Association between Branched-Chain amino acids and Epilepsy: A Mendelian randomized study.

BACKGROUND: Branched-chain amino acids (BCAAs) have been affected epilepsy, yet conclusions remain inconclusive, lacking causal evidence regarding whether BCAAs affect epilepsy. Systematic exploration of the causal relationship between BCAAs and epilepsy could hand out new ideas for the treatment of epilepsy. METHODS: Utilizing bidirectional Mendelian randomization (MR) study, we investigated the causal relationship between BCAA levels and epilepsy. BCAA levels from genome-wide association studies (GWAS), including total BCAAs, leucine levels, isoleucine levels, and valine levels, were employed. Causal relationships were explored applying the method of inverse variance-weighted (IVW) and MR-Egger, followed by sensitivity analyses of the results to evaluate heterogeneity and pleiotropy. RESULTS: Through strict genetic variant selection, we find some related SNPs, total BCAA levels (9), leucine levels (11), isoleucine levels (7), and valine levels (6) as instrumental variables for our MR analysis. Following IVW and sensitivity analysis, total BCAAs levels (OR = 1.14, 95 % CI = 1.019 âˆ¼ 1.285, P = 0.022) and leucine levels (OR = 1.15, 95 % CI = 1.018 âˆ¼ 1.304, P = 0.025) had significant correlation with epilepsy. CONCLUSIONS: There exists a causal relationship between the levels of total BCAAs and leucine with epilepsy, offering the new ideas into epilepsy potential mechanisms, holding significant implications for its prevention and treatment.

Serum Branched-Chain Amino Acids and Long-Term Complications of Liver Cirrhosis: Evidence from a Population-Based Prospective Study.

BACKGROUND AND AIMS: The role of serum branched-chain amino acids (BCAAs) in long-term liver cirrhosis complication events remains unclear. We aimed to evaluate the associations between serum BCAAs and the risk of liver-related events. METHODS: We included a total of 64,005 participants without liver cirrhosis complication events at baseline from the UK Biobank. Cox proportional hazards regression models were utilized to estimate multivariable hazard ratios (HRs) and 95% CIs for the incidence of liver cirrhosis complication events, adjusting for potential confounders, including sociodemographic and lifestyle factors. Relationships between serum BCAAs and liver cirrhosis complications were examined using nonparametrically restricted cubic spline regression. RESULTS: During a median follow-up of 12.7 years, 583 participants developed liver cirrhosis complication events. The multivariable Cox regression model suggested that total BCAAs (HR = 0.88, 95% CI 0.82-0.95), serum leucine (HR = 0.88, 95% CI 0.81-0.95), serum isoleucine (HR = 0.88, 95% CI 0.82-0.96), and serum valine (HR = 0.87, 95% CI 0.82-0.96) were all independent protective factors for liver cirrhosis complications after adjustment for sociodemographic and lifestyle factors. Cox models with restricted cubic splines showed U-shaped associations between serum valine and liver cirrhosis complication incidence. Serum total BCAA and isoleucine concentrations might reduce the risk of liver cirrhosis complications by raising the risk of (type 2 diabetes mellitus) T2DM. CONCLUSION: Lower serum BCAA levels exacerbate the long-term risk of liver cirrhosis complications. Future studies should confirm these findings and identify the biological pathways of these associations.

CPT1A loss disrupts BCAA metabolism to confer therapeutic vulnerability in TP53-mutated liver cancer.

Driver genomic mutations in tumors define specific molecular subtypes that display distinct malignancy competence, therapeutic resistance and clinical outcome. Although TP53 mutation has been identified as the most common mutation in hepatocellular carcinoma (HCC), current understanding on the biological traits and therapeutic strategies of this subtype has been largely unknown. Here, we reveal that fatty acid ß oxidation (FAO) is remarkable repressed in TP53 mutant HCC and which links to poor prognosis in HCC patients. We further demonstrate that carnitine palmitoyltransferase 1 (CPT1A), the rate-limiting enzyme of FAO, is universally downregulated in liver tumor tissues, and which correlates with poor prognosis in HCC and promotes HCC progression in the de novo liver tumor and xenograft tumor models. Mechanically, hepatic Cpt1a loss disrupts lipid metabolism and acetyl-CoA production. Such reduction in acetyl-CoA reduced histone acetylation and epigenetically reprograms branched-chain amino acids (BCAA) catabolism, and leads to the accumulation of cellular BCAAs and hyperactivation of mTOR signaling. Importantly, we reveal that genetic ablation of CPT1A renders TP53 mutant liver cancer mTOR-addicted and sensitivity to mTOR inhibitor AZD-8055 treatment. Consistently, Cpt1a loss in HCC directs tumor cell therapeutic response to AZD-8055. CONCLUSION: Our results show genetic evidence for CPT1A as a metabolic tumor suppressor in HCC and provide a therapeutic approach for TP53 mutant HCC patients.

Association between Childhood Overweight and Altered Concentrations of Circulating Amino Acids.

(1) Background: Dysregulated serum amino acids (AA) are known to be associated with obesity and risk of Type 2 Diabetes (T2D) in adults, and recent studies support the same notion in the pubertal age. It is, however, unknown whether childhood overweight may already display alterations of circulating AA. (2) Methods: We used liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS)-targeted metabolomics to determine plasma concentrations of AA and AA-related molecules in 36 children aged 7-12 years with normal weight or overweight. Clinical and anthropometric parameters were measured. (3) Results: Overweight in children is associated with an altered AA profile, with increased branched-chain amino acids (BCAA) and decreased glycine levels, with no clinically manifested metabolic conditions. Moreover, z-BMI was positively and negatively correlated with BCAA and glycine levels, respectively, even after adjustment for age and gender. We also found a correlation between the AA profile and clinical parameters such as lipids profile and glycemia. (4) Conclusions: A pattern of low glycine, and increased BCAA is correlated to z-BMI, total cholesterol, and triglycerides in overweight but otherwise healthy children. Our data suggest that, in childhood overweight, AA disturbances may precede other clinical parameters, thus providing an early indicator for the later development of metabolic disease.

Targeting IGF2BP1 alleviated benzene hematotoxicity by reprogramming BCAA metabolism and fatty acid oxidation.

Benzene is the main environmental pollutant and risk factor of childhood leukemia and chronic benzene poisoning. Benzene exposure leads to hematopoietic stem and progenitor cell (HSPC) dysfunction and abnormal blood cell counts. However, the key regulatory targets and mechanisms of benzene hematotoxicity are unclear. In this study, we constructed a benzene-induced hematopoietic damage mouse model to explore the underlying mechanisms. We identified that Insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) was significantly reduced in benzene-exposed mice. Moreover, targeting IGF2BP1 effectively mitigated damages to hematopoietic function and hematopoietic molecule expression caused by benzene in mice. On the mechanics, by metabolomics and transcriptomics, we discovered that branched-chain amino acid (BCAA) metabolism and fatty acid oxidation were key metabolic pathways, and Branched-chain amino acid transaminase 1 (BCAT1) and Carnitine palmitoyltransferase 1a (CPT1A) were critical metabolic enzymes involved in IGF2BP1-mediated hematopoietic injury process. The expression of the above molecules in the benzene exposure population was also examined and consistent with animal experiments. In conclusion, targeting IGF2BP1 alleviated hematopoietic injury caused by benzene exposure, possibly due to the reprogramming of BCAA metabolism and fatty acid oxidation via BCAT1 and CPT1A metabolic enzymes. IGF2BP1 is a potential regulatory and therapeutic target for benzene hematotoxicity.

Adipocytes Are the Only Site of Glutamine Synthetase Expression Within the Lactating Mouse Mammary Gland.

Background: Glutamine in milk is believed to play an important role in neonatal intestinal maturation and immune function. For lactating mothers, glutamine utilization is increased to meet the demands of the enlarged intestine and milk production. However, the source of such glutamine during lactation has not been studied. Objectives: We aimed to assess the effects of lactation on the expression of glutamine synthetase (GS) in the mammary gland and other tissues of lactating mice. Methods: Mouse tissues were sampled at 4 time points: 8-wk-old (virgin, control), post-delivery day 5 (PD5, early lactation), PD15 (peak lactation), and involution (4 days after weaning at PD21). We examined the gene expression and protein concentrations of GS and the first 2 enzymes of branched-chain amino acid catabolism: branched-chain aminotransferase 2 (BCAT2) and branched-chain ketoacid dehydrogenase subunit E1α (BCKDHA). Results: The messenger RNA (mRNA) expression and protein concentrations of GS in mammary glands were significantly lower at PD5 and PD15 compared with the control but were restored at involution. Within the mammary gland, GS protein was only detected in adipocytes with no evidence of presence in mammary epithelial cells. Compared with the control, mRNA and protein concentrations of BCAT2 and BCKDHA in mammary glands significantly decreased during lactation and involution. No changes in GS protein concentrations during lactation were found in the liver, skeletal muscle, and lung. In non-mammary adipose tissue, GS protein abundance was higher during lactation compared with the virgin. Conclusions: This work shows that, within the mouse mammary gland, GS is only expressed in adipocytes and that the relative GS abundance in mammary gland sections is lower during lactation. This suggests that mammary adipocytes may be a site of glutamine synthesis in the lactating mouse. Identifying the sources of glutamine production during lactation is important for optimizing milk glutamine concentration to enhance neonatal and maternal health.

Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency.

Branched chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a recently described inherited neurometabolic disorder of branched chain amino acid (BCAA) metabolism implying increased BCAA catabolism. It has been hypothesized that a severe reduction in systemic BCAA levels underlies the disease pathophysiology, and that BCAA supplementation may ameliorate disease phenotypes. To test this hypothesis, we characterized a recent mouse model of BCKDK deficiency and evaluated the efficacy of enteral BCAA supplementation in this model. Surprisingly, BCAA supplementation exacerbated neurodevelopmental deficits and did not correct biochemical abnormalities despite increasing systemic BCAA levels. These data suggest that aberrant flux through the BCAA catabolic pathway, not just BCAA insufficiency, may contribute to disease pathology. In support of this conclusion, genetic re-regulation of BCAA catabolism, through Dbt haploinsufficiency, partially rescued biochemical and behavioral phenotypes in BCKDK deficient mice. Collectively, these data raise into question assumptions widely made about the pathophysiology of BCKDK insufficiency and suggest a novel approach to develop potential therapies for this disease.

Transcriptomics and UHPLC-QQQ-MS analyses reveal the dysregulation of branched chain amino acids metabolism in renal fibrotic rats.

The dysregulated levels of branched chain amino acids (BCAA) contribute to renal fibrosis in chronic kidney disease (CKD), yet specific analysis of BCAA contents and how they are regulated still remain unclear. It is therefore of great scientific interest to understand BCAA catabolism in CKD and develop a sensitive method for simultaneous determination of individual BCAA and their metabolites branched chain α-ketoacids (BCKA). In this work, the important role of BCAA metabolism that drives renal fibrosis in the process of CKD was first revealed by using transcriptomics. The key target genes controlling BCAA metabolism were then validated, that is, mRNA levels of BCKDHA and BCKDHB, the regulating rate-limiting enzymes during BCAA metabolism were abnormally reduced by quantitative PCR (qPCR), and a similar drop-off trend of protein expression of BCKDH, HIBCH and MCCC2 that are closely related to BCAA metabolism was also confirmed by western blotting. Furthermore, we established a novel strategy that simultaneously determines 6 individual BCAA and BCKA in serum and tissue. The method based on dansylhydrazine derivatization and ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry (UHPLC-QQQ-MS) achieved to simultaneously determine the contents of BCAA and BCKA, which is efficient and stable. Compared with normal rats, levels of BCAA including leucine, isoleucine and valine in serum and kidney of CKD rats was decreased, while BCKA including α-ketoisocaproic acid, α-ketomethylvaleric acid and α-ketoisovaleric acid was increased. Together, these findings revealed the abnormality of BCAA metabolism in driving the course of kidney fibrosis and CKD. Our current study sheds new light on changes in BCAA metabolism during CKD, and may facilitate development of drugs to treat CKD and renal fibrosis.

Chilean Market Protein Shakes Composition.

Understanding the nutritional content of protein supplements is crucial for optimal nutritional planning among athletes and other people. Distribution of macronutrients and aminograms in the main products available in the national Chilean market remains unknown. A descriptive cross-sectional study was conducted to identify the main protein supplements available in the Chilean market. Information on macronutrients and aminograms from the nutritional labels of each product was extracted. The analysis considered the content per portion and per 100 g. Cluster analysis models and graphical representations were explored. Eighty protein shakes were assessed in the Santiago de Chile market. The median protein dosage was 32 g (range from 25 to 52), and the median energy value stood at 390 kcal (range from 312 to 514). The median protein content per 100 g of product was found to be 75 g (range from 42.5 to 97.2). The combined median concentration of amino acids was 4749.75 mg. Among these, the essential amino acid L-Tryptophan exhibited the lowest concentration at 1591.50 mg, while the conditional amino acid L-Glutamine had the highest median concentration at 17,336 mg. There was a significant prevalence of animal-derived products, placing specific emphasis on protein supplements that feature elevated levels of the amino acids L-Glutamine and L-Leucine.

The 8:1:1 Supplementation of Branched-Chain Amino Acids in High-Intensity Training: A Case Study of the Protective Effect on Rhabdomyolysis.

INTRODUCTION: The increasing prevalence of high-intensity sports activities, notably the burgeoning popularity of CrossFit, underscores the contemporary significance of such physical pursuits. The discernible protective impact of branched-chain amino acids on muscle fatigue and injuries is emerging as a noteworthy area of investigation. Within the realm of sports, integrating BCAA supplementation into dietary practices holds promise for aiding athletes in their recovery, particularly in mitigating Delayed-Onset Muscle Soreness. METHODOLOGY: This study adopted an experimental pilot design with repeated measures, employing a controlled and randomized approach through double-blind procedures. The participant engaged in high-intensity activity, specifically the CrossFit Karen® test, which entailed executing 150 wall ball throws (9 kg) to a height of 3 m. The trial incorporated three randomized supplementation conditions: BCAAs in an 8:1:1 ratio or a 2:1:1 ratio or a placebo condition. The participant consumed 15 g daily for 7 days, commencing 72 h prior to the initial blood sample and the first Karen® test. RESULTS: In this study, BCAA supplementation at an 8:1:1 ratio demonstrated a discernible protective effect against muscular damage, as evidenced by creatine kinase values and ratings of perceived exertion.

Improvement of branched-chain amino acid production by isolated high-producing protease from Bacillus amyloliquefaciens NY130 on isolated soy/whey proteins and their muscle cell protection.

Branched-chain amino acids (BCAAs) are vital components of human and animal nutrition that contribute to the building blocks of proteins. In this study, 170 protease-producing strains were isolated and screened from soy-fermented foods. Bacillus amyloliquefaciens NY130 was obtained from Cheonggukjang with high production of BCAAs. Optimal production of protease from B. amyloliquefaciens NY130 (protease NY130) was achieved at 42 °C and pH 6.0 for 21 h. It was purified and determined as 27- and 40 kDa. Protease NY130 showed maximum activity at pH 9.0 and 45 °C with Km value of 10.95 mg for ISP and 1.69 mg for WPI. Protease-treated ISP and WPI showed increased sweetness and saltiness via electronic tongue analysis and enhanced the protective effect against oxidative stress in C2C12 myocytes by increasing p-mTOR/mTOR protein expression to 160%. This work possesses potential in producing BCAAs by using protease for utilization in food.

BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been associated with the host dysmetabolism of branched-chain amino acids (BCAAs), however, the implications for the role of BCAA metabolism in PDAC development or progression are not clear. The mitochondrial catabolism of valine, leucine, and isoleucine is a multistep process leading to the production of short-chain R-CoA species. They can be subsequently exported from mitochondria as short-chain carnitines (SC-CARs), utilized in anabolic pathways, or released from the cells. METHODS: We examined the specificities of BCAA catabolism and cellular adaptation strategies to BCAA starvation in PDAC cells in vitro. We used metabolomics and lipidomics to quantify major metabolic changes in response to BCAA withdrawal. Using confocal microscopy and flow cytometry we quantified the fluorescence of BODIPY probe and the level of lipid droplets (LDs). We used BODIPY-conjugated palmitate to evaluate transport of fatty acids (FAs) into mitochondria. Also, we have developed a protocol for quantification of SC-CARs, BCAA-derived metabolites. RESULTS: Using metabolic profiling, we found that BCAA starvation leads to massive triglyceride (TG) synthesis and LD accumulation. This was associated with the suppression of activated FA transport into the mitochondrial matrix. The suppression of FA import into mitochondria was rescued with the inhibitor of the acetyl-CoA carboxylase (ACC) and the activator of AMP kinase (AMPK), which both regulate carnitine palmitoyltransferase 1A (CPT1) activation status. CONCLUSIONS: Our data suggest that BCAA catabolism is required for the import of long chain carnitines (LC-CARs) into mitochondria, whereas the disruption of this link results in the redirection of activated FAs into TG synthesis and its deposition into LDs. We propose that this mechanism protects cells against mitochondrial overload with LC-CARs and it might be part of the universal reaction to amino acid perturbations during cancer growth, regulating FA handling and storage.

Emerging drugs for the treatment of sarcopenia in cirrhosis of the liver.

INTRODUCTION: Malnutrition and sarcopenia are common and impact the prognosis in patients with liver cirrhosis. The etiology is multifactorial and includes periods of reduced caloric intake, increased catabolism and direct molecular mechanisms that inhibit muscle synthesis. Although these conditions are widely acknowledged, and there is a growing interest in their diagnosis, robust evidence regarding the treatment and reversibility of these conditions is still lacking. AREAS COVERED: We have explored the current evidence on the pharmacological treatment of sarcopenia in patients with cirrhosis. Additionally, we have searched for drugs already in use and ongoing trials for other chronic diseases. EXPERT OPINION: The current guidelines recommend the use of a protein-adequate diet and moderate physical activity for treating sarcopenia in patients with cirrhosis. Currently, robust evidence is derived only from the supplementation of Branched-Chain Amino Acids, capable of increasing muscle mass and function. There are many drugs targeting various pathways that contribute to sarcopenia. However, evidence is sporadic and insufficient to suggest their use in clinical practice.Novel drugs specifically designed to enhance muscle mass and function should be developed. Finally, gender significantly influences the type of muscle alteration and therapeutic mechanisms; therefore, future studies should be designed taking gender differences into consideration.

Differences in branched-chain amino acid to tyrosine ratio (BTR) among etiologies of chronic liver disease progression compared to healthy adults.

BACKGROUND: The branched-chain amino acids (BCAAs) to tyrosine (Tyr) ratio (BTR) test is used to evaluate the progression of chronic liver disease (CLD). However, the differences across sex, age, body mass index (BMI) and etiologies are still unclear. METHODS: We retrospectively reviewed data from 2,529 CLD cases with free amino acids (FAAs) in peripheral blood from four hospitals and 16,421 general adults with FAAs data from a biobank database. In total, 1,326 patients with CLD (covering seven etiologies) and 8,086 healthy controls (HCs) were analyzed after exclusion criteria. We investigated the change of BTR in HCs by sex, age and BMI and then compared these to patients divided by modified ALBI (mALBI) grade after propensity score matching. RESULTS: BTR is significantly higher in males than females regardless of age or BMI and decreases with aging in HCs. In 20 types of FAAs, 7 FAAs including BCAAs were significantly decreased, and 11 FAAs including Tyr were significantly increased by mALBI grade in total CLD. The decreasing timings of BTR were at mALBI grade 2b in all CLD etiologies compared to HCs, however in chronic hepatitis C (CHC), chronic hepatitis B (CHB) and alcoholic liver disease (ALD), BTR started to decrease at 2a. There was a positive correlation between BCAAs and albumin among parameters in BTR and mALBI. The correlation coefficients in PBC, ALD and MASLD were higher than those of other etiologies. CONCLUSIONS: BTR varies by sex and age even among healthy adults, and decreasing process and timing of BTR during disease progression is different among CLD etiologies.

PNPLA3 Genotype and Dietary Fat Modify Concentrations of Plasma and Fecal Short Chain Fatty Acids and Plasma Branched-Chain Amino Acids.

The GG genotype of the Patatin-like phosphatase domain-containing 3 (PNPLA3), dietary fat, short-chain fatty acids (SCFA) and branched-chain amino acids (BCAA) are linked with non-alcoholic fatty liver disease. We studied the impact of the quality of dietary fat on plasma (p) and fecal (f) SCFA and p-BCAA in men homozygous for the PNPLA3 rs738409 variant (I148M). Eighty-eight randomly assigned men (age 67.8 ± 4.3 years, body mass index 27.1 ± 2.5 kg/m2) participated in a 12-week diet intervention. The recommended diet (RD) group followed the National and Nordic nutrition recommendations for fat intake. The average diet (AD) group followed the average fat intake in Finland. The intervention resulted in a decrease in total p-SCFAs and iso-butyric acid in the RD group (p = 0.041 and p = 0.002). Valeric acid (p-VA) increased in participants with the GG genotype regardless of the diet (RD, 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.005 and AD, 3.8 ± 0.3 to 9.7 ± 8.5 µmol/g, p = 0.015). Also, genotype relation to p-VA was seen statistically significantly in the RD group (CC: 3.7 ± 0.4 to 4.2 ± 1.7 µmol/g and GG: 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.0026 for time and p = 0.004 for time and genotype). P-VA, unlike any other SCFA, correlated positively with plasma gamma-glutamyl transferase (r = 0.240, p = 0.025). Total p-BCAAs concentration changed in the AD group comparing PNPLA3 CC and GG genotypes (CC: 612 ± 184 to 532 ± 149 µmol/g and GG: 587 ± 182 to 590 ± 130 µmol/g, p = 0.015 for time). Valine decreased in the RD group (p = 0.009), and leucine decreased in the AD group (p = 0.043). RD decreased total fecal SCFA, acetic acid (f-AA), and butyric acid (f-BA) in those with CC genotype (p = 0.006, 0.013 and 0.005, respectively). Our results suggest that the PNPLA3 genotype modifies the effect of dietary fat modification for p-VA, total f-SCFA, f-AA and f-BA, and total p-BCAA.

Branched-Chain Amino Acids Supplementation and Post-Exercise Recovery: An Overview of Systematic Reviews.

Objective: This overview of systematic reviews (OoSRs) aimed, firstly, to systematically review, summarize, and appraise the findings of published systematic reviews with or without meta-analyses that investigate the effects of branched-chain amino acids (BCAA) on post-exercise recovery of muscle damage biomarkers, muscle soreness, and muscle performance. The secondary objective was to re-analyze and standardize the results of meta-analyses using the random-effects Hartung-Knapp-Sidik-Jonkman (HKSJ) method.Methods: The methodological quality of the reviews was assessed using A Measurement Tool to Assess Systematic Reviews 2.We searched on five databases (i.e., PubMed, Web of Science, Scopus, SPORTDiscus, ProQuest) for systematic reviews with or without meta-analyses that investigated the effects of BCAA supplementation on the post-exercise recovery of muscle damage biomarkers, muscle soreness, and muscle performance.Results: Eleven systematic reviews (seven with meta-analyses) of individual studies were included. Evidence suggests BCAA ingestion attenuates creatine kinase (CK) levels (medium effects) and muscle soreness (small effects) immediately post-exercise and accelerates their recovery process, with trivial-to-large effects for CK levels and small-to-large effects for muscle soreness. BCAA supplementation has no effect on lactate dehydrogenase, myoglobin, and muscle performance recovery. The re-analyses with HKSJ method using the original data reported a slight change in results significance, concluding the same evidence as the original results. The major flaws found in the analyzed reviews were the absence of justification for excluding studies, and the lack of provision of sources of funding for primary studies and sources of conflict of interest and/or funding description.Conclusions: BCAA supplementation is an effective method to reduce post-exercise muscle damage biomarkers, particularly CK levels, and muscle soreness, with no effect on muscle performance. Future systematic reviews with/without meta-analyses, with greater methodological rigor, are needed.

This is the first overview of systematic reviews investigating the impact of BCAA supplementation on muscle damage biomarkers, muscle soreness, and muscle performance post-exercise recovery.BCAA supplementation reduces creatine kinase levels and muscle soreness, especially when consuming a high dose of BCAA longitudinally.BCAA supplementation has no effect on muscle performance post-exercise recovery.

Late-life isoleucine restriction promotes physiological and molecular signatures of healthy aging.

In defiance of the paradigm that calories from all sources are equivalent, we and others have shown that dietary protein is a dominant regulator of healthy aging. The restriction of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan when initiated in young or adult mice. However, many interventions are less efficacious or even deleterious when initiated in aged animals. Here, we investigate the physiological, metabolic, and molecular consequences of consuming a diet with a 67% reduction of all amino acids (Low AA), or of isoleucine alone (Low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. We find that both diet regimens effectively reduce adiposity and improve glucose tolerance, which were benefits that were not mediated by reduced calorie intake. Both diets improve specific aspects of frailty, slow multiple molecular indicators of aging rate, and rejuvenate the aging heart and liver at the molecular level. These results demonstrate that Low AA and Low Ile diets can drive youthful physiological and molecular signatures, and support the possibility that these dietary interventions could help to promote healthy aging in older adults.

The role of dopamine in visual imagery-An experimental pharmacological study.

Mental imagery enables people to simulate experiences in their minds without the presence of an external stimulus. The underlying biochemical mechanisms are poorly understood but there is vague evidence that dopamine may play a significant role. A better understanding at the biochemical level could help to unravel the mechanisms of mental imagery and related phenomena such as aphantasia (= lack of voluntary mental imagery), but also opens up possibilities for interventions to enhance or restore mental imagery. To test the hypothesis that acute dopamine depletion leads to a decrease in the strength of mental imagery, N = 22 male participants will be administered an amino acid mixture containing branched-chain amino acids (BCAAs) and tryptophan (TRP) to transiently reduce dopamine synthesis and further N = 22 male participants will receive a placebo. Plasma prolactin (PRL) levels are determined as a peripheral marker of brain dopamine function. The strength of mental imagery will be measured before and after ingestion of the BCAA/TRP mixture using the method of mental imagery priming. Additional exploratory analyses will use genetic data to investigate possible effects of variations on dopaminergic gene loci (e.g., DAT1) on dopamine levels and strength of mental imagery. The results show […].

Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.

The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.

Functional profile of oral plaque microbiome: Further insight into the bidirectional relationship between type 2 diabetes and periodontitis.

Increasing evidence support the association between the oral microbiome and human systemic diseases. This association may be attributed to the ability of many oral microbes to influence the inflammatory microenvironment. Herein, we focused our attention on the bidirectional relationship between periodontitis and type 2 diabetes using high-resolution whole metagenomic shotgun analysis to explore the composition and functional profile of the subgingival microbiome in diabetics and non-diabetics subjects with different periodontal conditions. In the present study, the abundance of metabolic pathways encoded by oral microbes was reconstructed from the metagenome, and we identified a set of dysregulated metabolic pathways significantly enriched in the periodontitis and/or diabetic patients. These pathways were mainly involved in branched and aromatic amino acids metabolism, fatty acid biosynthesis and adipocytokine signaling pathways, ferroptosis and iron homeostasis, nucleotide metabolism, and finally in the peptidoglycan and lipopolysaccharides synthesis. Overall, the results of the present study provide evidence in favor of the hypothesis that during the primary inflammatory challenge, regardless of whether it is induced by periodontitis or diabetes, endotoxemia and/or the release of inflammatory cytokines cause a change in precursor and/or in circulating innate immune cells. Dysbiosis and inflammation, also via oral-gut microbiome axis or adipose tissue, reduce the efficacy of the host immune response, while fueling inflammation and can induce that metabolic/epigenetic reprogramming of chromatin accessibility of genes related to the immune response. Moreover, the presence of an enhanced ferroptosis and an imbalance in purine/pyrimidine metabolism provides new insights into the role of ferroptotic death in this comorbidity.