Potentially modifiable determinants of malnutrition in older adults: A systematic review.

BACKGROUND & AIMS: Malnutrition in older adults results in significant personal, social, and economic burden. To combat this complex, multifactorial issue, evidence-based knowledge is needed on the modifiable determinants of malnutrition. Systematic reviews of prospective studies are lacking in this area; therefore, the aim of this systematic review was to investigate the modifiable determinants of malnutrition in older adults. METHODS: A systematic approach was taken to conduct this review. Eight databases were searched. Prospective cohort studies with participants of a mean age of 65 years or over were included. Studies were required to measure at least one determinant at baseline and malnutrition as outcome at follow-up. Study quality was assessed using a modified version of the Quality in Prognosis Studies (QUIPS) tool. Pooling of data in a meta-analysis was not possible therefore the findings of each study were synthesized narratively. A descriptive synthesis of studies was used to present results due the heterogeneity of population source and setting, definitions of determinants and outcomes. Consistency of findings was assessed using the schema: strong evidence, moderate evidence, low evidence, and conflicting evidence. RESULTS: Twenty-three studies were included in the final review. Thirty potentially modifiable determinants across seven domains (oral, psychosocial, medication and care, health, physical function, lifestyle, eating) were included. The majority of studies had a high risk of bias and were of a low quality. There is moderate evidence that hospitalisation, eating dependency, poor self-perceived health, poor physical function and poor appetite are determinants of malnutrition. Moderate evidence suggests that chewing difficulties, mouth pain, gum issues co-morbidity, visual and hearing impairments, smoking status, alcohol consumption and physical activity levels, complaints about taste of food and specific nutrient intake are not determinants of malnutrition. There is low evidence that loss of interest in life, access to meals and wheels, and modified texture diets are determinants of malnutrition. Furthermore, there is low evidence that psychological distress, anxiety, loneliness, access to transport and wellbeing, hunger and thirst are not determinants of malnutrition. There appears to be conflicting evidence that dental status, swallowing, cognitive function, depression, residential status, medication intake and/or polypharmacy, constipation, periodontal disease are determinants of malnutrition. CONCLUSION: There are multiple potentially modifiable determinants of malnutrition however strong robust evidence is lacking for the majority of determinants. Better prospective cohort studies are required. With an increasingly ageing population, targeting modifiable factors will be crucial to the effective treatment and prevention of malnutrition.

Repeated cures with paracetamol worsen sarcopenia in old rats with suboptimal food intake.

The availability of all amino acids is of prime importance to prevent the ageing-associated decrease in skeletal muscle mass i.e. sarcopenia. Cysteine is the precursor of sulfate and glutathione that are both utilized in the liver to detoxify paracetamol (APAP). Cysteine availability could become limiting under repeated cures with APAP, especially when food intake is suboptimal. The aim of the study was to determine whether repeated cures with APAP could worsen sarcopenia. Twenty-two-month-old male Wistar rats received 3 two-week-long cures of APAP (1% of the diet) intercalated with washout periods of two weeks (APAP group). They were compared to untreated control rats euthanatized prior to the experiment (CT group) and rats pair-fed to the APAP group (PF group). Skeletal muscle mass and protein metabolism, as well as plasma amino acids and glutathione were assessed at the end of the third cure. APAP cures reduced food intake by 33, 23 and 33 % during the successive cures leading to an overall body weight loss of 8%. APAP rats lost lean mass during the experiment (-11%). This loss tended (P = 0.09) to be higher than in the PF group (-9%). The mass of hind limb muscles and the absolute synthesis rate of muscle proteins were 13 and 17% lower in the APAP group than the PF group, respectively. Plasma free cyst(e)ine (i.e. all free forms of cysteine not bound to proteins) and glutathione were 25% lower in the APAP group than the PF group. Repeated cures with APAP worsened sarcopenia in old rats with suboptimal food intake likely as a consequence of the APAP-induced shortage in cysteine/glutathione. Clinical studies are needed to clarify the effect of repeated treatments with paracetamol on skeletal muscle mass in older persons having suboptimal or insufficient dietary intakes.

Skeletal muscle wasting occurs in adult rats under chronic treatment with paracetamol when glutathione-dependent detoxification is highly activated.

The use of glutathione (GSH) and sulfate for the detoxification of paracetamol (acetaminophen, APAP) could occur at the expense of the physiological uses of cysteine (Cys). Indeed GSH and sulfate both originate from Cys. Significant APAP-induced Cys loss could generate alterations in GSH and protein metabolisms leading to muscle wasting. The study aimed to investigate the effects of chronic treatment with APAP on whole-body and tissue homeostasis (mass, GSH, proteins, and nitrogen balance) in relation to sulfur losses through APAP-detoxification pathways. Adult male Wistar rats were fed 0% APAP, 0.5% APAP or 1% APAP diets for 17 days. APAP doses were respectively around and largely above the threshold of sulfation saturation for rats. During the last days, the rats were placed in metabolic cages in order to quantify N balance and urinary APAP metabolites. Gastrocnemius muscle mass, protein and GSH contents, N balance and plasma free cyst(e)ine were 8% (P=0.02), 7% (P=0.03), 26% (P=0.01), 37% (P=0.01), and 33% (P=0.003) lower in the 1% APAP group than in the 0% APAP group, respectively. There was no significant difference in these parameters between the 0.5% APAP group and the 0% APAP group. Muscle wasting occurred when the detoxification of APAP through the GSH-dependent pathway was highly activated. Muscle protein synthesis could have been reduced due to a shortage in Cys and/or an increase in protein degradation in response to intra-muscular oxidative stress. Hence, without dietary sulphur amino acid increase, peripheral bioavailability of Cys and muscle GSH are potential players in the control of muscle mass under chronic treatment with APAP, an analgesic medication of widespread use, especially in the elderly.

Acetaminophen metabolism after major surgery: a greater challenge with increasing age.

Patients undergoing major surgery represent a good model for the study of the hepatic metabolism of acetaminophen (APAP) after surgery and for the evaluation of how the detoxification process is influenced by aging. Thirty patients received intravenous APAP (1 g/6 h) for 4 days (D1-D4). Daily 24-h urinary metabolites-cysteine-APAP, mercapturate-APAP, APAP, and glucuronide and sulfate conjugates-as well as blood glutathione levels were compared with repeated-measures analysis of variance (significance, P<0.05). Between D1 and D4, cysteine-APAP increased (308±308 mg vs. 570±512 mg, P=0.005), and sulfate and glucuronide conjugates decreased (1,365±1,084 mg vs. 694±600 mg, P<0.0001 and 2,418±817 mg vs. 1,513±1,076 mg, P=0.011, respectively). Blood glutathione decreased (790±125 vs. 623±132 µmol/l, P<0.0001. These changes increased with aging. APAP disposition after major surgery shifts toward the oxidative pathways of metabolism, and this is enhanced with aging. Supplementation with sulfur-containing amino acids should be investigated further as it might minimize the effect on antioxidant defenses, especially in older persons undergoing more extensive surgical procedures.

Dietary nitrogen-to-energy ratio alters amino acid partition in the whole body and among the splanchnic tissues of growing rams.

The aim of this study was to determine whether subtle changes in the energy-to-N ratio of medium-concentrate diets alters hepatic export protein synthesis and the partition of protein metabolism in the whole body of growing rams. Rams (n = 6; 41.5 +/- 2.6 kg of BW) were fitted with catheters for measurement of Leu and Phe tracer kinetics across the portal drained-viscera (PDV) and liver. Rams were assigned to receive 3 dietary treatments according to a duplicated Latin square design. Animals received forage-concentrate-based diets that were balanced for ME and available N (CON), 20% imbalanced (reduced) in available N (LN), or 20% imbalanced in ME (LE). After 15 d on each experimental diet, [ring-(2)H(5)]Phe (4.3 micromolxkg(-1)xh(-1)) and [1-(13)C]Leu (8.6 micromolxkg(-1)xh(-1)) were continuously infused into the vena cava for 10 h and, over the last 7 h of infusion, matched sets of blood samples were taken. Daily BW gain was less (P < 0.05) for the LE (0.191 kgxd(-1)) diet compared with CON (0.265 kg/d) and LN (258 kgxd(-1)) diets. Compared with CON, whole body irreversible loss rate (ILR) of Leu and Phe was less (10 to 16%, P < 0.02) for LN and LE diets, which for Leu reflected its decreased (20 to 24%, P < 0.05) net PDV absorption. The decreased whole body ILR is due to a decreased PDV ILR in both diets with a relative contribution of the PDV to the whole body ILR decreased (P < 0.05) in the LN (27%) diet compared with the CON (36%) and LE (33%) diets. This decreased PDV ILR was associated with a decreased net Leu PDV uptake in LN and LE diets (-25 and -20%, respectively; P < 0.05). Conversely, the decreased whole body Phe ILR is explained by a decreased hepatic ILR (and contribution to the whole body ILR) and was associated with a decreased net hepatic uptake of Phe in LN (-25%) and LE (-20%) diets compared with CON (P = 0.03). The fractional and absolute synthesis rates of total proteins and albumin were decreased by 10% in LE animals (P < 0.05), whereas they were not affected by the LN diet. These results suggest a specific decreased utilization of Leu at the PDV due to a specific sparing mechanism in the LN diet. Conversely, a decreased Phe utilization occurred in the liver in both diets (due to a decreased export protein synthesis and a probable decreased oxidation in LE diet, whereas only oxidation is reduced in LN diet).

HLA-B27 rats develop osteopaenia through increased bone resorption without any change in bone formation.

Osteopaenia is a common complication of inflammatory bowel diseases (IBD). However, the mechanisms of bone loss are still the subject of debate. The aims of this study were to investigate bone loss in HLA-B27 transgenic rats, a spontaneous model of colitis and to compare the results provided by the usual markers of bone remodelling and by direct measurement of bone protein synthesis. Systemic inflammation was evaluated in HLA-B27 rats and control rats from 18 to 27 months of age. Then bone mineral density, femoral failure load, biochemical markers of bone remodelling and protein synthesis in tibial epiphysis were measured. Bone mineral density was lower in HLA-B27 rats than in controls. Plasma osteocalcin, a marker of bone formation, and fractional protein synthesis rate in tibial epiphysis did not differ between the two groups of rats. In contrast, urinary excretion of deoxypyridinoline, a marker of bone resorption, was significantly increased in HLA-B27 rats. The present results indicate that bone fragility occurs in HLA-B27 rats and mainly results from an increase in bone resorption. Systemic inflammation may be the major cause of the disruption in bone remodelling homeostasis observed in this experimental model of human IBD.

Systemic low-grade inflammation does not decrease skeletal muscle mass and protein synthesis in old rats.

Age-associated low-grade systemic inflammation may contribute to sarcopenia. We hypothesized that skeletal muscle mass and protein synthesis rate would be reduced in old rats exhibiting persistent low-grade inflammation compared to age-matched controls. Male 24-month-old Wistar rats exhibiting a low-grade systemic inflammation for at least one month (LGI group) were compared to non-inflamed rats (C group). Tissue protein synthesis rates were quantified using the L-[1-(13)C]-valine flooding dose method. Body weight, gastrocnemius muscle and spleen weights were not significantly different between groups, but liver and small intestine weights were 13 and 14% higher in LGI than in C. Fractional and absolute protein synthesis rates were not significantly different between groups for gastrocnemius, spleen and small intestine, but higher for liver in LGI than in C. Despite an increase in liver protein synthesis, low-grade inflammation did not reduce skeletal muscle mass, suggesting that age-associated low-grade systemic inflammation occurs independently of sarcopenia.

Branched-chain amino acid aminotransferase activity decreases during development in skeletal muscles of sheep.

The catabolism of branched-chain amino acid (BCAA) differs between sheep and monogastric animals. The transamination of BCAA seems to be affected by development of the sheep. We studied the developmental changes in the activity and expression of the BCAA aminotransferase (BCAT) isoenzymes in skeletal muscle of sheep. Five muscles were taken from fetus, newborn, preruminant and ruminant lambs. BCAT specific activity and the contribution of each BCAT isoenzyme [mitochondrial and cytosolic (BCATm and BCATc, respectively)] were quantified using radioenzymatic and immunoprecipitation assays. BCATm and BCATc mRNAs were assessed by real-time reverse transcription-polymerase chain reaction. BCAT specific activities were 62% (diaphragma) to 83% (longissimus dorsi) lower in the ruminant lamb than in the fetal sheep. BCATm and BCATc were both expressed in sheep skeletal muscle at all developmental stages. BCATc was mainly responsible for the developmental decrease in BCAT specific activity. BCATc specific activities were 77% (diaphragma) to 92% (longissimus dorsi) lower in the ruminant lamb than in the fetal sheep, whereas BCATm specific activities were only 36% (semimembranosus) to 56% (longissimus dorsi) lower. BCATc and BCATm mRNAs in the longissimus dorsi were not affected by development of the sheep. The developmental decrease in BCATc activity, and to a lesser extent in BCATm activity, probably involves posttranscriptional mechanisms in sheep. The present results are consistent with lower in vivo metabolism of BCAA in ruminant than in the fetal sheep.

Sheep cytosolic branched-chain amino acid aminotransferase: cDNA cloning, primary structure and molecular modelling and its unique expression in muscles.

This paper presents the cloning and the molecular modelling of the cytosolic branched-chain amino acid aminotransferase (BCATc) from sheep brain. The sheep BCATc cDNA (3 kb) encodes a mature polypeptide of 385 amino acids with a calculated molecular mass of 43072.93 Da. The sequence of the sheep BCATc cDNA is more similar to other mammalian BCATc cDNAs (53-87% identical) than to the sheep mitochondrial branched-chain amino acid aminotransferase (52%). Sheep BCATc belongs to the IV Folding class of pyridoxal-5'-phosphate-depending enzymes. Based on the known structure of the branched-chain amino acid aminotransferase (BCAT) from Escherichia coli, a molecular model of sheep BCATc (amino acid residues 62-385) was built. This is the first three-dimensional model of any mammalian BCAT. It suggests that the enzymatic mechanism of sheep BCATc and likely of all mammalian BCAT is very similar to the mechanism of the E. coli BCAT and confirms the hypotheses regarding to the substrate binding sites of E. coli BCAT. Sheep skeletal muscle, which is the main in vivo site for transamination of branched-chain amino acids, exhibits an unique expression of BCATc.

Purification and cloning of the mitochondrial branched-chain amino acid aminotransferase from sheep placenta.

This paper presents the first purification of the mitochondrial branched-chain amino acid aminotransferase (BCATm) from sheep placenta. It is a homodimer with an apparent subunit molecular mass of 41 kDa. The enzyme differs from those of the rat and human as it appears to form at least one intermolecular disulfide bond. The sheep BCATm cDNA (1.4 kb) encodes a mature polypeptide of 366 amino acids with a calculated molecular mass of 41 329 Da and a partial mitochondrial targeting sequence of seven amino acids. The sheep BCATm sequence shares higher identity with other mammalian BCATm isoenzymes (82-85%) than with the cytosolic isoenzymes (60%). By Northern blot analysis, a message of 1.7 kb was detected in sheep placenta and skeletal muscle. Measurements of BCAT activity, mRNA and BCATm protein in sheep placenta and skeletal muscle revealed that BCATm is the sole BCAT isoenzyme expressed in placenta, whereas it contributes 57 and 71% of the BCAT activity in tensor fascia latae and masseter muscles from weaned lambs respectively. Skeletal muscle, the main site of branched-chain amino acid transamination, exhibits significantly lower BCAT activity in sheep than in rat. Our results suggest that the low BCATm mRNA level probably accounts for the low BCAT activity in sheep skeletal muscle, and that the metabolic scheme for branched-chain amino acid catabolism is specific to each species.

The effect of a high dose of 3-hydroxy-3-methylbutyrate on protein metabolism in growing lambs.

The effect of a high dose of 3-hydroxy-3-methylbutyrate (HMB, a leucine catabolite) on protein metabolism was investigated in growing male lambs fed on hay and concentrate. Concentrate was supplemented with either Ca(HMB)2 (4 g/kg) or Ca(CO3)2 in experimental (HMB) and control groups respectively. Both groups consisted of six 2-month old lambs. Three complementary methods to study protein metabolism were carried out consecutively 2.5 months after beginning the dietary treatment: whole body phenylalanine fluxes, postprandial plasma free amino acid time course and fractional rates of protein synthesis in skeletal muscles. Feeding a high dose of HMB led to a significant increase in some plasma free amino acids compared with controls. Total, oxidative and non-oxidative phenylalanine fluxes were not modified by dietary HMB supplementation. Similarly, an acute infusion of HMB, in the control group, did not change these fluxes. In skeletal muscles, fractional rates of protein synthesis were not affected by long-term dietary supplementation with HMB. Taken together our results showed that administration of a high dose of HMB to lambs was able to modify plasma free amino acid pattern without any effect on whole-body protein turnover and skeletal muscle protein synthesis.

Leucine metabolism in lactating and dry goats: effect of insulin and substrate availability.

Early lactating goats show insulin resistance with respect to extramammary glucose utilization. However, much less is known about the two major factors, insulin and plasma amino acid concentration, that regulate protein metabolism in lactating goats. To examine this question, the in vivo effect of acute insulin was studied in goats during early lactation (12-31 days postpartum), midlactation (98-143 days postpartum), and the dry period (approximately 1 yr postpartum). Insulin was infused (at 0.36 or 1.79 nmol/min) under euglycemic and eukaliemic clamps. In addition, appropriate amino acid infusion was used to blunt insulin-induced hypoaminoacidemia or to create hyperaminoacidemia and maintain this condition under insulin treatment. Leucine kinetics were assessed using a primed continuous infusion of L-[1-14C]-leucine, which started 2.5 h before insulin. In all animals the insulin treatments failed to stimulate the nonoxidative leucine disposal (an estimate of whole body protein synthesis) under both euaminoacidemic and hyperaminoacidemic conditions. Thus, in goat as well as humans, infusion of insulin fails to stimulate protein synthesis even when combined with a substantially increased provision of amino acids. In contrast, insulin treatments caused a dose-dependent inhibition of the endogenous leucine appearance (an estimate of whole body protein degradation). Under euaminoacidemia the initial slope from the plot of the endogenous leucine appearance as a function of plasma insulin (an insulin sensitivity index) was steeper during early lactation than when compared with the dry period. A similar trend occurred during midlactation but not to any significant degree. These differences were abolished under hyperaminoacidemia. It was concluded that the ability of physiological insulin to inhibit protein degradation was improved during lactation, demonstrating a clear-cut dissociation between the effects of insulin on protein and glucose metabolism. This adaptation no doubt may provide a mechanism to save body protein.

Leucine excess under conditions of low or compensated aminoacidemia does not change skeletal muscle and whole-body protein synthesis in suckling lambs during postprandial period.

We determined the effect of a 4-h leucine infusion, leading to 15-fold elevated plasma leucine concentrations, on skeletal muscle and whole-body protein synthesis in suckling lambs during the postprandial period. The [3H]phenylalanine large dose method was validated and used to quantify the fractional rates of protein synthesis (Ks in %/d) at the end of the leucine infusion. In the first experiment leucine infusion lowered plasma amino acid concentrations but did not change the Ks, the capacity for protein synthesis (Cs, mg RNA/g protein) or the efficiency of translation [g protein synthesized/(d-g RNA)] in any muscles studied or the whole body. In the second experiment the leucine-induced decreases in plasma amino acid concentrations were compensated by the simultaneous infusion of substantial amounts of amino acids. Again leucine excess did not significantly change Ks, Cs and efficiency of protein synthesis. These results indicated that leucine excess in suckling lambs during the postprandial period lowered aminoacidemia without any change of the protein synthesis rates in skeletal muscles or the whole body.

Regulation of branched chain amino acid metabolism in ruminants.

The regulation of branched-chain amino acid (BCAA) metabolism has been studied in ruminants mainly during the last decade. Evidences support that the rate of BCAA catabolism is lower in ruminants than in monogastrics. This is associated with a low specific BCAA aminotransferase (first catabolic enzyme) activity and a relatively low degree of activation of the second catabolic enzyme in post-natal ruminant tissues. Similarly to monogastrics in vivo BCAA catabolism involves an interorgan cooperation in ruminants. The benefic effect of leucine excess in protein turnover has also been raised. By contrast leucine excess does not stimulate the rate of isoleucine and valine catabolism in ruminants as much as in monogastrics.

Influence of dietary leucine content on the activities of branched-chain amino acid aminotransferase (EC 2.6.1.42) and branched-chain alpha-keto acid dehydrogenase (EC 1.2.4.4) complex in tissues of preruminant lambs.

1. Branched-chain amino acid aminotransferase (EC 2.6.1.42; BCAAT) and branched-chain alpha-keto acid dehydrogenase (EC 1.2.4.4; BCKDH) activities were measured preruminant lamb liver, longissimus dorsi muscle, kidney, jejunum and adipose tissue, 2 h after a meal with or without an excess of leucine. 2. Skeletal muscle contained about 70% of the total basal BCAAT activities of the tissues studied whereas liver contained about 60% of the total BCKDH activities of these tissues. 3. BCAAT activities were very low in preruminant lamb tissues. BCKDH was more phosphorylated in tissues of preruminant lambs than in rats, especially in liver. These low catalytic potentialities might contribute to a low rate of branched-chain amino acid catabolism in sheep. 4. Ingestion of an excess of leucine led to an increase in liver and jejunum BCAAT activities and activation of BCKDH in jejunum.

Nutritional and metabolic effects of dietary leucine excess in preruminant lamb.

The effects of excess leucine intake on food intake, branched-chain amino acid and branched-chain alpha-keto acid concentrations in plasma and nitrogen retention were investigated in the preruminant lamb. Lambs were fed leucine in excess in either an adequate protein diet [24% of dry matter (DM)] or a low protein diet (15% DM) for 2 d. Increasing the dietary leucine content of 2.3 to 10.6 or 12.6% DM led to a significant decrease in food intake. This depressing effect was not influenced by dietary protein content. Increasing the dietary leucine content from 2.3 to 6.4% DM in an adequate protein diet for a week did not significantly improve nitrogen retention in the preruminant lamb. Plasma leucine and its alpha-keto acid concentrations increased with leucine intake. Plasma valine and isoleucine concentrations were significantly decreased only in lambs fed the highest excess leucine diet. Surprisingly, a maximal 50% decrease of their plasma alpha-keto acid concentrations occurred even in the group fed the lowest excess leucine diet. Our results might be explained by an inhibition of the rate of transamination of valine and isoleucine by high leucine concentration.

[Absence of effects of a dietary excess of leucine on the postprandial kinetics of plasma glucagon and cortisol in the preruminant lamb]. / Absence d'effets d'un excès alimentaire en leucine sur les cinétiques postprandiales du glucagon et du cortisol plasmatiques chez l'agneau préruminant.

Plasma concentrations of cortisol and glucagon have been measured in preruminant lambs after feeding a meal containing either 2.3 or 10.6 g leucine/100 g dry matter and were found similar. These two hormones are probably not involved in the effects induced by dietary leucine excess.