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. Although cachexia may be a component of sarcopenia, the 2 conditions are not the same. The diagnosis of sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health. Sarcopenia should specifically be considered in patients who are bedridden, cannot independently rise from a chair, or who have a measured gait speed less that 1 m/s(-1). Patients who meet these criteria should further undergo body composition assessment using dual energy x-ray absorptiometry with sarcopenia being defined using currently validated definitions. A diagnosis of sarcopenia is consistent with a gait speed of less than 1 m·s(-1) and an objectively measured low muscle mass (eg, appendicular mass relative to ht(2) that is ≤ 7.23 kg/m(2) in men and ≤ 5.67 kg/m(2) in women). Sarcopenia is a highly prevalent condition in older persons that leads to disability, hospitalization, and death.

title: Is the optimal level of protein intake for older adults greater than the recommended dietary allowance?
abstract: Protein is a macronutrient essential for growth, muscle function, immunity and overall tissue homeostasis. Suboptimal protein intake can significantly impact physical function and overall health in older adults.



This article reviews the literature on the recommendations for protein intake in older adults in light of the new evidence linking protein intake with sarcopenia and physical function. Challenges and opportunities for optimal protein nutrition in older persons are discussed.



Recent metabolic and epidemiological studies suggest that the current recommendations of protein intake may not be adequate for maintenance of physical function and optimal health in older adults. Methodological limitations and novel concepts in protein nutrition are also discussed.



We conclude that new research and novel research methodologies are necessary to establish the protein needs and optimal patterns of protein intake for older persons.

title: Nutritional recommendations for the management of sarcopenia.
abstract: The Society for Sarcopenia, Cachexia, and Wasting Disease convened an expert panel to develop nutritional recommendations for prevention and management of sarcopenia. Exercise (both resistance and aerobic) in combination with adequate protein and energy intake is the key component of the prevention and management of sarcopenia. Adequate protein supplementation alone only slows loss of muscle mass. Adequate protein intake (leucine-enriched balanced amino acids and possibly creatine) may enhance muscle strength. Low 25(OH) vitamin D levels require vitamin D replacement.

title: Pre-Hospital Dietary Intake Correlates with Muscle Mass at the Time of Fracture in Older Hip-Fractured Patients
abstract: Failure to meet an adequate dietary intake is involved in the pathogenesis of sarcopenia and osteoporosis, which in turn increase the risk for falls and fractures, respectively. Older people with hip fracture are often protein-malnourished at hospitalization. Whether low protein-energy intake is associated with muscle atrophy in hip-fractured patients is presently unknown. This information is necessary for the development of novel strategies to manage this especially vulnerable patient population. The aim of this study was, therefore, to explore the relationship between dietary intake and muscle mass in older hip-fractured patients.  Analyses were conducted in hip-fractured elderly admitted to an orthopedic and trauma surgery ward (University Hospital). Muscle mass was estimated by bioelectrical impedance analysis within 24 h from admission. Dietary information was collected via 24-h dietary recall and nutrient intake calculated by a nutrition software.  Among 62 hip-fractured patients (mean age 84.6 ± 7.6 years, 84% women), the average energy intake was 929.2 ± 170.3 Kcal day−1, with higher values reported by men (1.046.8 ± 231.4 Kcal day−1) relative to women (906.5 ± 148.3 Kcal day−1; p = 0.01). Absolute and normalized protein intake was 50.0 ± 13.5 g day−1 and 0.88 ± 0.27 g kg (body weight)–1 day–1, respectively, with no gender differences. A positive correlation was determined between total energy intake and muscle mass (r = 0.384; p = 0.003). Similarly, protein and leucine consumption was positively correlated with muscle mass (r = 0.367 and 0.311, respectively; p = 0.005 for both).  A low intake of calories, protein, and leucine is associated with reduced muscle mass in hip-fractured elderly. Given the relevance of sarcopenia as a risk factor for adverse outcomes in this patient population, our findings highlight the importance of a comprehensive dietary assessment for the detection of nutritional deficits predisposing to or aggravating muscle atrophy.

title: Sarcopenia as a risk factor for falls in elderly individuals: results from the ilSIRENTE study.
abstract: Sarcopenia has been indicated as a reliable marker of frailty and poor prognosis among the oldest individuals. We evaluated the relationship between sarcopenia and 2-year risk of falls in a population of persons aged 80 years or older.



Data are from the baseline and follow-up evaluations of the Aging and Longevity Study in the Sirente Geographic Area (ilSIRENTE Study) (n=260). According to the European Working Group on Sarcopenia in Older People (EWGSOP), sarcopenia was diagnosed in presence of low muscle mass (mid-arm muscle circumference) plus either low muscle strength (hand grip) or low physical performance (4-m walking speed). The primary outcome measure was the incident falls during the follow-up period of 2 years. The relationship between sarcopenia and incident falls was estimated by deriving hazard ratios (HRs) from multiple logistic regression models considering the dependent variable of interest at least one fall during the follow-up period.



Sixty-six participants (25.4%) were identified as affected by sarcopenia. Eighteen out of 66 (27.3%) participants with sarcopenia and 19 out of 194 (9.8%) without sarcopenia reported incident falls during the two-year follow-up of the study (p<0.001). After adjusting for age, gender, cognitive impairment, ADL impairment, sensory impairments, BMI, depression, physical activity, cholesterol, stroke, diabetes, number of medications, and C-reactive protein, participants with sarcopenia had a higher risk of incident falls compared with non sarcopenic subjects (adjusted hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.25-8.29).



The present study suggests that sarcopenia - assessed using the EWGSOP algorithm - is highly prevalent among elderly persons without gender differences (25%). Sarcopenic participants were over three times more likely to fall during a follow-up period of 2 years relative to non sarcopenic individuals, regardless of age, gender and other confounding factors.

title: Sarcopenia and mortality risk in frail older persons aged 80 years and older: results from ilSIRENTE study.
abstract: sarcopenia has been indicated as a reliable marker of frailty and poor prognosis among the oldest individuals. We evaluated the impact of sarcopenia on the risk of all-cause death in a population of frail older persons living in community.



we analysed data from the Aging and Longevity Study, a prospective cohort study that collected data on all subjects aged 80 years and older residing in the Sirente geographic area (n = 364). The present analysis was conducted among those subjects who were between 80 and 85 years of age at the time of the baseline assessment (n = 197). The main outcome measure was all-cause mortality over 7-year follow-up. According to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, the diagnosis of sarcopenia required the documentation of low muscle mass and the documentation of either low muscle strength or low physical performance. Cox proportional regression models were used to estimate crude and adjusted hazard ratios and 95% confidence intervals of death by the presence of sarcopenia.



using the EWGSOP-suggested criteria, 43 subjects with sarcopenia (21.8%) were identified. During the 7-year follow-up, 29 (67.4%) participants died among subjects with sarcopenia compared with 63 subjects (41.2%) without sarcopenia (P < 0.001). After adjusting for potential confounders including age, gender, education, activities of daily living (ADL) impairment, body mass index, hypertension, congestive heart failure, chronic obstructive pulmonary disease, number of diseases, TNF-α, participants with sarcopenia had a higher risk of death for all causes compared with non-sarcopenic subjects (HR: 2.32, 95% CI: 1.01-5.43).



our results obtained from a representative sample of very old and frail subjects show that sarcopenia is associated with mortality, independently of age and other clinical and functional variables.

title: Protein supplementation improves physical performance in frail elderly people: a randomized, double-blind, placebo-controlled trial.
abstract: Protein supplementation has been proposed as an effective dietary strategy to increase skeletal muscle mass and improve physical performance in frail elderly people. Our objective was to assess the impact of 24 weeks of dietary protein supplementation on muscle mass, strength, and physical performance in frail elderly people.



A total of 65 frail elderly subjects were included and randomly allocated to either daily protein or placebo supplementation (15 g protein at breakfast and lunch).



Skeletal muscle mass (DXA), muscle fiber size (muscle biopsy), strength (1-RM), and physical performance (SPPB) were assessed at baseline, and after 12 and 24 weeks of dietary intervention.



Skeletal muscle mass did not change in the protein- (from 45.8 ± 1.7 to 45.8 ± 1.7 kg) or placebo-supplemented group (from 46.7 ± 1.7 to 46.6 ± 1.7 kg) following 24 weeks of intervention (P > .05). In accordance, type I and II muscle fiber size did not change over time (P > .05). Muscle strength increased significantly in both groups (P < .01), with leg extension strength tending to increase to a greater extent in the protein (57 ± 5 to 68 ± 5 kg) compared with the placebo group (57 ± 5 to 63 ± 5 kg) (treatment × time interaction effect: P = .059). Physical performance improved significantly from 8.9 ± 0.6 to 10.0 ± 0.6 points in the protein group and did not change in the placebo group (from 7.8 ± 0.6 to 7.9 ± 0.6 points) (treatment × time interaction effect: P = .02).



Dietary protein supplementation improves physical performance, but does not increase skeletal muscle mass in frail elderly people.

title: Protein supplementation increases muscle mass gain during prolonged resistance-type exercise training in frail elderly people: a randomized, double-blind, placebo-controlled trial.
abstract: Protein supplementation has been proposed as an effective dietary strategy to augment the skeletal muscle adaptive response to prolonged resistance-type exercise training in elderly people. Our objective was to assess the impact of protein supplementation on muscle mass, strength, and physical performance during prolonged resistance-type exercise training in frail elderly men and women.



A randomized, double-blind, placebo-controlled trial with 2 arms in parallel among 62 frail elderly subjects (78 ± 1 year). These elderly subjects participated in a progressive resistance-type exercise training program (2 sessions per week for 24 weeks) during which they were supplemented twice daily with either protein (2 * 15 g) or a placebo.



Lean body mass (DXA), strength (1-RM), and physical performance (SPPB) were assessed at baseline, and after 12 and 24 weeks of intervention.



Lean body mass increased from 47.2 kg (95% CI, 43.5-50.9) to 48.5 kg (95% CI, 44.8-52.1) in the protein group and did not change in the placebo group (from 45.7 kg, 95% CI, 42.1-49.2 to 45.4 kg, 95% CI, 41.8-48.9) following the intervention (P value for treatment × time interaction = .006). Strength and physical performance improved significantly in both groups (P = .000) with no interaction effect of dietary protein supplementation.



Prolonged resistance-type exercise training represents an effective strategy to improve strength and physical performance in frail elderly people. Dietary protein supplementation is required to allow muscle mass gain during exercise training in frail elderly people.

title: Criteria and significance of dietary protein sources in humans. Summary of the workshop with recommendations.
abstract: *U.S. Department of Agriculture/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030; †Center of Expertise Nutrition, DMV International-Campina Melkunie, 6700 AA, Wageningen, the Netherlands; **Institut National Agronomique Patis-Grignon, Paris, France and ‡Laboratory of Human Nutrition, School of Science and Clinical Research Center, Massachusetts Institute of Technology, Cambridge, MA 02139

title: Amino acid requirements in humans: with a special emphasis on the metabolic availability of amino acids
abstract: Due to advances made in the development of stable isotope based carbon oxidation methods, the determination of amino acid requirements in humans has been an active area of research for the past 2 decades. The indicator amino acid oxidation (IAAO) method developed in our laboratory for humans has been systematically applied to determine almost all indispensable amino acid requirements in adult humans. Nutritional application of experimentally derived amino acid requirement estimates depends upon the capacity of food proteins to meet the amino acid requirements in humans. Therefore, there is a need to know the proportion of dietary amino acids which are bioavailable, or metabolically available to the body for protein synthesis following digestion and absorption. Although this concept is widely applied in animal nutrition, it has not been applied to human nutrition due to lack of data. We developed a new in vivo method in growing pigs to identify the metabolic availability of amino acids in foods using the IAAO concept. This metabolic availability method has recently been adapted for use in humans. As this newly developed IAAO based method to determine metabolic availability of amino acids in foods is suitable for rapid and routine analysis in humans, it is a major step forward in defining the protein quality of food sources and integrating amino acid requirement data with dietary amino acid availability of foods.

title: Slow and fast dietary proteins differently modulate postprandial protein accretion.
abstract: The speed of absorption of dietary amino acids by the gut varies according to the type of ingested dietary protein. This could affect postprandial protein synthesis, breakdown, and deposition. To test this hypothesis, two intrinsically 13C-leucine-labeled milk proteins, casein (CAS) and whey protein (WP), of different physicochemical properties were ingested as one single meal by healthy adults. Postprandial whole body leucine kinetics were assessed by using a dual tracer methodology. WP induced a dramatic but short increase of plasma amino acids. CAS induced a prolonged plateau of moderate hyperaminoacidemia, probably because of a slow gastric emptying. Whole body protein breakdown was inhibited by 34% after CAS ingestion but not after WP ingestion. Postprandial protein synthesis was stimulated by 68% with the WP meal and to a lesser extent (+31%) with the CAS meal. Postprandial whole body leucine oxidation over 7 h was lower with CAS (272 +/- 91 micromol.kg-1) than with WP (373 +/- 56 micromol.kg-1). Leucine intake was identical in both meals (380 micromol.kg-1). Therefore, net leucine balance over the 7 h after the meal was more positive with CAS than with WP (P < 0.05, WP vs. CAS). In conclusion, the speed of protein digestion and amino acid absorption from the gut has a major effect on whole body protein anabolism after one single meal. By analogy with carbohydrate metabolism, slow and fast proteins modulate the postprandial metabolic response, a concept to be applied to wasting situations.

title: The Rate of Protein Digestion affects Protein Gain Differently during Aging in Humans
abstract: In young men ingesting protein meals, slowly digested proteins (caseins: CAS) induce a higher protein gain than those that are rapidly digested (whey proteins: WP). Our aim was to assess whether or not this is true in elderly men receiving mixed meals. The effects of meals containing either CAS or two different amounts of WP (WP‐iN: isonitrogenous with CAS, or WP‐iL: providing the same amount of leucine as CAS) on protein metabolism (assessed by combining oral and intravenous leucine tracers) were compared in nine healthy, elderly (mean ±s.e.m. age 72 ± 1 years) and six young men (24 ± 1 years). In both age groups, WP‐iL and WP‐iN were digested faster than CAS (P < 0.001, ANOVA). Proteolysis was inhibited similarly whatever the meal and age groups (P= NS). Protein synthesis was higher with WP‐iN than with CAS or WP‐iL (P < 0.01), irrespective of age (P= NS). An age‐related effect (P < 0.05) was found with postprandial leucine balance. Leucine balance was higher with CAS than with WP‐iL (P < 0.01) in young men, but not in elderly subjects (P= NS). In isonitrogenous conditions, leucine balance was higher with WP‐iN than with CAS (P < 0.001) in both age groups, but the magnitude of the differences was higher in the elderly men (P= 0.05). In conclusion, during aging, protein gain was greater with WP (rapidly digested protein), and lower with CAS (slowly digested protein). This suggests that a ‘fast’ protein might be more beneficial than a ‘slow’ one to limit protein losses during aging.

title: Whey protein stimulates postprandial muscle protein accretion more effectively than do casein and casein hydrolysate in older men.
abstract: Sarcopenia has been attributed to a diminished muscle protein synthetic response to food intake. Differences in digestion and absorption kinetics of dietary protein, its amino acid composition, or both have been suggested to modulate postprandial muscle protein accretion.



The objective was to compare protein digestion and absorption kinetics and subsequent postprandial muscle protein accretion after ingestion of whey, casein, and casein hydrolysate in healthy older adults.



A total of 48 older men aged 74 ± 1 y (mean ± SEM) were randomly assigned to ingest a meal-like amount (20 g) of intrinsically l-[1-(13)C]phenylalanine-labeled whey, casein, or casein hydrolysate. Protein ingestion was combined with continuous intravenous l-[ring-(2)H(5)]phenylalanine infusion to assess in vivo digestion and absorption kinetics of dietary protein. Postprandial mixed muscle protein fractional synthetic rates (FSRs) were calculated from the ingested tracer.



The peak appearance rate of dietary protein-derived phenylalanine in the circulation was greater with whey and casein hydrolysate than with casein (P < 0.05). FSR values were higher after whey (0.15 ± 0.02%/h) than after casein (0.08 ± 0.01%/h; P < 0.01) and casein hydrolysate (0.10 ± 0.01%/h; P < 0.05) ingestion. A strong positive correlation (r = 0.66, P < 0.01) was observed between peak plasma leucine concentrations and postprandial FSR values.



Whey protein stimulates postprandial muscle protein accretion more effectively than do casein and casein hydrolysate in older men. This effect is attributed to a combination of whey's faster digestion and absorption kinetics and higher leucine content.

title: Protein and healthy aging.
abstract: Our understanding of the potential benefits and challenges of optimizing dietary protein intake in older adults continues to evolve. An overarching hypothesis generated during Protein Summit 2.0 was that consuming an adequate amount of high-quality protein at each meal, in combination with physical activity, may delay the onset of sarcopenia, slow its progression, reduce the magnitude of its functional consequences, or all of these. The potential benefits of young and middle-aged adults adopting a diet pattern whereby adequate protein is consumed at each meal as a countermeasure to sarcopenia are presented and discussed. For example, meeting a protein threshold (∼25-30 g/meal) represents a promising, yet still largely unexplored dietary strategy to help maintain muscle mass and function. For many older adults, breakfast is a carbohydrate-dominated lower-protein meal and represents an opportunity to improve and more evenly distribute daily protein intake. Although both animal and plant-based proteins can provide the required essential amino acids for health, animal proteins generally have a higher proportion of the amino acid leucine. Leucine plays a key role in stimulating translation initiation and muscle protein anabolism and is the focus of ongoing research. Protein requirements should be assessed in the light of habitual physical activity. An evenly distributed protein diet provides a framework that allows older adults to benefit from the synergistic anabolic effect of protein and physical activity. To fully understand the role of dietary protein intake in healthy aging, greater efforts are needed to coordinate and integrate research design and data acquisition and interpretation from a variety of disciplines.

title: Minced beef is more rapidly digested and absorbed than beef steak, resulting in greater postprandial protein retention in older men.
abstract: Older individuals generally experience a reduced food-chewing efficiency. As a consequence, food texture may represent an important factor that modulates dietary protein digestion and absorption kinetics and the subsequent postprandial protein balance.



We assessed the effect of meat texture on the dietary protein digestion rate, amino acid availability, and subsequent postprandial protein balance in vivo in older men.



Ten older men (mean ± SEM age: 74 ± 2 y) were randomly assigned to a crossover experiment that involved 2 treatments in which they consumed 135 g of specifically produced intrinsically L-[1-(13)C]phenylalanine-labeled beef, which was provided as beef steak or minced beef. Meat consumption was combined with continuous intravenous L-[ring-(2)H5]phenylalanine and L-[ring-(2)H2]tyrosine infusion to assess beef protein digestion and absorption kinetics as well as whole-body protein balance and skeletal muscle protein synthesis rates.



Meat protein-derived phenylalanine appeared more rapidly in the circulation after minced beef than after beef steak consumption (P < 0.05). Also, its availability in the circulation during the 6-h postprandial period was greater after minced beef than after beef steak consumption (61 ± 3% compared with 49 ± 3%, respectively; P < 0.01). The whole-body protein balance was more positive after minced beef than after beef steak consumption (29 ± 2 compared with 19 ± 3 μmol phenylalanine/kg, respectively; P < 0.01). Skeletal muscle protein synthesis rates did not differ between treatments when assessed over a 6-h postprandial period.



Minced beef is more rapidly digested and absorbed than beef steak, which results in increased amino acid availability and greater postprandial protein retention. However, this does not result in greater postprandial muscle protein synthesis rates.

title: Protein pulse feeding improves protein retention in elderly women.
abstract: Adequate protein nutrition could be used to limit gradual body protein loss and improve protein anabolism in the elderly.



We tested the hypothesis that an uneven protein feeding pattern was more efficient in improving protein anabolism than was an even pattern.



After a controlled period, 15 elderly women (mean age: 68 y) were fed for 14 d either a pulse diet (n = 7), providing 80% of the daily protein intake at 1200, or a spread diet (n = 8), in which the same daily protein intake was spread over 4 meals. Both diets provided 1.7 g protein x kg fat-free mass (FFM)(-1) x d(-1). Protein accretion and daily protein turnover were determined by using the nitrogen balance method and the end product method (ammonia and urea) after an oral dose of [15N]glycine.



Nitrogen balance was more positive with the pulse than with the spread diet (54 +/- 7 compared with 27 +/- 6 mg N x kg FFM(-1) x d(-1); P < 0.05). Protein turnover rates were also higher with the pulse than with the spread diet (5.58 +/- 0.22 compared with 4.98 +/- 0.17 g protein x kg FFM(-1) x d(-1); P < 0.05), mainly because of higher protein synthesis in the pulse group (4.48 +/- 0.19 g protein x kg FFM(-1) x d(-1)) than in the spread group (3.75 +/- 0.19 g protein x kg FFM(-1) x d(-1)) (P < 0.05).



A protein pulse-feeding pattern was more efficient than was a protein spread-feeding pattern in improving, after 14 d, whole-body protein retention in elderly women.

title: Amino acid absorption and subsequent muscle protein accretion following graded intakes of whey protein in elderly men.
abstract: Whey protein ingestion has been shown to effectively stimulate postprandial muscle protein accretion in older adults. However, the impact of the amount of whey protein ingested on protein digestion and absorption kinetics, whole body protein balance, and postprandial muscle protein accretion remains to be established. We aimed to fill this gap by including 33 healthy, older men (73 ± 2 yr) who were randomly assigned to ingest 10, 20, or 35 g of intrinsically l-[1-¹³C]phenylalanine-labeled whey protein (n = 11/treatment). Ingestion of labeled whey protein was combined with continuous intravenous l-[ring-²H₅]phenylalanine and l-[ring-²H₂]tyrosine infusion to assess the metabolic fate of whey protein-derived amino acids. Dietary protein digestion and absorption rapidly increased following ingestion of 10, 20, and 35 g whey protein, with the lowest and highest (peak) values observed following 10 and 35 g, respectively (P < 0.05). Whole body net protein balance was positive in all groups (19 ± 1, 37 ± 2, and 58 ± 2 μmol/kg), with the lowest and highest values observed following ingestion of 10 and 35 g, respectively (P < 0.05). Postprandial muscle protein accretion, assessed by l-[1-¹³C]phenylalanine incorporation in muscle protein, was higher following ingestion of 35 g when compared with 10 (P < 0.01) or 20 (P < 0.05) g. We conclude that ingestion of 35 g whey protein results in greater amino acid absorption and subsequent stimulation of de novo muscle protein synthesis compared with the ingestion of 10 or 20 g whey protein in healthy, older men.

title: Timing and distribution of protein ingestion during prolonged recovery from resistance exercise alters myofibrillar protein synthesis
abstract: A single bolus of ∼20 g of protein after a bout of resistance exercise provides a maximal anabolic stimulus during the early post‐exercise recovery period (∼5 h), but the effect of various protein feeding strategies on skeletal muscle protein synthesis during an extended recovery period (12 h) is unknown. We compared three different patterns of ingestion of 80 g of protein during 12 h recovery after resistance exercise and the associated anabolic response in human skeletal muscle. Protein was ingested in 10, 20 or 40 g feedings using a pulsed, intermediate or bolus ingestion regimen, respectively. Our results indicate that repeated ingestion of 20 g of protein was superior for stimulating muscle protein synthesis during the 12 h experimental period. The three dietary treatments induced differential phosphorylation of signalling proteins and changes in mRNA abundance. This study shows that the distribution of protein intake is an important variable to promote attainment and maintenance of peak muscle mass.

title: Dietary Protein Distribution Positively Influences 24-h Muscle Protein Synthesis in Healthy Adults123
abstract: The RDA for protein describes the quantity that should be consumed daily to meet population needs and to prevent deficiency. Protein consumption in many countries exceeds the RDA; however, intake is often skewed toward the evening meal, whereas breakfast is typically carbohydrate rich and low in protein. We examined the effects of protein distribution on 24-h skeletal muscle protein synthesis in healthy adult men and women (n = 8; age: 36.9 ± 3.1 y; BMI: 25.7 ± 0.8 kg/m2). By using a 7-d crossover feeding design with a 30-d washout period, we measured changes in muscle protein synthesis in response to isoenergetic and isonitrogenous diets with protein at breakfast, lunch, and dinner distributed evenly (EVEN; 31.5 ± 1.3, 29.9 ± 1.6, and 32.7 ± 1.6 g protein, respectively) or skewed (SKEW; 10.7 ± 0.8, 16.0 ± 0.5, and 63.4 ± 3.7 g protein, respectively). Over 24-h periods on days 1 and 7, venous blood samples and vastus lateralis muscle biopsy samples were obtained during primed (2.0 μmol/kg) constant infusion [0.06 μmol/(kg⋅min)] of l-[ring-13C6]phenylalanine. The 24-h mixed muscle protein fractional synthesis rate was 25% higher in the EVEN (0.075 ± 0.006%/h) vs. the SKEW (0.056 ± 0.006%/h) protein distribution groups (P = 0.003). This pattern was maintained after 7 d of habituation to each diet (EVEN vs. SKEW: 0.077 ± 0.006 vs. 0.056 ± 0.006%/h; P = 0.001). The consumption of a moderate amount of protein at each meal stimulated 24-h muscle protein synthesis more effectively than skewing protein intake toward the evening meal.

title: Total protein, animal protein and physical activity in relation to muscle mass in middle-aged and older Americans
abstract: Resistance training is recognised as a good strategy for retarding age-related declines in muscle mass and strength. Recent studies have also highlighted the potential value of protein intakes in excess of present recommendations. The roles that leisure-time physical activity and protein quality play in the preservation of skeletal muscle during ageing, and how such influences interact in free-living people are unclear. We sought to clarify these issues using data collected on 2425 participants aged ≥ 50 years in the US National Health and Nutrition Examination Survey (2003–2006). We estimated subjects’ usual intakes of total protein and beef from two 24 h diet recalls and computed the appendicular skeletal muscle mass index from anthropometric measures. Participants self-reported their physical activity levels. Analyses accounted for demographic factors and smoking. The association between muscle-strengthening activity and the appendicular skeletal muscle mass index varied with protein intake. Furthermore, among obese subjects with protein intakes < 70 g/d, those who performed such activities had a lower appendicular skeletal muscle mass index than those who were physically inactive. Protein intakes above the present recommendations were associated with benefits to obese subjects only. The appendicular skeletal muscle mass index of non-obese subjects who performed vigorous aerobic activities was consistently high; in obese subjects, it varied with protein intake. High-protein intake was associated with a modest increase in the appendicular skeletal muscle mass index in non-obese, physically inactive subjects. The present findings reinforce the idea that muscle-strengthening exercise preserves muscle when combined with adequate dietary protein. Vigorous aerobic activity may also help.

title: Amino Acid Supplements and Recovery from High-Intensity Resistance Training
abstract: Sharp, CPM and Pearson, DR. Amino acid supplements and recovery from high-intensity training.  2010-The purpose of this study was to investigate whether short-term amino acid supplementation could maintain a short-term net anabolic hormonal profile and decrease muscle cell damage during a period of high-intensity resistance training (overreaching), thereby enhancing recovery and decreasing the risk of injury and illness. Eight previously resistance trained males were randomly assigned to either a high branched chain amino acids (BCAA) or placebo group. Subjects consumed the supplement for 3 weeks before commencing a fourth week of supplementation with concomitant high-intensity total-body resistance training (overreaching) (3 × 6-8 repetitions maximum, 8 exercises). Blood was drawn prior to and after supplementation, then again after 2 and 4 days of training. Serum was analyzed for testosterone, cortisol, and creatine kinase. Serum testosterone levels were significantly higher (p < 0.001), and cortisol and creatine kinase levels were significantly lower (p < 0.001, and p = 0.004, respectively) in the BCAA group during and following resistance training. These findings suggest that short-term amino acid supplementation, which is high in BCAA, may produce a net anabolic hormonal profile while attenuating training-induced increases in muscle tissue damage. Athletes' nutrient intake, which periodically increases amino acid intake to reflect the increased need for recovery during periods of overreaching, may increase subsequent competitive performance while decreasing the risk of injury or illness.

title: Nutrition and sport
abstract: Contributors. Foreword. Preface. Chapter 1 - asessment of energy expenditure (Klaas R Westerterp). Chapter 2 - Dietary survey methods (Allan Hackett). Chapter 3 - Carbohydrate as an energy source for sport and exercise (Clyde Williams). Chapter 4 - The role of fats as an energy source (Asker Jeukendrup). Chapter 5 - Protein and amino acid requirements for athletes (Joanna Bowtell). Chapter 6 - Micronutrients important for exercise (Kathleen Woolf and Melinda M. Manore). Chapter 7 - Maintenance of fluid balance in sport and exercise (Susan Shirreffs). Chapter 8 - Antioxidants and free radicals (Graeme L. Close). Chapter 9 - Dietary supplements and nutritional ergogenic aids (R.J. Maughan). Chapter 10 - Nutritional concerns of female athletes (Katherine A. Beals). Chapter 11 - Chronobiology and nutrition (J. Waterhouse, G. Atkinson, B. Edwards, B. Drust and T. Reilly). Chapter 12 - The practical aspects of sports nutrition (Jeanette Crosland). Index.

title: Exercise and Nutrition to Target Protein Synthesis Impairments in Aging Skeletal Muscle
abstract: The loss of skeletal muscle size and function with aging and sarcopenia may be related, in part, to an age-related muscle protein synthesis impairment. In this review, we discuss to what extent aging affects skeletal muscle protein synthesis and how nutrition and exercise can be used strategically to overcome age-related protein synthesis impairments and slow the progression of sarcopenia.

title: Enhanced amino acid sensitivity of myofibrillar protein synthesis persists for up to 24 h after resistance exercise in young men.
abstract: We aimed to determine whether an exercise-mediated enhancement of muscle protein synthesis to feeding persisted 24 h after resistance exercise. We also determined the impact of different exercise intensities (90% or 30% maximal strength) or contraction volume (work-matched or to failure) on the response at 24 h of recovery. Fifteen men (21 ± 1 y, BMI = 24.1 ± 0.8 kg · m(-2)) received a primed, constant infusion of l-[ring-(13)C(6)]phenylalanine to measure muscle protein synthesis after protein feeding at rest (FED; 15 g whey protein) and 24 h after resistance exercise (EX-FED). Participants performed unilateral leg exercises: 1) 4 sets at 90% of maximal strength to failure (90FAIL); 2) 30% work-matched to 90FAIL (30WM); or 3) 30% to failure (30FAIL). Regardless of condition, rates of mixed muscle protein and sarcoplasmic protein synthesis were similarly stimulated at FED and EX-FED. In contrast, protein ingestion stimulated rates of myofibrillar protein synthesis above fasting rates by 0.016 ± 0.002%/h and the response was enhanced 24 h after resistance exercise, but only in the 90FAIL and 30FAIL conditions, by 0.038 ± 0.012 and 0.041 ± 0.010, respectively. Phosphorylation of protein kinase B on Ser473 was greater than FED at EX-FED only in 90FAIL, whereas phosphorylation of mammalian target of rapamycin on Ser2448 was significantly increased at EX-FED above FED only in the 30FAIL condition. Our results suggest that resistance exercise performed until failure confers a sensitizing effect on human skeletal muscle for at least 24 h that is specific to the myofibrillar protein fraction.

title: Anorexia of Aging: Risk Factors, Consequences, and Potential Treatments
abstract: Older people frequently fail to ingest adequate amount of food to meet their essential energy and nutrient requirements. Anorexia of aging, defined by decrease in appetite and/or food intake in old age, is a major contributing factor to under-nutrition and adverse health outcomes in the geriatric population. This disorder is indeed highly prevalent and is recognized as an independent predictor of morbidity and mortality in different clinical settings. Even though anorexia is not an unavoidable consequence of aging, advancing age often promotes its development through various mechanisms. Age-related changes in life-style, disease conditions, as well as social and environmental factors have the potential to directly affect dietary behaviors and nutritional status. In spite of their importance, problems related to food intake and, more generally, nutritional status are seldom attended to in clinical practice. While this may be the result of an “ageist” approach, it should be acknowledged that simple interventions, such as oral nutritional supplementation or modified diets, could meaningfully improve the health status and quality of life of older persons.

title: Anorexia, physical function, and incident disability among the frail elderly population: results from the ilSIRENTE study.
abstract: Increasing evidence suggests that anorexia of aging can cause physical and mental impairment. The aim of the present study was to evaluate the relationship between anorexia of aging and measures of physical performance, muscle strength, and functional status in older persons aged 80 years or older.



Data are from baseline evaluation of 364 subjects enrolled in the ilSIRENTE study. The ilSIRENTE study is a prospective cohort study performed in the mountain community living in the Sirente geographic area (L'Aquila, Abruzzo) in central Italy. Physical performance was assessed using the physical performance battery score (SPPB), which is based on 3 timed tests: 4-meter walking speed, balance, and chair stand tests. Muscle strength was measured by hand grip strength. We defined anorexia as the presence of loss of appetite and/or lower food intake. Analyses of covariance were performed to evaluate the relationship of anorexia with physical function.



In the unadjusted model, all the physical performance, muscle strength, and functional measures showed significant associations with the presence of anorexia. After adjustment for potential confounders (age, gender, BMI, number of diseases, depression, congestive heart failure, lung diseases) these associations were weaker but still statistically significant (physical performance battery score: subjects without anorexia 6.8, SE 0.2, subjects with anorexia 5.8, SE 0.4, P = .03; 4-meter walking speed: subjects without anorexia 0.5 m/s, SE 0.1, subjects with anorexia 0.3 m/s, SE 0.1, P = 5.001 hand grip strength: subjects without anorexia 30.8 kg, SE 0.7, subjects with anorexia 27.9 kg, SE 1.5, P = .03). Furthermore, relative to participants without anorexia, those subjects with anorexia showed a significantly higher risk of developing disability after 2 years of follow-up (hazard ratio 2.25; 95% confidence intervals 1.15-4.39).



Anorexia is common among community older subjects in Italy. Our results suggest that among old-old subjects, the presence of anorexia is associated with impaired physical performance and with a significant increased risk of incident disability, irrespective of potential confounders.

title: The new metabolic treatments for sarcopenia
abstract: In terms of managing sarcopenia, many studies have shown that physical activity (in particular resistance exercise) and specific nutrition interventions such as protein and amino acids supplementation can improve muscle mass and strength in older adults. Moreover, several drugs have been suggested to have an impact on muscle outcomes, with various levels of scientific evidence. In the present paper we have reviewed the evidence regarding the effect of some new metabolic agents (vitamin D, leucine, β-hydroxy β-methylbutyrate, citrulline malate, ornithine, isoflavones) on sarcopenia and muscular outcomes in older adults. For each metabolic agent, we have also discussed the biological plausibility of the described effect.

title: A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly.
abstract: This study was designed to evaluate the effects of enriching an essential amino acid (EAA) mixture with leucine on muscle protein metabolism in elderly and young individuals. Four (2 elderly and 2 young) groups were studied before and after ingestion of 6.7 g of EAAs. EAAs were based on the composition of whey protein [26% leucine (26% Leu)] or were enriched in leucine [41% leucine (41% Leu)]. A primed, continuous infusion of L-[ring-2H5]phenylalanine was used together with vastus lateralis muscle biopsies and leg arteriovenous blood samples for the determinations of fractional synthetic rate (FSR) and balance of muscle protein. FSR increased following amino acid ingestion in both the 26% (basal: 0.048 +/- 0.005%/h; post-EAA: 0.063 +/- 0.007%/h) and the 41% (basal: 0.036 +/- 0.004%/h; post-EAA: 0.051 +/- 0.007%/h) Leu young groups (P < 0.05). In contrast, in the elderly, FSR did not increase following ingestion of 26% Leu EAA (basal: 0.044 +/- 0.003%/h; post-EAA: 0.049 +/- 0.006%/h; P > 0.05) but did increase following ingestion of 41% Leu EAA (basal: 0.038 +/- 0.007%/h; post-EAA: 0.056 +/- 0.008%/h; P < 0.05). Similar to the FSR responses, the mean response of muscle phenylalanine net balance, a reflection of muscle protein balance, was improved (P < 0.05) in all groups, with the exception of the 26% Leu elderly group. We conclude that increasing the proportion of leucine in a mixture of EAA can reverse an attenuated response of muscle protein synthesis in elderly but does not result in further stimulation of muscle protein synthesis in young subjects.

title: 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.
abstract: 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.



To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of sarcopenia.



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.



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.



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.

title: Supplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in men
abstract: Essential amino acids (EAAs) stimulate increased rates of myofibrillar protein synthesis (MPS). Leucine is a key regulator of MPS in rodents; however, its importance relative to the other EAAs is not clear. We report that a suboptimal dose of whey protein (6.25 g) supplemented with either leucine or a mixture of EAAs without leucine stimulates MPS similar to 25 g of whey protein under resting conditions; however, only 25 g of whey sustains exercise‐induced rates of MPS. Adding leucine or a mixture of EAAs without leucine to a suboptimal dose of whey is as effective as 25 g whey at stimulating fed rates of MPS; however, 25 g of whey is better suited to increase resistance exercise‐induced muscle anabolism.

title: Leucine supplementation chronically improves muscle protein synthesis in older adults consuming the RDA for protein.
abstract: Protein-energy supplementation is routinely employed to combat muscle loss. However, success is often compromised by increased satiety, poor palatability, high costs and low compliance.



For 2-weeks we supplemented meals of older individuals with leucine (4 g/meal; 3 meals/day; days 2-14). Metabolic studies were performed prior to (Day 1) and following (Day 15) supplementation. Leucine was not provided on metabolic study days. Venous blood and vastus lateralis muscle biopsies were obtained during a primed constant infusion of L-[ring-(13)C(6)] phenylalanine. Mixed muscle fractional synthesis rate (FSR), body composition and markers of nutrient signaling (mTOR, 4E-BP1 and p70S6K1 phosphorylation) were measured before and after a low protein/carbohydrate simulated meal.



The meal modestly increased FSR on Day 1 (postabsorptive: 0.063 ± 0.004 vs. postprandial: 0.075 ± 0.006%/h; p = 0.03), however, two weeks of leucine supplementation increased postabsorptive FSR (p = 0.004) and the response to the meal (p = 0.01) (postabsorptive: 0.074 ± 0.007 vs. postprandial: 0.10 ± 0.007%/h). Changes in FSR were mirrored by increased phosphorylation of mTOR, 4E-BP1 and p70S6K1 (p ≤ 0.1). No change in fat free mass was observed (p > 0.05).



In older adults, leucine supplementation may improve muscle protein synthesis in response to lower protein meals.

title: Leucine supplementation improves muscle protein synthesis in elderly men independently of hyperaminoacidaemia
abstract: The present study was designed to assess the effects of dietary leucine supplementation on muscle protein synthesis and whole body protein kinetics in elderly individuals. Twenty healthy male subjects (70 ± 1 years) were studied before and after continuous ingestion of a complete balanced diet supplemented or not with leucine. A primed (3.6 μmol kg−1) constant infusion (0.06 μmol kg−1 min−1) of l‐[1‐13C]phenylalanine was used to determine whole body phenylalanine kinetics as well as fractional synthesis rate (FSR) in the myofibrillar fraction of muscle proteins from vastus lateralis biopsies. Whole body protein kinetics were not affected by leucine supplementation. In contrast, muscle FSR, measured over the 5‐h period of feeding, was significantly greater in the volunteers given the leucine‐supplemented meals compared with the control group (0.083 ± 0.008 versus 0.053 ± 0.009% h−1, respectively, P < 0.05). This effect was due only to increased leucine availability because only plasma free leucine concentration significantly differed between the control and leucine‐supplemented groups. We conclude that leucine supplementation during feeding improves muscle protein synthesis in the elderly independently of an overall increase of other amino acids. Whether increasing leucine intake in old people may limit muscle protein loss during ageing remains to be determined.

title: Effect of beta-hydroxy-beta-methylbutyrate, arginine, and lysine supplementation on strength, functionality, body composition, and protein metabolism in elderly women.
abstract: With advancing age, there is a gradual loss of muscle mass, strength, and functionality. The current studies were conducted to determine whether a mixture of specific nutrients, arginine and lysine, which support protein synthesis, and beta-hydroxy-beta-methylbutyrate (HMB), which can slow protein breakdown, could blunt the gradual loss of muscle that occurs in the elderly, thus improving strength and functionality.



In double-blind studies conducted at two separate sites, women (mean 76.7 y) were randomized to a placebo group (n = 23) or an experimental treatment group (2 g beta-hydroxy-beta-methylbutyrate, 5 g arginine, and 1.5 g lysine daily; n = 27).



After 12 wk, there was a 17% improvement in the "get-up-and-go" functionality test in the experimental group (-2.3 +/- 0.5 s) but no change in the placebo group (0.0 +/- 0.5 s; P = 0.002). The improvement in functionality also was reflected by increased limb circumference, leg strength, and handgrip strength (all P < 0.05) and positive trends in fat-free mass (P = 0.08). Whole-body protein synthesis, estimated with the (15)N-glycine tracer technique over a 24-h free-living period, increased approximately 20% in the experimental treatment group as opposed to the placebo group (P = 0.03).



These studies indicated that daily supplementation of beta-hydroxy-beta-methylbutyrate, arginine, and lysine for 12 wk positively alters measurements of functionality, strength, fat-free mass, and protein synthesis, suggesting that the strategy of targeted nutrition has the ability to affect muscle health in elderly women.

title: Sarcopenia as the Biological Substrate of Physical Frailty.
abstract: Physical function decreases with aging, which may result in adverse outcomes (eg, disability, loss of independence, institutionalization, death). Physical function impairment is a common trait of frailty and sarcopenia. These two conditions, albeit highly common, have not yet received a unique operational definition, which has impeded their implementation in standard practice. Here, we introduce a conceptual model in which sarcopenia is proposed as the biological substrate and the pathway whereby the consequences of physical frailty develop. This conceptualization may open new venues for the design of interventions against physical frailty and promote the translation of findings to the clinical arena.