Association between the systemic immune-inflammation index and sarcopenia: a systematic review and meta-analysis.

BACKGROUND: Sarcopenia is associated with increased morbidity and mortality. The systemic immune-inflammation index (SII) has been correlated to a variety of disorders. The present study conducted a systematic review and meta-analysis to investigate the relationship between SII and sarcopenia. METHODS: A literature search was performed in Web of Science, PubMed, Embase, Cochrane Library, CINAHL, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wanfang Database, and VIP Chinese Science and Technology Database, from inception to March 2024. Then, the literature quality was assessed. After the heterogeneity test, a random effects or fixed effects model was applied to establish the forest plot, and investigate the relationship between SII and sarcopenia. Then, the sensitivity analysis and publication bias were examined. RESULTS: Nine articles, which included 18,634 adults, were analyzed. Sarcopenic adults had higher SII levels, when compared to non-sarcopenic adults (standardized mean difference [SMD] = 0.66, 95% confidence interval [CI] = 0.22 - 0.19, p = 0.003). The high SII level was associated to the increased risk of sarcopenia (odds ratio = 1.52, 95% CI = 1.09-2.13, p = 0.01). In addition, the subgroup analysis revealed that the SII levels were higher in the sarcopenic group, when compared to the non-sarcopenic group, in elderly adults, as well as in adults with or without gastrointestinal disorders. The analysis was robust with a low risk of publication bias. CONCLUSIONS: SII is closely associated to sarcopenia. Sarcopenic adults had elevated SII levels. The high SII level increased the risk of sarcopenia. Large scale multi-center prospective studies are required to validate these study findings.

A low-intensity lifelong exercise routine changes miRNA expression in aging and prevents osteosarcopenic obesity by modulating inflammation.

Osteosarcopenic obesity (OSO) has been associated with increase immobility, falls, fractures, and other dysfunctions, which could increase mortality risk during aging. However, its etiology remains unknown. Recent studies revealed that sedentarism, fat gain, and epigenetic regulators are critical in its development. One effective intervention to prevent and treat OSO is exercise. Therefore, in the present study, by keeping rats in conditions of sedentarism and others under a low-intensity exercise routine, we established an experimental model of OSO. We determined the degree of sarcopenia, obesity, and osteopenia at different ages and analyzed the miRNA expression during the lifespan using miRNA microarrays from gastrocnemius muscle. Interestingly microarrays results showed that there is a set of miRNAs that changed their expression with exercise. The pathway enrichment analysis showed that these miRNAs are strongly associated with immune regulation. Further inflammatory profiles with IL-6/IL-10 and TNF-α/IL-10 ratios showed that exercised rats presented a lower pro-inflammatory profile than sedentary rats. Also, the body fat gain in the sedentary group increased the inflammatory profile, ultimately leading to muscle dysfunction. Exercise prevented strength loss over time and maintained skeletal muscle functionality over time. Differential expression of miRNAs suggests that they might participate in this process by regulating the inflammatory response associated with aging, thus preventing the development of OSO.

Inflammatory cytokines and sarcopenia in Iranian adults-results from SARIR study.

Some studies suggested the effects of inflammatory cytokines in reducing muscle mass and muscle strength and, performance. This study aimed to compare pro-inflammatory cytokines in sarcopenic and non-sarcopenic subjects. 120 men and women were selected out from the cross-sectional study 'sarcopenia and its determinants among Iranian elders' (SARIR). Sarcopenia was defined based on the first 'European Working Group on sarcopenia in older people' (EWGSOP1) guidelines. A fasting blood sample was taken from each participant to measure serum high-sensitivity C-reactive protein (hs-CRP), Interleukin 6 (IL-6), and tumor necrosis factor α (TNFα). A total of 120 participants were included in this study. Mean age was 66.7 ± 7.7 years and mean body mass index (BMI) was 27.3 ± 4.2 kg/m2. Forty participants had the criteria of EWGSOP1 sarcopenia. A statistically significant difference was seen between normal and abnormal groups of muscle strength in hs-CRP (P-value = 0.04). Furthermore, we did not observe any remarkable association between inflammatory biomarkers including IL-6 (OR 1.15; 95% CI 0.31-4.28), TNF-α (OR 0.68; 95% CI 0.17-2.77), and hs-CRP (OR 2.39; 95% CI 0.87-6.55) and the presence of sarcopenia even after controlling for plausible confounders. We found that inflammatory biomarkers level was not associated with odds of sarcopenia. The lack of correlation between inflammatory cytokines and sarcopenia could be due to the participants' age and genetics. Future studies are required to confirm these findings.

Dulaglutide improves muscle function by attenuating inflammation through OPA-1-TLR-9 signaling in aged mice.

Dulaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effects on muscle wasting due to aging are poorly understood. In the current study, we investigated the therapeutic potential and underlying mechanism of dulaglutide in muscle wasting in aged mice. Dulaglutide improved muscle mass and strength in aged mice. Histological analysis revealed that the cross-sectional area of the tibialis anterior (TA) in the dulaglutide-treated group was thicker than that in the vehicle group. Moreover, dulaglutide increased the shift toward middle and large-sized fibers in both young and aged mice compared to the vehicle. Dulaglutide increased myofiber type I and type IIa in young (18.5% and 8.2%) and aged (1.8% and 19.7%) mice, respectively, compared to the vehicle group. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, decreased but increased by dulaglutide in aged mice. The expression of atrophic factors such as myostatin, atrogin-1, and muscle RING-finger protein-1 was decreased in aged mice, whereas that of the myogenic factor, MyoD, was increased in both young and aged mice following dulaglutide treatment. In aged mice, optic atrophy-1 (OPA-1) protein was decreased, whereas Toll-like receptor-9 (TLR-9) and its targeting inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]) were elevated in the TA and quadriceps (QD) muscles. In contrast, dulaglutide administration reversed this expression pattern, thereby significantly attenuating the expression of inflammatory cytokines in aged mice. These data suggest that dulaglutide may exert beneficial effects in the treatment of muscle wasting due to aging.

Prognostic Impact of Sarcopenia and Radiotherapy in Patients With Advanced Gastric Cancer Treated With Anti-PD-1 Antibody.

Background: We explored the combined effects of sarcopenia (SAR) and radiotherapy (RT) on outcomes in patients with advanced gastric cancer (AGC) treated with immune-checkpoint blockade (ICB). Methods: Among 185 patients with AGC treated with ICB, we defined SAR as skeletal muscle index <49 cm2/m2 for men and <31 cm2/m2 for women; 93 patients met criteria. We defined high neutrophil-to-lymphocyte ratio (hNLR) as NLR≥3. Palliative RT was performed in 37 patients (20%) before ICB. Results: We frequently observed hNLR in patients with SAR (53% vs. 35%, p = 0.02). The median overall survival (OS) for the entire cohort was 5 months. Stratification by risk factors of SAR or hNLR revealed a significant difference in median OS (0 [N = 60] vs. 1 [N = 76] vs. 2 [N = 49]: 7.6 vs. 6.4 vs. 2.2 months, p < 0.001). Patients with microsatellite instability-high (MSI-H, N = 19) or Epstein-Barr virus (EBV)-positive tumors (N = 13) showed favorable outcomes compared to those with microsatellite stable (MSS, N = 142) tumors (median OS, not reached vs. 16.8 vs. 3.8 months, respectively). The benefit of RT was evident in patients with both SAR and hNLR (median OS, 3.1 vs. 1.3 months, p = 0.02) and MSS/EBV-negative tumor (median OS, 6.5 vs. 3.5 months, p = 0.03), but outcomes after RT in MSI-H tumor were not significantly different. In multivariable analysis, SAR/hNLR, molecular subtypes, and a history of RT were associated with OS (all p < 0.05). Conclusions: We demonstrated the negative predictive value of SAR/hNLR on outcomes after ICB for AGC, and the history of RT could overcome the negative impact of SAR/hNLR and the MSS/EBV-negative subtype.

Inflammatory Bowel Diseases and Sarcopenia: The Role of Inflammation and Gut Microbiota in the Development of Muscle Failure.

Sarcopenia represents a major health burden in industrialized country by reducing substantially the quality of life. Indeed, it is characterized by a progressive and generalized loss of muscle mass and function, leading to an increased risk of adverse outcomes and hospitalizations. Several factors are involved in the pathogenesis of sarcopenia, such as aging, inflammation, mitochondrial dysfunction, and insulin resistance. Recently, it has been reported that more than one third of inflammatory bowel disease (IBD) patients suffered from sarcopenia. Notably, the role of gut microbiota (GM) in developing muscle failure in IBD patient is a matter of increasing interest. It has been hypothesized that gut dysbiosis, that typically characterizes IBD, might alter the immune response and host metabolism, promoting a low-grade inflammation status able to up-regulate several molecular pathways related to sarcopenia. Therefore, we aim to describe the basis of IBD-related sarcopenia and provide the rationale for new potential therapeutic targets that may regulate the gut-muscle axis in IBD patients.

Sarcopenia and Systemic Inflammation Synergistically Impact Survival in Oral Cavity Cancer.

OBJECTIVES: Sarcopenia and systemic inflammation can affect survival of advanced-stage oral squamous cell carcinoma (OSCC) patients; however, their reciprocal associations with survival outcomes are yet to be investigated. STUDY DESIGN: Retrospective review at a tertiary cancer center. METHODS: Patients with stage III-IVB OSCC that underwent surgery and (chemo)radiotherapy at our institution between 2010 and 2015 were reviewed. Skeletal muscle index (SMI) was assessed using computed tomography scans at the C3 vertebra. Sarcopenia was defined at the lowest sex-specific tertile for SMI. Systemic inflammation was estimated using the modified Glasgow prognostic score (mGPS), which ranges from 0 to 2 based on serum C-reactive protein and albumin levels. The predictors of overall survival (OS) were evaluated using Cox regression models. RESULTS: A total of 174 patients were included in the study. The cut-off values for sarcopenia were set at SMI <52.4 cm2 /m2 (men) and < 36.2 cm2 /m2 (women) corresponding to the lowest sex-specific tertile. An mGPS 1-2 was independently associated with sarcopenia (odds ratio: 2.05; 95% confidence interval: 1.06-3.97; P = .03). On multivariate analysis for OS, sarcopenia and mGPS 1-2 independently predicted OS (hazard ratio: 2.12; 95% confidence interval: 1.17-3.85; P = .01 and hazard ratio: 7.85; 95% confidence interval: 3.7-16.65; P < .001, respectively). Patients with both sarcopenia and mGPS 1-2 (vs. neither) had worse OS (hazard ratio: 16.80; 95% confidence interval: 6.01-46.99; P < .001). CONCLUSIONS: Sarcopenia and systemic inflammation may exert a negative synergistic prognostic impact in advanced-stage OSCC patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1530-E1538, 2021.

Sarcopenia and high NLR are associated with the development of hyperprogressive disease after second-line pembrolizumab in patients with non-small-cell lung cancer.

The aim of this multi-center retrospective study was to evaluate the incidence of hyperprogressive disease (HPD) after second-line treatment with pembrolizumab in patients (n = 167) with metastatic non-small-cell lung cancer (NSCLC) whose tumors expressed programmed cell death ligand 1 (PD-L1) in ≥ 1% and to search for hematological and imaging biomarkers associated with its development. Prior to chemotherapy, neutrophil : lymphocyte ratio (NLR1) and platelet : lymphocyte ratio (PLR1), and prior to immunotherapy, NLR2 and PLR2 were retrospectively analyzed. The psoas major muscle area (PMMA) was calculated at the L3 position on computed tomography before chemotherapy (PMMA1) and before immunotherapy (PMMA2) (n = 112). Patients with ∆PMMA (1-PMMA2/PMMA1) × 100 ≥ 10% were considered to have sarcopenia (low muscle mass). After treatment with pembrolizumab on the first computerized tomography (CT) scan evaluation, patients were subdivided as follows as: hyperprogressors (HPs), progressors (Ps), non-progressors (NPs) and pseudoprogressors (PPs). HPs had significantly higher ∆PMMA levels, NLR2 and PLR2 than the other patients. Moreover, in multinomial logistic regression analysis, higher levels of ∆PMMA were associated with a decreased likelihood of being a P [odds ratio (OR) = 0·81; 95% confidence interval (CI) = 0·65-0·99; P = 0·047] or an NP (OR = 0·76; 95% CI = 0·62-0·94; P = 0·012) versus an HP. Higher NLRs tended to decrease the likelihood of being a P versus an HP (OR = 0·66; 95% CI = 0·42-1·06; P = 0·09) and significantly decreased the likelihood of being an NP versus an HP (OR = 0·44; 95% CI = 0·28-0·69; P < 0·0001). Our data suggest that a high pre-immunotherapy NLR2 and the presence of sarcopenia are potential risk factors for the development of HPD.

Immunosenescence profiles are not associated with muscle strength, physical performance and sarcopenia risk in very old adults: The Newcastle 85+ Study.

Decline in immune system function (immunosenescence) has been implicated in several age-related disorders. However, little is known about whether alteration in T-cell senescence, a process underlying immunological ageing, is related to muscle health in very old adults (aged ≥85 years). Utilising data from the Newcastle 85+ Study, we aimed to (a) derive and characterise immunosenescence profiles by clustering 13 baseline immunosenescence-related biomarkers of lymphocyte compartments in 657 participants; (b) explore the association between the profiles and 5-year change in muscle strength (grip strength) and physical performance (Timed Up-and-Go test), and (c) determine whether immunosenescence profiles predict 3-year incident sarcopenia. Two distinct clusters were identified; Cluster 1 ('Senescent-like phenotype', n = 421), and Cluster 2 ('Less senescent-like phenotype', n = 236) in individuals with complete biomarker data. Although Cluster 1 was characterised by T-cell senescence (e.g., higher frequency of CD4 and CD8 senescence-like effector memory cells), and elements of the immune risk profile (lower CD4/CD8 ratio, CMV+), it was not associated with change in muscle function over time, or with prevalent or incident sarcopenia. Future studies will determine whether more in-depth characterisation or change in T-cell phenotypes predict the decline in muscle health in late adulthood.

Inflammation-dependent downregulation of miR-532-3p mediates apoptotic signaling in human sarcopenia through targeting BAK1.

Inflammation and apoptosis are considered as two major pathological causes of human sarcopenia. The current understanding based on different models recognizes that apoptosis does not trigger inflammation, while emerging evidence indicates that inflammation can induce apoptosis. Here, we provide solid evidence to suggest that the inflammation-dependent downregulation of miR-532 causes apoptosis through targeting a proapoptotic gene BAK1 (BCL2 antagonist/killer 1). To identify miRNAs and genes that are aberrantly expressed in the muscle tissues of sarcopenia patients, we conducted two independent microarray analyses. In total, we identified 53 miRNAs and 69 genes with differential expression levels. Of these aberrantly expressed miRNAs, miR-532-3p showed the most obvious changes in sarcopenia tissues, and more importantly, it can be repressed by the well-known inflammatory inducer lipopolysaccharide (LPS) in vitro. According to gene-based microarray results and the predicted targets of miR-532-3p, we presumed that BAK1 was a putative target of miR-532-3p. Further in vitro and in vivo analyses verified that miR-532-3p could directly bind to the three prime untranslated region (3'-UTR) of BAK1 through the seed sequence CUCCCAC. In addition, we found that NFKB1 (also known as p50), a subunit of the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), could specifically bind to the promoter region of miR-532-3p and repress its expression. Further analysis revealed that the activation of TLR4 (Toll-like receptor 4) signaling led to the translocation of p50 from the cytoplasm to the nucleus, where it repressed miR-532-3p expression and thus led to an increase of BAK1. The accumulated BAK1 activated its downstream apoptotic signaling pathways and resulted in apoptosis, eventually causing the pathogenesis underlying sarcopenia. Overall, our results uncovered a new mechanism by which the inflammation-dependent downregulation of miR-532-3p contributed to the pathogenesis of sarcopenia through mediating BAK1 expression.

Sarcopenia and Variation in the Human Leukocyte Antigen Complex.

BACKGROUND: Aging is characterized by chronic inflammation plus loss of muscle mass and strength, termed sarcopenia. Human leukocyte antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants are associated with sarcopenia in autoimmune disease-free older people. METHODS: Data were collected from 181,301 UK Biobank European descent volunteers aged 60-70 with measured hand grip strength and impedance. Logistic regression analysis estimated HLA type and sarcopenia associations, adjusted for confounders and multiple testing. RESULTS: Having any autoimmune diagnosis was associated with sarcopenia (odds ratio [OR] 1.83, 95% confidence interval (CI) 1.74-1.92, p = 4.0*10-125). After excluding autoimmune diagnoses, 6 of 100 HLA types (allele frequency >1%) were associated with sarcopenia (low grip strength and muscle mass). Having two HLA-DQA1*03:01 alleles increased odds of sarcopenia by 19.3% (OR 1.19, CI 1.09-1.29, p = 2.84*10-5), compared to no alleles. Having ≥6 of the 12 HLA alleles increased sarcopenia odds by 23% (OR 1.23, CI 1.12-1.35, p = 7.28*10-6). Of 658 HLA region non-coding genetic variants previously implicated in disease, 4 were associated with sarcopenia, including rs41268896 and rs29268645 (OR 1.08, CI 1.05-1.11, p = 1.06*10-8 and 1.07, CI 1.04-1.09, p = 1.5*10-6, respectively). Some HLA associations with sarcopenia were greater in female participants. CONCLUSION: Autoimmune diagnoses are strongly associated with sarcopenia in 60- to 70-year olds. Variation in specific HLA types and non-coding single nucleotide polymorphisms is also associated with sarcopenia in older carriers free of diagnosed autoimmune diseases. Patients with sarcopenia might benefit from targeted treatment of autoimmune processes.

Sarcopenia in Chronic Kidney Disease: Factors, Mechanisms, and Therapeutic Interventions.

Chronic kidney disease (CKD), a chronic catabolic condition, is characterized by muscle wasting and decreased muscle endurance. Many insights into the molecular mechanisms of muscle wasting in CKD have been obtained. A persistent imbalance between protein degradation and synthesis in muscle causes muscle wasting. During muscle wasting, high levels of reactive oxygen species (ROS) and inflammatory cytokines are detected in muscle. These increased ROS and inflammatory cytokine levels induce the expression of myostatin. The myostatin binding to its receptor activin A receptor type IIB stimulates the expression of atrogenes such as atrogin-1 and muscle ring factor 1, members of the muscle-specific ubiquitin ligase family. Impaired mitochondrial function also contributes to reducing muscle endurance. The increased protein-bound uremic toxin, parathyroid hormone, glucocorticoid, and angiotensin II levels that are observed in CKD all have a negative effect on muscle mass and endurance. Among the protein-bound uremic toxins, indoxyl sulfate, an indole-containing compound has the potential to induce muscle atrophy by stimulating ROS-mediated myostatin and atrogenes expression. Indoxyl sulfate also impairs mitochondrial function. Some potential therapeutic approaches based on the muscle wasting mechanisms in CKD are currently in the testing stages.

Sarcopenia Affects Systemic and Local Immune System and Impacts Postoperative Outcome in Patients with Extrahepatic Cholangiocarcinoma.

BACKGROUND: A decrease in skeletal muscle mass and function, defined as sarcopenia, is associated with poor postoperative outcome in patients with cancers. Although systemic or local immune status impacts cancer progression, the relationship between sarcopenia and these statuses remains unclear. The aim of this study is to investigate the clinical impact of sarcopenia and its relationship to immune systems in patients with extrahepatic cholangiocarcinoma (ECC). METHODS: A total of 110 consecutive ECC patients with curative resection between 2005 and 2014 were enrolled. Sarcopenia was determined from skeletal muscle index, assessed by a L3 skeletal muscle mass on axial computed tomography images, and their relationships with patients' clinicopathological characteristics and survival were evaluated. Systemic immune status was calculated using preoperative laboratory data, and tumor-infiltrating (TI) immune cells (CD8+ T cells, CD66b+ neutrophils, CD163+ M2 macrophages) assayed by immunohistochemistry, and their relationship to sarcopenia were evaluated. RESULTS: Sarcopenia was present in 31 patients (28.2%). Patients with sarcopenia had a worse recurrence-free survival (HR 1.87, p = 0.009) and overall survival (OS) (HR 2.47, p = 0.0004) than patients without sarcopenia. Moreover, patients with sarcopenia had a higher level of platelet-lymphocyte ratio (159 vs. 119; p = 0.003) and lower number of TI CD8+ T cells (47 vs. 66 cells/spot; p = 0.03) than patients without sarcopenia. On multivariate analysis, the presence of sarcopenia (HR 2.60, p = 0.0008) was an independent predictor of poor OS. CONCLUSIONS: Our data showed that sarcopenia and systemic or local immune cells may interact with each other and play a pivotal role in clinical outcomes of patients with ECC.

Elevated leptin levels induce inflammation through IL-6 in skeletal muscle of aged female rats.

BACKGROUND: Chronic inflammation with aging contributes to sarcopenia. Previous studies have suggested that the accumulation of adipose tissue in skeletal muscle, referred to as intermuscular adipose tissue (IMAT), increases with age and is associated with inflammation. However, the mechanism governing ectopic inflammation in skeletal muscle due to aging is not fully understood. Leptin, an adipocytokine derived from adipose tissue, is an important mediator of inflammatory processes. We examined changes in leptin levels with age and whether leptin contributes to ectopic inflammation. METHODS: To evaluate ectopic inflammation in skeletal muscle, we measured alterations to the expression of inflammatory cytokine genes (Il1b, Il6, and Tnfa) and muscle break down-related gene (MuRF1 and Atrogin1) in the quadricep muscles of young (10 weeks) and aged (48 weeks) female rats using quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR). Histological examination was performed to identify the extent of IMAT. Leptin mRNA and leptin protein expression were examined using Q-RT-PCR and enzyme-linked immunosorbent assay, respectively. The effect of leptin on the mRNA expression of Il1b, Il6, and Tnfa in quadricep muscle-derived cells was also examined by stimulating the cells with 0 (control), 1, or 10 µg/mL rat recombinant leptin using Q-RT-PCR. RESULTS: Aged rats had significantly higher Il6, MuRF1, and Atrogin1 but not Il1b and Tnfa, expression and greater levels of IMAT in their quadricep muscles than young rats. Aged rats also had significantly higher leptin expression and leptin protein concentration in their quadricep muscles than young rats. The addition of exogenous leptin to quadricep muscle-derived cells significantly increased the gene expression of Il1b and Il6 but not Tnfa. CONCLUSIONS: Our results suggest that elevated leptin levels due to aging cause ectopic inflammation through IL-6 in the skeletal muscle of aged rats.

Circulating factors associated with sarcopenia during ageing and after intensive lifestyle intervention.

BACKGROUND: Ageing, chronic diseases, prolonged inactivity, and inadequate nutrition pose a severe threat to skeletal muscle health and function. To date, experimental evidence suggests that ageing-related subclinical inflammation could be an important causative factor in sarcopenia. Although inflammatory signalling has been implicated in the pathogenesis of experimental animal models of sarcopenia, few studies have surveyed the clinical association between circulating factors and muscle mass in patients before and after lifestyle interventions. In this study, we evaluated whether proinflammatory cytokines are associated with the onset of sarcopenia, which circulating factors are associated with the severity of sarcopenia, and how these factors change after lifestyle interventions in sarcopenic elderly persons. METHODS: A total of 56 elderly subjects (age ≥ 60 years) with sarcopenia and 56 elderly non-sarcopenic subjects, who met entry criteria and had given informed consent, were selected from the Peking Union Medical College Hospital multicentre prospective longitudinal sarcopenia study for testing relevant circulating factors. Thirty-two elderly subjects from the sarcopenic cohort completed a 12 week intensive lifestyle intervention programme with whey supplements (30 g/day) and a personalized resistance training regimen. The levels of proinflammatory cytokines and metabolic hormones, pre-intensive and post-intensive lifestyle interventions, were measured. RESULTS: The sarcopenic group was significantly older (72.05 ± 6.54 years; P < 0.001), more likely to be inactive and female (57.1% of all sarcopenic patients), and had a higher prevalence of type 2 diabetes (16% higher risk). Compared with non-sarcopenic subjects, serum interleukin (IL)-6, IL-18, tumour necrosis factor-α (TNF-α), TNF-like weak inducer of apoptosis (TWEAK), and leptin were significantly higher, while insulin growth factor 1, insulin, and adiponectin were significantly lower in sarcopenic patients (all P < 0.05). Logistic regression analyses revealed that high levels of TNF-α (>11.15 pg/mL) and TWEAK (>1276.48 pg/mL) were associated with a 7.6-fold and 14.3-fold increased risk of sarcopenia, respectively. After adjustment for confounding variables, high levels of TWEAK were still associated with a 13.4-fold increased risk of sarcopenia. Intensive lifestyle interventions led to significant improvements in sarcopenic patients' muscle mass and serum profiles of TWEAK, TNF-α, IL-18, insulin, and adiponectin (all P < 0.05). CONCLUSIONS: High levels of the inflammatory cytokines TWEAK and TNF-α are associated with an increased risk of sarcopenia, while the metabolic hormones insulin growth factor 1, insulin, and adiponectin are associated with a decreased risk of sarcopenia in our Chinese patient cohort. Intensive lifestyle interventions could significantly improve muscle mass, reduce inflammation, and restore metabolic hormone levels in sarcopenic patients. This trial was registered at clinicaltrials.gov as NCT02873676.

Gut microbiota in common elderly diseases affecting activities of daily living.

Gut microbiota are involved in the development or prevention of various diseases such as type 2 diabetes, fatty liver, and malignancy such as colorectal cancer, breast cancer and hepatocellular carcinoma. Alzheimer's disease, osteoporosis, sarcopenia, atherosclerotic stroke and cardiovascular disease are major diseases associated with decreased activities of daily living (ADL), especially in elderly people. Recent analyses have revealed the importance of gut microbiota in the control of these diseases. The composition or diversity of these microbiota is different between patients with these conditions and healthy controls, and administration of probiotics or prebiotics has been shown effective in the treatment of these diseases. Gut microbiota may affect distant organs through mechanisms that include regulating the absorption of nutrients and/or the production of microbial metabolites, regulating and interacting with the systemic immune system, and translocating bacteria/bacterial products through disrupted mucosal barriers. Thus, the gut microbiota may be important regulators in the development of diseases that affect ADL. Although adequate exercise and proper diet are important for preventing these diseases, their combination with interventions that manipulate the composition and/or diversity of gut microbiota could be a promising strategy for maintaining health condition and preserving ADL. This review thus summarizes current understanding of the role of gut microbiota in the development or prevention of diseases closely associated with the maintenance of ADL.

Age-related loss of VGLUT1 excitatory, but not VGAT inhibitory, immunoreactive terminals on motor neurons in spinal cords of old sarcopenic male mice.

Age-related changes in ventral lumbar spinal cord (L3-L5) were compared in young [3 month, (M)] and old (27 M) C57BL/6J male mice. The aged mice had previously been shown to exhibit sarcopenia and changes to peripheral nerve morphology. The putative connectivity of ß-III tubulin positive α-motor neurons was compared in immunostained transverse sections using excitatory and inhibitory terminal markers vesicular glutamate transporter-1 (VGLUT1) and vesicular GABA transporter (VGAT). Glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) immunostaining was used to monitor changes in astrocyte and microglial phenotype respectively. For a given motor neuron, the neuronal perimeter was outlined and terminals immunoreactive for VGLUT1 or VGAT in close apposition to the soma were identified. By 27 M, the percentage coverage and total number of VGLUT1 immunoreactive terminals immediately adjacent to the soma of α-motor neurons was significantly decreased compared with young mice. However, percentage coverage of immunoreactive VGAT inhibitory terminals did not change significantly with age. The gray matter of 27 M spinal cords showed increased astrocytic and microglial activity. The loss of VGLUT1 terminals on α-motor neurons, terminals known to be derived from proprioceptive muscle afferents, may further impair sensorimotor control of hind limb skeletal muscle function in old mice.

The pulmonary rehabilitation regimen: a treatment for frailty and 'inflammaging'?

Pulmonary rehabilitation is an exercise-based intervention that improves walking endurance, strength, functional independence, wellbeing and the risk of re-admission to hospital. It was developed for patients recovering from acute exacerbations of chronic obstructive pulmonary disease, and sometimes other long-term inflammatory lung diseases. Many other conditions have a chronic inflammatory component, including type 2 diabetes, obesity, osteoarthritis and old age. Such background inflammation is linked to a range of adverse outcomes, including all-cause mortality, sarcopenia and other markers of frailty. Exercise, including pulmonary rehabilitation, has an anti-inflammatory effect on innate immune chemistry, and improves outcomes in a variety of conditions, although for most diagnostic groups there is no consistent structured programme similar to pulmonary rehabilitation. The authors contend that the pulmonary rehabilitation model could be used generically to treat other chronic and post-acute inflammatory states and thereby reduce the risk of frailty and other adverse outcomes.

l-Citrulline Supplementation: Impact on Cardiometabolic Health.

Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l-citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine. Unlike l-arginine, l-citrulline is not quantitatively extracted from the gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is therefore more effective at increasing l-arginine levels and NO synthesis. Supplementation with l-citrulline has shown promise as a blood pressure lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic-endothelial protection. Preliminary evidence is also available for l-citrulline-induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible/older populations. In this review, we examine the impact of supplementing this important urea cycle intermediate on cardiovascular and metabolic health outcomes and identify future directions for investigating its therapeutic impact on cardiometabolic health.

Long-Term Effects of Dietary Protein and Branched-Chain Amino Acids on Metabolism and Inflammation in Mice.

Aging is the main factor involved in the onset of degenerative diseases. Dietary protein restriction has been shown to increase the lifespan of rodents and improve metabolic phenotype. Branched-chain amino acids (BCAA) can act as nutrient signals that increase the lifespan of mice after prolonged supplementation. It remains unclear whether the combination of protein restriction and BCAA supplementation improves metabolic and immunological profiles during aging. Here, we investigated how dietary protein levels and BCAA supplementation impact metabolism and immune profile during a 12-month intervention in adult male C57BL/6J mice. We found that protein restriction improved insulin tolerance and increased hepatic fibroblast growth factor 21 mRNA, circulating interleukin (IL)-5 concentration, and thermogenic uncoupling protein 1 in subcutaneous white fat. Surprisingly, BCAA supplementation conditionally increased body weight, lean mass, and fat mass, and deteriorated insulin intolerance during protein restriction, but not during protein sufficiency. BCAA also induced pro-inflammatory gene expression in visceral adipose tissue under both normal and low protein conditions. These results suggest that dietary protein levels and BCAA supplementation coordinate a complex regulation of metabolism and tissue inflammation during prolonged feeding.