Impact of a Whole-Food, High-Soluble Fiber Diet on the Gut-Muscle Axis in Aged Mice.

Previous studies have identified a role for the gut microbiome and its metabolic products, short-chain fatty acids (SCFAs), in the maintenance of muscle mass and physical function (i.e., the gut-muscle axis), but interventions aimed at positively impacting the gut-muscle axis during aging are sparse. Gut bacteria ferment soluble fiber into SCFAs, and accordingly, to evaluate the impact of a high-soluble-fiber diet (HSFD) on the gut-muscle axis, we fed a whole-food, 3×-higher-soluble fiber-containing diet (relative to standard chow) to aged (98 weeks) C57BL/6J mice for 10 weeks. The HSFD significantly altered gut bacterial community structure and composition, but plasma SCFAs were not different, and a positive impact on muscle-related measures (when normalized to body weight) was not identified. However, when evaluating sex differences between dietary groups, female (but not male) HSFD-fed mice had significant increases for SCFAs, the quadriceps/body weight (BW) ratio, and treadmill work performance (distance run × BW), which suggests that an HSFD can positively impact the gut-muscle axis. In contrast, consistent effects in both male and female HSFD-fed mice included weight and fat loss, which suggests a positive role for an HSFD on the gut-adipose axis in aged mice.

Model organism life extending therapeutics modulate diverse nodes in the drug-gene-microbe tripartite human longevity interactome.

Advances in antiaging drug/lead discovery in animal models constitute a large body of literature on novel senotherapeutics and geroprotectives. However, with little direct evidence or mechanism of action in humans-these drugs are utilized as nutraceuticals or repurposed supplements without proper testing directions, appropriate biomarkers, or consistent in-vivo models. In this study, we take previously identified drug candidates that have significant evidence of prolonging lifespan and promoting healthy aging in model organisms, and simulate them in human metabolic interactome networks. Screening for drug-likeness, toxicity, and KEGG network correlation scores, we generated a library of 285 safe and bioavailable compounds. We interrogated this library to present computational modeling-derived estimations of a tripartite interaction map of animal geroprotective compounds in the human molecular interactome extracted from longevity, senescence, and dietary restriction-associated genes. Our findings reflect previous studies in aging-associated metabolic disorders, and predict 25 best-connected drug interactors including Resveratrol, EGCG, Metformin, Trichostatin A, Caffeic Acid and Quercetin as direct modulators of lifespan and healthspan-associated pathways. We further clustered these compounds and the functionally enriched subnetworks therewith to identify longevity-exclusive, senescence-exclusive, pseudo-omniregulators and omniregulators within the set of interactome hub genes. Additionally, serum markers for drug-interactions, and interactions with potentially geroprotective gut microbial species distinguish the current study and present a holistic depiction of optimum gut microbial alteration by candidate drugs. These findings provide a systems level model of animal life-extending therapeutics in human systems, and act as precursors for expediting the ongoing global effort to find effective antiaging pharmacological interventions.Communicated by Ramaswamy H. Sarma.

A metabolomic signature of the APOE2 allele.

With the goal of identifying metabolites that significantly correlate with the protective e2 allele of the apolipoprotein E (APOE) gene, we established a consortium of five studies of healthy aging and extreme human longevity with 3545 participants. This consortium includes the New England Centenarian Study, the Baltimore Longitudinal Study of Aging, the Arivale study, the Longevity Genes Project/LonGenity studies, and the Long Life Family Study. We analyzed the association between APOE genotype groups E2 (e2e2 and e2e3 genotypes, N = 544), E3 (e3e3 genotypes, N = 2299), and E4 (e3e4 and e4e4 genotypes, N = 702) with metabolite profiles in the five studies and used fixed effect meta-analysis to aggregate the results. Our meta-analysis identified a signature of 19 metabolites that are significantly associated with the E2 genotype group at FDR < 10%. The group includes 10 glycerolipids and 4 glycerophospholipids that were all higher in E2 carriers compared to E3, with fold change ranging from 1.08 to 1.25. The organic acid 6-hydroxyindole sulfate, previously linked to changes in gut microbiome that were reflective of healthy aging and longevity, was also higher in E2 carriers compared to E3 carriers. Three sterol lipids and one sphingolipid species were significantly lower in carriers of the E2 genotype group. For some of these metabolites, the effect of the E2 genotype opposed the age effect. No metabolites reached a statistically significant association with the E4 group. This work confirms and expands previous results connecting the APOE gene to lipid regulation and suggests new links between the e2 allele, lipid metabolism, aging, and the gut-brain axis.

In silico insights into potential gut microbial modulation of NAD+ metabolism and longevity.

Recent evidence has prompted the notion of gut-microbial signatures as an indirect marker of aging and aging-associated decline in humans. However, the underlying host-symbiont molecular interactions contributing to these signatures remain poorly understood. In this study, we address this gap using cheminformatic analyses to elucidate potential gut microbial metabolites that may perturb the longevity-associated NAD+ metabolic network. In silico ADMET, KEGG interaction analysis, molecular docking, molecular dynamics simulation, and molecular mechanics calculation predict a large number of safe and bioavailable microbial metabolites to be direct and/or indirect activators of NAD+-dependent sirtuin proteins. Our simulation results suggest dihydropteroate, phenylpyruvic acid, indole-3-propionic acid, phenyllactic acid, all-trans-retinoic acid, and multiple deoxy-, methyl-, and cyclic nucleotides from intestinal microbiota as the best-performing regulators of NAD+ metabolism. Retracing these molecules to their source microorganisms also suggest commensal Escherichia, Bacteroides, Bifidobacteria, and Lactobacilli to be associated with the highest number of pro-longevity metabolites. These findings from our early-stage study, therefore, provide an informatics-based context for previous evidence in the area and grant novel insights for future clinical investigation intersecting anti-aging drug discovery, probiotics, and gut microbial signatures.

Self-reported sleep quality is associated with gut microbiome composition in young, healthy individuals: a pilot study.

OBJECTIVES: The microbiota-gut-brain axis is an intricate communication network that is emerging as a key modulator of psychological and physiological wellbeing. Recent pioneering work in the field has suggested a possible link between gut microbiome composition with sleep, an evolutionarily conserved behavior demonstrated to play a critical role in health. This study is the first to address relationships between self-reported sleep habits and gut microbiome composition in young, healthy individuals. METHODS: A total of 28 young, healthy subjects (17 males/11 females; 29.8 ± 10.4 years) that were free of metabolic or cardiovascular disease, and that did not take sleep medication or antibiotics within the past six months were included in the study. Relationships between self-reported sleep quality, obtained using the Pittsburgh Sleep Quality Index (PSQI), with microbial diversity (Shannon Index), the Firmicutes/Bacteroidetes (F/B) ratio, and select bacterial taxa were assessed. RESULTS: Alpha diversity (r = -0.50) and F/B ratio (r = -0.47) were inversely associated (P < 0.05) with the PSQI score. Ten bacterial taxa were associated (P < 0.05) with the PSQI score, including genus-level Blautia (r = -0.57), Ruminococcus (r = -0.39), and Prevotella (r = 0.39). CONCLUSIONS: In young healthy individuals, self-reported sleep quality was positively associated with microbial diversity. We also observed a positive association between sleep quality with F/B ratio, seemingly due to a greater relative abundance of Blautia and Ruminococcus (Firmicutes) and lower proportions of Prevotella (Bacteroidetes) in individuals reporting superior sleep quality. Future studies are encouraged to evaluate mechanistic links between the gut microbiome with sleep, as well as the health implications of this relationship.

Superoxide-mediated oxidative stress accelerates skeletal muscle atrophy by synchronous activation of proteolytic systems.

The maintenance of skeletal muscle mass depends on the overall balance between the rates of protein synthesis and degradation. Thus, age-related muscle atrophy and function, commonly known as sarcopenia, may result from decreased protein synthesis, increased proteolysis, or simultaneous changes in both processes governed by complex multifactorial mechanisms. Growing evidence implicates oxidative stress and reactive oxygen species (ROS) as an essential regulator of proteolysis. Our previous studies have shown that genetic deletion of CuZn superoxide dismutase (CuZnSOD, Sod1) in mice leads to elevated oxidative stress, muscle atrophy and weakness, and an acceleration in age-related phenotypes associated with sarcopenia. The goal of this study is to determine whether oxidative stress directly influences the acceleration of proteolysis in skeletal muscle of Sod1-/- mice as a function of age. Compared to control, Sod1-/- muscle showed a significant elevation in protein carbonyls and 3-nitrotyrosine levels, suggesting high oxidative and nitrosative protein modifications were present. In addition, age-dependent muscle atrophy in Sod1-/- muscle was accompanied by an upregulation of the cysteine proteases, calpain, and caspase-3, which are known to play a key role in the initial breakdown of sarcomeres during atrophic conditions. Furthermore, an increase in oxidative stress-induced muscle atrophy was also strongly coupled with simultaneous activation of two major proteolytic systems, the ubiquitin-proteasome and lysosomal autophagy pathways. Collectively, our data suggest that chronic oxidative stress in Sod1-/- mice accelerates age-dependent muscle atrophy by enhancing coordinated activation of the proteolytic systems, thereby resulting in overall protein degradation.

Muscle strength is increased in mice that are colonized with microbiota from high-functioning older adults.

Evidence in support of a gut-muscle axis has been reported in rodents, but studies in older adult humans are limited. Accordingly, the primary goals of the present study were to compare gut microbiome composition in older adults that differed in terms of the percentage of whole body lean mass and physical functioning (high-functioning, HF, n = 18; low-functioning, LF, n = 11), and to evaluate the causative role of the gut microbiome on these variables by transferring fecal samples from older adults into germ-free mice. Family-level Prevotellaceae, genus-level Prevotella and Barnesiella, and the bacterial species Barnesiella intestinihominis were higher in HF older adults at the initial study visit, at a 1-month follow-up visit, in HF human fecal donors, and in HF-colonized mice, when compared with their LF counterparts. Grip strength was significantly increased by 6.4% in HF-, when compared with LF-colonized mice. In contrast, despite significant differences for the percentage of whole body lean mass and physical functioning when comparing the human fecal donors, the percentage of whole body lean mass and treadmill endurance capacity were not different when comparing human microbiome-containing mice. In sum, these data suggest a role for gut bacteria on the maintenance of muscle strength, but argue against a role for gut bacteria on the maintenance of the percentage of whole body lean mass or endurance capacity, findings that collectively add to elucidation of the gut-muscle axis in older adults.

The Role of the Gut Microbiome on Skeletal Muscle Mass and Physical Function: 2019 Update.

Within the past year, several studies have reported a positive role for the gut microbiome on the maintenance of skeletal muscle mass, evidence that contrasts previous reports of a negative role for the gut microbiome on the maintenance of whole body lean mass. The purpose of this mini-review is to clarify these seemingly discordant findings, and to review recently published studies that further elucidate the gut-muscle axis.

The Kidney-Gut-Muscle Axis in End-Stage Renal Disease is Similarly Represented in Older Adults.

Decreased renal function, elevated circulating levels of urea, intestinal levels of urea-degrading bacteria, and gut-derived uremic metabolites are present in end-stage renal disease (ESRD), a cohort that has reduced muscle mass and physical function, and poor muscle composition. This phenotype, defined as the kidney-gut-muscle axis, is similarly represented in older adults that do not have ESRD. The purpose of this short communication is to illuminate these findings, and to propose a strategy that can positively impact the kidney-gut-muscle axis. For example, dietary fiber is fermented by intestinal bacteria, thereby producing the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate, which affect each component of the kidney-gut-muscle axis. Accordingly, a high-fiber diet may be an important approach for improving the kidney-gut-muscle axis in ESRD and in older adults that do not have ESRD.

Gut Microbiota Contribute to Age-Related Changes in Skeletal Muscle Size, Composition, and Function: Biological Basis for a Gut-Muscle Axis.

Skeletal muscle is a highly plastic tissue that plays a central role in human health and disease. Aging is associated with a decrease in muscle mass and function (sarcopenia) that is associated with a loss of independence and reduced quality of life. Gut microbiota, the bacteria, archaea, viruses, and eukaryotic microbes residing in the gastrointestinal tract are emerging as a potential contributor to age-associated muscle decline. Specifically, advancing age is characterized by a dysbiosis of gut microbiota that is associated with increased intestinal permeability, facilitating the passage of endotoxin and other microbial products (e.g., indoxyl sulfate) into the circulation. Upon entering the circulation, LPS and other microbial factors promote inflammatory signaling and skeletal muscle changes that are hallmarks of the aging muscle phenotype. This review will summarize existing literature suggesting cross-talk between gut microbiota and skeletal muscle health, with emphasis on the significance of this axis for mediating changes in aging skeletal muscle size, composition, and function.

Metabolites related to renal function, immune activation, and carbamylation are associated with muscle composition in older adults.

Reduced skeletal muscle density in older adults is associated with insulin resistance, decreased physical function, and an increased all-cause mortality risk. To elucidate mechanisms that may underlie the maintenance of skeletal muscle density, we conducted a secondary analysis of previously published muscle composition and serum metabolomic data in 73 older adults (average age, 78y). Multivariable-adjusted linear regression was used to examine associations between 321 metabolites with muscle composition, defined as the ratio between normal density (NDM) with low density (LDM) thigh muscle cross sectional area (NDM/LDM). Sixty metabolites were significantly (p≤0.05 and q<0.30) associated with NDM/LDM. Decreased renal function and the immune response have been previously linked with reduced muscle density, but the mechanisms underlying these connections are less clear. Metabolites that were significantly associated with muscle composition were then tested for their association with circulating markers of renal function (blood urea nitrogen, creatinine, uric acid), and with the immune response (neutrophils/lymphocytes) and activation (kynurenine/tryptophan). 43 significant NDM/LDM metabolites (including urea) were co-associated with at least 1 marker of renal function; 23 of these metabolites have been previously identified as uremic solutes. The neutrophil/lymphocyte ratio was significantly associated with NDM/LDM (ß±SE: -0.3±0.1, p=0.01, q=0.04). 35 significant NDM/LDM metabolites were co-associated with immune activation. Carbamylation (defined as homocitrulline/lysine) was identified as a pathway that may link renal function and immune activation with muscle composition, as 29 significant NDM/LDM metabolites were co-associated with homocitrulline/lysine, with at least 2 markers of renal function, and with kynurenine/tryptophan. When considering that elevated urea and uremic metabolites have been linked with an increased systemic microbial burden, that antimicrobial defense can be reduced in the presence of carbamylation, and that adipocytes can promote host defense, we propose the novel hypothesis that the age-related increase in adipogenesis within muscle may be a compensatory antimicrobial response to protect against an elevated microbial burden.

Metabolites Associated With Circulating Interleukin-6 in Older Adults.

BACKGROUND: Circulating levels of the pro-inflammatory cytokine interleukin-6 (IL-6) levels are elevated in older adults, but mechanisms are unclear. In the current study, we used an untargeted metabolomic approach to develop an improved understanding about mechanisms related to circulating IL-6 in older adults. METHODS: Serum IL-6 values were log-transformed to normalize its distribution. Multivariable-adjusted linear regression was used to examine the association between 324 serum metabolites with log IL-6. Backward elimination linear regression was used to develop a metabolite predictor set representative of log IL-6. RESULTS: Thirty-six metabolites were significantly associated (p < 0.05 and q < 0.30) with log IL-6 in 73 older adults (average age, 78 years). Metabolites related to tryptophan metabolism (kynurenine, 3-indoxyl sulfate, indoleacetate, indolepropionate, C-glycosyltryptophan), infectious burden (C-glycosyltryptophan, N6-carbamoylthreonyladenosine, 1-methylurate, N-formylmethionine, N1-methyladenosine, 3-indoxyl sulfate, bilirubin (E,E), indoleacetate, γ-CEHC, N-acetylneuraminate), aryl hydrocarbon receptor activation and cytochrome P450 (CYP) 1A expression (kynurenine, 3-indoxyl sulfate, indoleacetate, N6-carbamoylthreonyladenosine, bilirubin, 1-methylurate) were positively associated, whereas metabolites related to CYP-mediated ω-oxidation (adipate, 8-hydroxyoctanoate, azelate, sebacate, undecanedioate, γ-CEHC), and peroxisome proliferator activated receptor-alpha (PPAR-α) activation (13 + 9-HODE, bilirubin, 5-oxoproline, cholesterol, glycerate, uridine) were negatively associated with log IL-6. The use of backward elimination regression identified tyrosine, cysteine, uridine, bilirubin, N-formylmethionine, indoleacetate, and 3-indoxyl sulfate to collectively explain 51% of the variance inherent in log IL-6. CONCLUSIONS: These data suggest roles for tryptophan metabolism, infectious burden, activation of host defense, and detoxification through CYP1A-mediated pathways in mechanisms related to elevated inflammation, whereas CYP-mediated ω-oxidation and PPAR-α activation may be related to decreased inflammation in older adults.

Serum Predictors of Percent Lean Mass in Young Adults.

Lustgarten, MS, Price, LL, Phillips, EM, Kirn, DR, Mills, J, and Fielding, RA. Serum predictors of percent lean mass in young adults. J Strength Cond Res 30(8): 2194-2201, 2016-Elevated lean (skeletal muscle) mass is associated with increased muscle strength and anaerobic exercise performance, whereas low levels of lean mass are associated with insulin resistance and sarcopenia. Therefore, studies aimed at obtaining an improved understanding of mechanisms related to the quantity of lean mass are of interest. Percent lean mass (total lean mass/body weight × 100) in 77 young subjects (18-35 years) was measured with dual-energy x-ray absorptiometry. Twenty analytes and 296 metabolites were evaluated with the use of the standard chemistry screen and mass spectrometry-based metabolomic profiling, respectively. Sex-adjusted multivariable linear regression was used to determine serum analytes and metabolites significantly (p ≤ 0.05 and q ≤ 0.30) associated with the percent lean mass. Two enzymes (alkaline phosphatase and serum glutamate oxaloacetate aminotransferase) and 29 metabolites were found to be significantly associated with the percent lean mass, including metabolites related to microbial metabolism, uremia, inflammation, oxidative stress, branched-chain amino acid metabolism, insulin sensitivity, glycerolipid metabolism, and xenobiotics. Use of sex-adjusted stepwise regression to obtain a final covariate predictor model identified the combination of 5 analytes and metabolites as overall predictors of the percent lean mass (model R = 82.5%). Collectively, these data suggest that a complex interplay of various metabolic processes underlies the maintenance of lean mass in young healthy adults.

Analytes and Metabolites Associated with Muscle Quality in Young, Healthy Adults.

PURPOSE: Identification of mechanisms that underlie lower extremity muscle quality (leg press one repetition maximum/total lean mass; LP/Lean) may be important for individuals interested in optimizing fitness and sport performance. The purpose of the current study was to provide observational insight into mechanisms that may underlie muscle quality by characterizing the association between 286 mass spectrometry metabolites and 17 chemistry screen analytes with LP/Lean in young, healthy adults (N = 77 (49 women and 28 men); mean age, 24.4 ± 4.2 yr; BMI, 23.5 ± 2.6 kg·m). METHODS: Principal components analysis (PCA) was used to reduce the 286 metabolites into 73 metabolite-containing PCA factors. Sex-adjusted linear regression was used to examine the association between PCA factors and chemistry screen analytes with LP/Lean. Q values were computed to account for multiple comparison testing. Stepwise linear regression and leave-one-out cross validation were used to identify a predictor set representative of LP/Lean and to assess internal validity, respectively. RESULTS: Metabolites or analytes related to dietary protein intake (albumin, branched-chain amino acids (BCAA)) and excitation-contraction coupling (calcium and magnesium) were positively associated, whereas metabolites related to gut bacterial metabolism (cinnamoylglycine, hydrocinnamate, hippurate, indolepropionate) and peroxisome proliferator-activated receptor-alpha (PPAR-α) (methylglutarylcarnitine and cinnamoylglycine) activation were negatively associated with LP/Lean. Use of leave-one-out cross validation identified magnesium, sex, and the PCA factors containing BCAAs and methionine and methylglutarylcarnitine to be present in more than 90% of the stepwise regression models, thereby explaining 26.7% of the variance (adjusted R) inherent in muscle quality. CONCLUSION: Collectively, these data suggest that mechanisms related to dietary protein intake, excitation-contraction coupling, gut microbial metabolism, and PPAR-α activation may underlie lower extremity muscle quality in young, healthy adults.

Metabolites related to gut bacterial metabolism, peroxisome proliferator-activated receptor-alpha activation, and insulin sensitivity are associated with physical function in functionally-limited older adults.

Identification of mechanisms underlying physical function will be important for addressing the growing challenge that health care will face with physical disablement in the expanding aging population. Therefore, the goals of the current study were to use metabolic profiling to provide insight into biologic mechanisms that may underlie physical function by examining the association between baseline and the 6-month change in serum mass spectrometry-obtained amino acids, fatty acids, and acylcarnitines with baseline and the 6-month change in muscle strength (leg press one repetition maximum divided by total lean mass, LP/Lean), lower extremity function [short physical performance battery (SPPB)], and mobility (400 m gait speed, 400-m), in response to 6 months of a combined resistance exercise and nutritional supplementation (whey protein or placebo) intervention in functionally-limited older adults (SPPB ≤ 10; 70-85 years, N = 73). Metabolites related to gut bacterial metabolism (cinnamoylglycine, phenol sulfate, p-cresol sulfate, 3-indoxyl sulfate, serotonin, N-methylproline, hydrocinnamate, dimethylglycine, trans-urocanate, valerate) that are altered in response to peroxisome proliferator-activated receptor-alpha (PPAR-α) activation (α-hydroxyisocaproate, α-hydroxyisovalerate, 2-hydroxy-3-methylvalerate, indolelactate, serotonin, 2-hydroxypalmitate, glutarylcarnitine, isobutyrylcarnitine, cinnamoylglycine) and that are related to insulin sensitivity (monounsaturated fatty acids: 5-dodecenoate, myristoleate, palmitoleate; γ-glutamylamino acids: γ-glutamylglutamine, γ-glutamylalanine, γ-glutamylmethionine, γ-glutamyltyrosine; branched-chain amino acids: leucine, isoleucine, valine) were associated with function at baseline, with the 6-month change in function or were identified in backward elimination regression predictive models. Collectively, these data suggest that gut microbial metabolism, PPAR-α activation, and insulin sensitivity may be involved in mechanisms that underlie physical function in functionally-limited older adults.

Diminished skeletal muscle microRNA expression with aging is associated with attenuated muscle plasticity and inhibition of IGF-1 signaling.

Older individuals have a reduced capacity to induce muscle hypertrophy with resistance exercise (RE), which may contribute to the age-induced loss of muscle mass and function, sarcopenia. We tested the novel hypothesis that dysregulation of microRNAs (miRNAs) may contribute to reduced muscle plasticity with aging. Skeletal muscle expression profiling of protein-coding genes and miRNA was performed in younger (YNG) and older (OLD) men after an acute bout of RE. 21 miRNAs were altered by RE in YNG men, while no RE-induced changes in miRNA expression were observed in OLD men. This striking absence in miRNA regulation in OLD men was associated with blunted transcription of mRNAs, with only 42 genes altered in OLD men vs. 175 in YNG men following RE, demonstrating a reduced adaptability of aging muscle to exercise. Integrated bioinformatics analysis identified miR-126 as an important regulator of the transcriptional response to exercise and reduced lean mass in OLD men. Manipulation of miR-126 levels in myocytes, in vitro, revealed its direct effects on the expression of regulators of skeletal muscle growth and activation of insulin growth factor 1 (IGF-1) signaling. This work identifies a mechanistic role of miRNA in the adaptation of muscle to anabolic stimulation and reveals a significant impairment in exercise-induced miRNA/mRNA regulation with aging.

Branched chain amino acids are associated with muscle mass in functionally limited older adults.

BACKGROUND: Metabolic profiling may provide insight into biologic mechanisms related to the maintenance of muscle and fat-free mass in functionally limited older adults. The objectives of the study were to characterize the association between thigh muscle cross-sectional area (CSA) and the fat-free mass index (FFMI; total lean mass/height(2)) with the serum metabolite profile, to further identify significant metabolites as associated with markers of insulin resistance or inflammation, and to develop a metabolite predictor set representative of muscle CSA and the FFMI in functionally limited older adults. METHODS: Multivariable-adjusted linear regression was used on mass spectrometry-based metabolomic data to determine significant associations between serum metabolites with muscle CSA and the FFMI in 73 functionally limited (Short Physical Performance Battery ≤ 10) older adults (age range: 70-85 years). Significant metabolites were further examined for associations with markers of insulin resistance (homeostasis model assessment of insulin resistance) or inflammation (tumor necrosis factor-α and interleukin-6). Multivariable-adjusted stepwise regression was used to develop a metabolite predictor set representative of muscle CSA and the FFMI. RESULTS: Seven branched chain amino acid-related metabolites were found to be associated with both muscle CSA and the FFMI. Separately, two metabolites were identified as insulin resistance-associated markers of the FFMI, whereas four metabolites were identified as inflammation-associated markers of either muscle CSA or the FFMI. Stepwise models identified combinations of metabolites to explain approximately 68% of the variability inherent in muscle CSA or the FFMI. CONCLUSIONS: Collectively, we report multiple branched chain amino acids and novel inflammation-associated tryptophan metabolites as markers of muscle CSA or the FFMI in functionally limited older adults.

Serum glycine is associated with regional body fat and insulin resistance in functionally-limited older adults.

BACKGROUND: Metabolic profiling may provide insight into biologic mechanisms related to age-related increases in regional adiposity and insulin resistance. OBJECTIVES: The objectives of the current study were to characterize the association between mid-thigh intermuscular and subcutaneous adipose tissue (IMAT, SCAT, respectively) and, abdominal adiposity with the serum metabolite profile, to identify significant metabolites as further associated with the homeostasis model assessment of insulin resistance (HOMA-IR), and, to develop a HOMA-IR associated metabolite predictor set representative of regional adiposity, in 73 functionally-limited (short physical performance battery ≤10; SPPB) older adults (age range, 70-85 y). METHODS: Fasting levels of 181 total metabolites, including amino acids, fatty acids and acylcarnitines were measured with use of an untargeted mass spectrometry-based metabolomic approach. Multivariable-adjusted linear regression was used in all analyses. RESULTS: Thirty-two, seven and one metabolite(s) were found to be associated with IMAT, abdominal adiposity and, SCAT, respectively, including the amino acid glycine, which was positively associated with SCAT and, negatively associated with both IMAT and abdominal adiposity. Glycine and four metabolites found to be significantly associated with regional adiposity were additionally associated with HOMA-IR. Separate stepwise regression models identified glycine as a HOMA-IR associated marker of both IMAT (model R(2) = 0.51, p<0.0001) and abdominal adiposity (model R(2) = 0.41, p<0.0001). CONCLUSION: Our findings for a positive association between glycine with SCAT but, a negative association between glycine with IMAT and abdominal adiposity supports the hypothesis that SCAT metabolic processes are different from that found in other fat depots. In addition, because of the significant associations found between glycine with HOMA-IR, IMAT, SCAT and abdominal adiposity, our results suggest glycine as a serum biomarker of both insulin sensitivity and regional fat mass in functionally-limited older adults.

Identification of serum analytes and metabolites associated with aerobic capacity.

Studies aimed at identifying serum markers of cellular metabolism (biomarkers) that are associated at baseline with aerobic capacity (VO2max) in young, healthy individuals have yet to be reported. Therefore, the goal of the present study was to use the standard chemistry screen and untargeted mass spectrometry (MS)-based metabolomic profiling to identify significant associations between baseline levels of serum analytes or metabolites with VO2max (77 subjects, age range 18-35 years). Use of multivariable linear regression identified three analytes (standard chemistry screen) and twenty-three metabolites (MS-based metabolomics) containing significant, sex-adjusted associations with VO2max. In addition, fourteen metabolites were found to contain sex-specific associations with aerobic capacity. Subsequent stepwise multivariable linear regression identified the combination of SGOT, 4-ethylphenylsulfate, tryptophan, γ-tocopherol, and α-hydroxyisovalerate as overall, sex-adjusted baseline predictors of VO2max (adjusted R(2) = 0.66). However, the results of the stepwise model were found to be sensitive to outliers; therefore, random forest (RF) regression was performed. Use of RF regression identified a combination of seven covariates that explained 57.6 % of the variability inherent in VO2max. Furthermore, inclusion of significant analytes, metabolites and sex-specific metabolites into a stepwise regression model identified the combination of five metabolites in males and seven metabolites in females as being able to explain 80 and 58 % of the variability inherent in VO2max, respectively. In conclusion, the evidence presented in the current report is the first attempt to identify baseline serum biomarkers that are significantly associated with VO2max in young, healthy adult humans.