Long-term Protein Restriction Research Articles

Correlated changes in stress resistance and biochemical parameters in response to long-term protein restriction in Drosophila melanogaster

Studies in fruit flies, Drosophila melanogaster , have observed considerable variation in the effect of dietary protein restriction (PR) on various fitness traits. In addition, not only are there inconsistent results relating lifespan to stress resistance, but also the long-term effects of PR are unexplored. We study PR implementation across generations (long term) hypothesizing that it will be beneficial for fitness traits, stress resistance and storage reserves due to nutritional plasticity transferred by parents to offspring in earlier Drosophila studies. By imposing two concentrations of PR diets (50% and 70% of control protein) from the pre-adult and adult (age 1 day) stages of the flies, we assessed the stage-specific and long-term effect of the imposed PR. All long-term PR flies showed increased resistance against the tested stressors (starvation, desiccation, H 2 O 2 -induced oxidative stress). In addition, we also found long-term PR-induced increased stress resistance across generations. The PR flies also possessed higher protein and triglyceride (TG) content, reduced glucose and unaffected glycogen levels. We also assayed the effect of returning the PR flies to control (AL) food for a single generation and assessed their biochemical parameters to witness the transient PR effect. It was seen that TG content upon reversal was similar to AL flies except for PRI70 males; however, the glucose levels of PR males increased, while they were consistently lower in females. Taken altogether, our study suggests that long-term PR implementation contributes to increased stress resistance and was found to influence storage reserves in D. melanogaster .

Treatment of HMG-CoA Lyase Deficiency-Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases.

3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL) deficiency can be a very severe disorder that typically presents with acute metabolic decompensation with features of hypoketotic hypoglycemia, hyperammonemia, and metabolic acidosis. A retrospective chart and literature review of Australian patients over their lifespan, incorporating acute and long-term dietary management, was performed. Data from 10 patients contributed to this study. The index case of this disorder was lost to follow-up, but there is 100% survival in the remainder of the cases despite several having experienced life-threatening episodes. In the acute setting, five of nine patients have used 900 mg/kg/day of sodium D,L 3-hydroxybutyrate in combination with intravenous dextrose-containing fluids (delivering glucose above estimated basal utilization requirements). All patients have been on long-term protein restriction, and those diagnosed more recently have had additional fat restriction. Most patients take L-carnitine. Three children and none of the adults take nocturnal uncooked cornstarch. Of the cohort, there were two patients that presented atypically-one with fulminant liver failure and the other with isolated developmental delay. Dietary management in patients with HMGCL deficiency is well tolerated, and rapid institution of acute supportive metabolic treatment is imperative to optimizing survival and improve outcomes in this disorder.

Long-Term Protein Restriction Modulates Lipid Metabolism in White Adipose Tissues and Alters Colonic Microbiota of Shaziling Pigs.

Obesity is a matter of concern to the public. Abundant evidence has been accumulated that nutritional intervention is a promising strategy to address this health issue. The objective of this study is to investigate alterations in the lipid metabolism in white adipose tissues and the gut microbiota of Shaziling pigs challenged by long-term protein restriction. Results showed that compared with the control group, reducing the protein level by 20% (-20%) increased the mRNA abundance of FABP4 in white adipose tissues (p < 0.05). This occurred in conjunction with increases in PPARγ protein expression. Conversely, the protein expression of C/EBPα was reduced in the -20% group (p < 0.05). Moreover, the -20% group had increased/decreased phosphorylation of AMPKα/mTOR, respectively (p < 0.05). As for the colonic gut microbiota, a 20% reduction in the protein level led to increased Lachnospiraceae XPB1014 group abundance at the genus level (p < 0.01). Collectively, these results indicated that a 20% protein reduction could modulate lipid metabolism and alter the colonic microbiota of Shaziling pigs, an approach which might be translated into a treatment for obesity.

Effects of Long-Term Protein Restriction on Meat Quality and Muscle Metabolites of Shaziling Pigs.

Simple SummaryThe effects of long-term protein restriction on meat quality of Shaziling pigs and the underlying mechanism remain relatively unexplored. The aim of this study is to investigate the changes in meat quality and muscle metabolites of Shaziling pigs under the condition of low-protein diets and to provide a practical nutritional manipulation for swine production. After a 24-week trial, we found that reducing dietary crude protein by 20% led to improved meat quality (the reduced L* value and the increased a* value) and altered metabolite profiles of longissimus thoracis, without impairing growth performance and carcass traits. Moreover, results showed that the improvement on meat quality might be credited to diminished concentrations of Danazol, N,N-dimethyl-Safingol, and cer(d18:0/14:0). Our findings suggested long-term protein restriction (20% reduction) is suitable to improve meat quality and sustain growth performance.Background: It has been demonstrated that low-protein diets can improve the meat quality of pork. This study aimed to investigate the effects of long-term protein restriction from piglets to finishing pigs for 24 weeks on meat quality and muscle metabolites of Shaziling pigs. Results: Compared to the control group, reducing dietary protein levels by 20% reduced the L* value (p < 0.05), increased the a* value (p < 0.01), and tended to decrease pressing loss (p = 0.06) of longissimus thoracis muscle (LTM). Furthermore, compared to the control group, the −20% group had significantly lower levels of muscular danazol, N,N-dimethyl-Safingol, and cer(d18:0/14:0) (p < 0.05), all of which were positively associated with the L* value and negatively associated with the a* value (p < 0.05). Therefore, danazol, N,N-dimethyl-Safingol, and cer(d18:0/14:0) might be potential biomarkers for meat color. Conclusions: These results indicated that reducing dietary crude protein by 20% for 24 weeks could improve meat quality and alter muscular metabolites of Shaziling pigs, and the improvement in meat quality might be ascribable to decreased danazol, N,N-dimethyl-Safingol and cer(d18:0/14:0).

Evolution of a novel female reproductive strategy in Drosophila melanogaster populations subjected to long-term protein restriction.

Reproductive output is often constrained by availability of macronutrients, especially protein. Long-term protein restriction, therefore, is expected to select for traits maximizing reproduction even under nutritional challenge. We subjected four replicate populations of Drosophila melanogaster to a complete deprivation of yeast supplement, thereby mimicking a protein-restricted ecology. Following 24 generations, compared to their matched controls, females from experimental populations showed increased reproductive output early in life, both in presence and absence of yeast supplement. The observed increase in reproductive output was without associated alterations in egg size, development time, preadult survivorship, body mass at eclosion, and life span of the females. Further, selection was ineffective on lifelong cumulative fecundity. However, females from experiment regime were found to have a significantly faster rate of reproductive senescence following the attainment of the reproductive peak early in life. Therefore, adaptation to yeast deprivation ecology in our study involved a novel reproductive strategy whereby females attained higher reproductive output early in life followed by faster reproductive aging. To the best of our knowledge, this is one of the cleanest demonstrations of optimization of fitness by fine-tuning of reproductive schedule during adaptation to a prolonged nutritional deprivation.

FGF21 prevents low-protein diet-induced renal inflammation in aged mice.

Low-protein (LP) diets extend lifespan through a comprehensive improvement in metabolic health across multiple tissues and organs. Many of these metabolic responses to protein restriction are secondary to transcriptional activation and release of FGF21 from the liver. However, the effects of an LP diet on the kidney in the context of aging has not been examined. Therefore, the goal of the current study was to investigate the impact of chronic consumption of an LP diet on the kidney in aging mice lacking FGF21. Wild-type (WT; C57BL/6J) and FGF21 knockout (KO) mice were fed a normal protein diet (20% casein) or an LP (5% casein) diet ad libitum from 3 to 22 mo of age. The LP diet led to a decrease in kidney weight and urinary albumin-to-creatinine ratio in both WT and FGF21 KO mice. Although the LP diet produced only mild fibrosis and infiltration of leukocytes in WT kidneys, the effects were significantly exacerbated by the absence of FGF21. Accordingly, transcriptomic analysis showed that inflammation-related pathways were significantly enriched and upregulated in response to LP diet in FGF21 KO mice but not WT mice. Collectively, these data demonstrate that the LP diet negatively affected the kidney during aging, but in the absence of FGF21, the LP diet-induced renal damage and inflammation were significantly worse, indicating a protective role of FGF21 in the kidney.NEW & NOTEWORTHY Long-term protein restriction is not advantageous for an otherwise healthy, aging kidney, as it facilitates the development of renal tubular injury and inflammatory cell infiltration. We provide evidence using FGF21 knockout animals that FGF21 is essential to counteract the renal injury and inflammation during aging on a low-protein diet.

Metabolic and Proteomic Responses to Long-Term Protein Restriction in a Pig Model.

Protein restriction is associated with extended lifespan and reduced incidence and progression of multiple age-related diseases. The underlying mechanism of metabolic and proteomic responses to the long-term dietary protein restriction, however, has not been fully uncovered. The present study aimed to identify the metabolic and proteomic profiles in a low-protein diet-fed pig model. Intestinal and liver metabolomics showed that amino acid metabolism was highly associated with dietary protein restriction. Interestingly, blood was characterized by markedly higher abundances of Ser, Gly, Glu, Thr, Ala, Lys, and Met levels, and lower abundances of His, Val, and Ile levels regardless of the age of pigs from piglets to adult pigs. Amino acid transporters might contribute to the changed amino acid pools and serve as a feedback regulatory mechanism in response to protein restriction. iTRAQ-based quantitative proteomics approach identified more than 10 differently expressed proteins in protein restricted pigs and KEGG pathway analysis showed that significant enrichment of proteins involved in metabolic pathways, PI3K-Akt signaling pathway, lysosome, spliceosome, oxidative phosphorylation, phagosome, and DNA replication. Western blot analysis further confirmed that protein restriction markedly inactivated Akt and mTOR signals in pigs. This study indicates that dietary protein restriction leads to a shift in the host metabolism in a pig model, especially for amino acid metabolism. Along with proteomics, our findings unveil potential mechanisms for integrating how protein restriction modulates host metabolism.

Effects of Long-Term Protein Restriction on Meat Quality, Muscle Amino Acids, and Amino Acid Transporters in Pigs.

This study aimed to investigate the long-term effects of protein restriction from piglets to finishing pigs for 16 weeks on meat quality, muscle amino acids, and amino acid transporters. Thirty-nine piglets were randomly divided into three groups: a control (20-18-16% crude protein, CP) and two protein restricted groups (17-15-13% CP and 14-12-10% CP). The results showed that severe protein restriction (14-12-10% CP) inhibited feed intake and body weight, while moderate protein restriction (17-15-13% CP) had little effect on growth performance in pigs. Meat quality (i.e., pH, color traits, marbling, water-holding capacity, and shearing force) were tested, and the results exhibited that 14-12-10% CP treatment markedly improved muscle marbling score and increased yellowness (b*). pH value (45 min) was significantly higher in 17-15-13% CP group than that in other groups. In addition, protein restriction reduced muscle histone, arginine, valine, and isoleucine abundances and enhanced glycine and lysine concentrations compared with the control group, while the RT-PCR results showed that protein restriction downregulated amino acids transporters. Mechanistic target of rapamycin (mTOR) signaling pathway was inactivated in the moderate protein restricted group (17-15-13% CP), while severe protein restriction with dietary 14-12-10% CP markedly enhanced mTOR phosphorylation. In conclusion, long-term protein restriction affected meat quality and muscle amino acid metabolism in pigs, which might be associated with mTOR signaling pathway.

Prevention of Progression of Kidney Disease

SUMMARY OF THE EVIDENCE In summary, there is no convincing or conclusive evidencethat long-term protein restriction delays the progression ofCKD. The longest lasting, largest and best-designed RCT(MDRD study) argues against an important benefit. Fourmeta-analyses have demonstrated either a modest or sub-stantial benefit of protein-restricted diets, but three of theseused an inappropriate outcome measure (renal survival),which does not allow distinction between delay of dialysisdue to suppression of uraemic symptoms vs. slowing renalfailure progression. The only meta-analysis which used esti-mated GFR as an outcome measure found only a very weakbenefit of dietary protein restriction. It also found evidenceof possible publication bias favouring a beneficial effect oflow protein diets. The trials showed some heterogeneity andcannot substitute for properly conducted RCTs. Moreover,the possibility of a modest benefit of low-protein diets onrenal failure progression must be weighed against the risk ofa concomitant decline in nutritional parameters. Only threeof the 11 RCTs in non-diabetics have addressed the effect ofrestricted protein diets on nutrition

Age-related Reference Values for Serum Selenium Concentrations in Infants and Children

Children are at particular risk for selenium deficiency, which has potentially serious medical implications. Reliable age-specific reference values for serum selenium concentrations in children are sparse, but are essential for the identification of selenium deficiency and decisions regarding selenium supplementation. Using electrothermal atomic absorption spectrometry, we analyzed serum selenium concentrations from 1010 apparently healthy children (age range, 1 day to 18 years) and from 60 patients on a protein-restricted diet because of inborn errors of metabolism. Reference intervals were defined according to recommended guidelines. Medians for serum selenium concentrations showed a statistically significant age dependency: a decrease from the age <1 month (0.64 micromol/L) to 4 months (0.44 micromol/L); an increase to 0.62 micromol/L in the 4-12 months age group; constant values in children between 1 and 5 years of age (0.90 micromol/L); and an additional slight increase to reach a plateau between 5 and 18 years (0.99 micromol/L). Of 43 children older than 1 year and on a protein-restricted diet, 87% showed serum selenium concentrations below the 2.5 percentile. Because of nutritional changes, serum selenium concentrations are significantly higher in older children than in infants under 1 year of age. The application of age-adjusted reference values may provide more specific criteria for selenium supplementation. Long-term protein restriction in children is reflected by a failure to achieve higher serum selenium concentrations with increasing age.

Corrigendum to: IGF-I is not a useful marker for nutritional status in the growing pig under commercial conditions

Plasma hormone concentrations were measured in gilts after fasting, long-term protein restriction, or supplementation. In 11-week-old pigs fasted overnight, plasma insulin, glucagon, gastrin, urea, and glucose were increased 30 min after re-feeding (P &lt; 0.05), whereas IGF-I did not change. In 16-week-old gilts fed a standard commercial diet [14.6% crude protein (CP)], or a high-protein diet (16.7% CP) for 4 weeks, the high-protein diet increased weight gain (13%; P &lt; 0.05) and carcass weight (4%; P &lt; 0.05), but did not alter plasma IGF-I, insulin, or glucagon. In 10-week-old gilts fed high-protein diets (19.4% and 18.3% CP), or low-protein diets (15.5% and 13.3% CP) for 12 weeks during the grower and finisher phases, respectively, the low-protein diet decreased weight gain (18%; P &lt; 0.001) and carcass weight (11%; P &lt; 0.01), with a marked increase in plasma glucagon (P &lt; 0.05), no change in insulin, and only a trend towards decreased IGF-I (P = 0.1). The pigs were more sensitive to altered dietary protein at 10 weeks of age than at 16 weeks. Plasma IGF-I was not responsive to the short-term effects of feeding or the long-term effects of dietary protein. Glucagon could provide a useful marker for nutritional status in young pigs, provided that time of feeding is taken into account.

IGF-I is not a useful marker for nutritional status in the growing pig under commercial conditions

Plasma hormone concentrations were measured in gilts after fasting, long-term protein restriction, or supplementation. In 11-week-old pigs fasted overnight, plasma insulin, glucagon, gastrin, urea, and glucose were increased 30 min after re-feeding (P &lt; 0.05), whereas IGF-I did not change. In 16-week-old gilts fed a standard commercial diet [14.6% crude protein (CP)], or a high-protein diet (16.7% CP) for 4 weeks, the high-protein diet increased weight gain (13%; P &lt; 0.05) and carcass weight (4%; P &lt; 0.05), but did not alter plasma IGF-I, insulin, or glucagon. In 10-week-old gilts fed high-protein diets (19.4% and 18.3% CP), or low-protein diets (15.5% and 13.3% CP) for 12 weeks during the grower and finisher phases, respectively, the low-protein diet decreased weight gain (18%; P &lt; 0.001) and carcass weight (11%; P &lt; 0.01), with a marked increase in plasma glucagon (P &lt; 0.05), no change in insulin, and only a trend towards decreased IGF-I (P = 0.1). The pigs were more sensitive to altered dietary protein at 10 weeks of age than at 16 weeks. Plasma IGF-I was not responsive to the short-term effects of feeding or the long-term effects of dietary protein. Glucagon could provide a useful marker for nutritional status in young pigs, provided that time of feeding is taken into account.

Dietary protein restriction and the progression of chronic renal insufficiency: a review of the literature

It is well known that dietary protein restriction can delay the appearance of uraemic symptoms and give symptomatic relief in patients with chronic renal failure. During the last decade, several investigators have argued that protein restriction instituted at an early phase in renal disease may influence the rate of progression of renal failure favourably. Animal experiments have given strong evidence that, in the case of nephron loss, high dietary protein promotes further loss of renal function. Many studies have been conducted to investigate the possible favourable effect of a protein-restricted diet in patients with renal disease. However, the scientific proof that long-term protein restriction delays the progression of chronic renal insufficiency in man is still missing.

Nutritional therapy for progressive renal failure.

Results of the Diabetes Control and Complications Trial indicate that intensive insulin treatment of patients with type I diabetes would greatly reduce the incidence of diabetic nephropathy. Another multicenter trial indicates that modest protein restriction is of no value in children with chronic renal failure. The relationship between urea nitrogen excretion and total nitrogen excretion in children differs from that in adults. A repeated crossover study found that ketoacids slow progression of renal failure, in comparison with amino acid supplements to the same diet. Long-term protein restriction does not lead to protein deficiency at the onset of dialysis. When combined with essential amino acid supplements, a low-protein diet may gradually correct hypoalbuminemia in nephrotic subjects.