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Oxidative Stress and Inflammation Are Associated With Age-Related Endothelial Dysfunction in Men With Low Testosterone.
Babcock, MC, DuBose, LE, Witten, TL, Stauffer, BL, Hildreth, KL, Schwartz, RS, Kohrt, WM, Moreau, KL
The Journal of clinical endocrinology and metabolism. 2022;107(2):e500-e514
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Serum testosterone declines gradually with age at a rate of ~1% per year after the third decade. Vascular aging, featuring endothelial dysfunction mediated by oxidative stress and inflammation, is a major risk factor for the development of age-associated cardiovascular disease (CVD). The aim of this study was to examine the effects of low testosterone on cardiovascular aging in men. This study is a cross-sectional study which recruited 58 healthy men of all races/ethnic backgrounds aged 50-75 years (middle-aged/older) and 18-40 years (young). Results show that middle-aged/older men with lower testosterone have evidence of “accelerated” vascular aging, as indicated by a greater age-associated endothelial dysfunction of large arteries compared with their age-matched peers. The greater macrovascular endothelial dysfunction in middle-aged/older men with chronically low testosterone was independent of CVD risk factors or symptoms of androgen deficiency. Furthermore, increased systemic oxidative stress and inflammation are mechanistically linked to the greater age-associated endothelial dysfunction in middle-aged/older men with lower testosterone. Authors conclude that normal physiological levels of testosterone may be beneficial to cardiovascular health by attenuating the age-related decline in endothelial function.
Abstract
CONTEXT Vascular aging, including endothelial dysfunction secondary to oxidative stress and inflammation, increases the risk for age-associated cardiovascular disease (CVD). Low testosterone in middle-aged/older men is associated with increased CVD risk. OBJECTIVE We hypothesized that low testosterone contributes to age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. METHODS This cross-sectional study included 58 healthy, nonsmoking men categorized as young (N = 20; age 29 ± 4 years; testosterone 500 ± 58 ng/dL), middle-aged/older with higher testosterone (N = 20; age 60 ± 6 years; testosterone 512 ± 115 ng/dL), and middle-aged/older lower testosterone (N = 18; age 59 ± 8 years; testosterone 269 ± 48 ng/dL). Brachial artery flow-mediated dilation (FMDBA) was measured during acute infusion of saline (control) and vitamin C (antioxidant). Markers of oxidative stress (total antioxidant status and oxidized low-density lipoprotein cholesterol), inflammation (interleukin [IL]-6 and C-reactive protein [CRP]), and androgen deficiency symptoms were also examined. RESULTS During saline, FMDBA was reduced in middle-aged/older compared with young, regardless of testosterone status (P < 0.001). FMDBA was reduced in middle-aged/older lower testosterone (3.7% ± 2.0%) compared with middle-aged/older higher testosterone (5.7% ± 2.2%; P = 0.021), independent of symptoms. Vitamin C increased FMDBA (to 5.3% ± 1.6%; P = 0.022) in middle-aged/older lower testosterone but had no effect in young (P = 0.992) or middle-aged/older higher testosterone (P = 0.250). FMDBA correlated with serum testosterone (r = 0.45; P < 0.001), IL-6 (r = -0.41; P = 0.002), and CRP (r = -0.28; P = 0.041). CONCLUSION Healthy middle-aged/older men with low testosterone appear to have greater age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. These data suggest that low testosterone concentrations may contribute to accelerated vascular aging in men.
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Associations of Dietary Intake on Biological Markers of Inflammation in Children and Adolescents: A Systematic Review.
Bujtor, M, Turner, AI, Torres, SJ, Esteban-Gonzalo, L, Pariante, CM, Borsini, A
Nutrients. 2021;13(2)
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Inflammation is the normal physiological response to injury in the body and is designed to protect the host. However, in children and adolescents, chronic low-grade inflammation has been linked to a wide range of conditions. Certain markers in the blood can be measured and used to determine levels of inflammation in the body. This review of 53 studies provides the first evidence for the association between dietary intake and biological markers of inflammation in children and adolescents. Results show that adhering to a healthy way of eating such as the Mediterranean diet, are associated with decreased levels of pro-inflammatory biomarkers. The Western Dietary pattern, as well as intake of ultra-processed foods is associated with higher levels of the same pro-inflammatory markers. A good quality diet, high in fruit and vegetables, wholegrains, fibre and healthy fats ameliorates low-grade inflammation, and therefore represents a potential therapeutic approach. It is also an important element for disease prevention in both children and adolescents.
Abstract
BACKGROUND In children and adolescents, chronic low-grade inflammation has been implicated in the pathogenesis of co- and multi-morbid conditions to mental health disorders. Diet quality is a potential mechanism of action that can exacerbate or ameliorate low-grade inflammation; however, the exact way dietary intake can regulate the immune response in children and adolescents is still to be fully understood. METHODS Studies that measured dietary intake (patterns of diet, indices, food groups, nutrients) and any inflammatory biomarkers in children and adolescents aged 2 to19 years and published until November 2020 were included in this systematic review, and were selected in line with PRISMA guidelines through the following databases: Academic Search Complete, CINAHL, Global Health, Medline COMPLETE and Web of Science-Core Collection. A total of 53 articles were identified. RESULTS Results show that adequate adherence to healthful dietary patterns such as the Mediterranean diet, or food groups such as vegetables and fruit, or macro/micro nutrients such as fibre or vitamin C and E, are associated with decreased levels of pro-inflammatory biomarkers, mainly c-reactive protein (CRP), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α), whereas adherence to a Western dietary pattern, as well as intake of food groups such as added sugars, macro-nutrients such as saturated fatty acids or ultra-processed foods, is associated with higher levels of the same pro-inflammatory biomarkers. CONCLUSIONS This is the first systematic review examining dietary intake and biological markers of inflammation in both children and adolescents. A good quality diet, high in vegetable and fruit intake, wholegrains, fibre and healthy fats ameliorates low-grade inflammation, and therefore represents a promising therapeutic approach, as well as an important element for disease prevention in both children and adolescents.
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The Impact of Coconut Oil and Epigallocatechin Gallate on the Levels of IL-6, Anxiety and Disability in Multiple Sclerosis Patients.
Platero, JL, Cuerda-Ballester, M, Ibáñez, V, Sancho, D, Lopez-Rodríguez, MM, Drehmer, E, Ortí, JER
Nutrients. 2020;12(2)
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Multiple Sclerosis (MS) is associated with high levels of inflammation, especially the inflammatory molecule interleukin 6 (IL-6). Anxiety has been reported to be linked to inflammation and IL-6. Epigallocatechin gallate (EGCG) is a naturally occurring chemical, which has anti-inflammatory properties and has been related to improvements in anxiety. This pilot study of 51 individuals with MS aimed to assess the impact of EGCG and coconut oil on IL-6 and anxiety over 4 months. The results showed that individuals receiving EGCG and coconut oil had decreased IL-6 and anxiety. However, the individuals who did not also showed decreased IL-6 but not anxiety. It was concluded that anxiety was decreased in individuals with MS when taking EGCG and coconut oil, but this does not appear to be as a direct result of decreased IL-6 levels. It may be due to the Mediterranean diet all participants were asked to follow during the intervention. This study could be used by healthcare professionals to understand the relationship between IL-6 and anxiety in patients with MS.
Abstract
BACKGROUND Due to the inflammatory nature of multiple sclerosis (MS), interleukin 6 (IL-6) is high in blood levels, and it also increases the levels of anxiety related to functional disability. Epigallocatechin gallate (EGCG) decreases IL-6, which could be enhanced by the anti-inflammatory effect of high ketone bodies after administering coconut oil (both of which are an anxiolytic). Therefore, the aim of this study was to assess the impact of coconut oil and EGCG on the levels of IL-6, anxiety and functional disability in patients with MS. METHODS A pilot study was conducted for four months with 51 MS patients who were randomly divided into an intervention group and a control group. The intervention group received 800 mg of EGCG and 60 mL of coconut oil, and the control group was prescribed a placebo. Both groups followed the same isocaloric Mediterranean diet. State and trait anxiety were determined before and after the study by means of the State-Trait Anxiety Inventory (STAI). In addition, IL-6 in serum was measured using the ELISA technique and functional capacity was determined with the Expanded Disability Status Scale (EDSS) and the body mass index (BMI). RESULTS State anxiety and functional capacity decreased in the intervention group and IL-6 decreased in both groups. CONCLUSIONS EGCG and coconut oil improve state anxiety and functional capacity. In addition, a decrease in IL-6 is observed in patients with MS, possibly due to the antioxidant capacity of the Mediterranean diet and its impact on improving BMI.
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Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study.
Pedersen, M, Asprusten, TT, Godang, K, Leegaard, TM, Osnes, LT, Skovlund, E, Tjade, T, Øie, MG, Wyller, VBB
Brain, behavior, and immunity. 2019;75:94-100
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Chronic fatigue is defined as substantial fatigue lasting for more than six months. The main aim of this study is to investigate predictors of chronic fatigue six months after an acute Epstein-Barr virus (EBV) infection. This study includes the prospective results from the first six months of the CEBA project (chronic fatigue following acute Epstein-Barr virus infection in adolescents), which encompasses a prospective, a cross-sectional and a randomized controlled design with a total follow-up time of 21 months. A total of 200 adolescents with EBV and 70 healthy controls were included. Results indicate that fatigue six months after acute EBV infection is significantly and independently predicted by baseline clinical symptoms, functional impairments, negative emotions, verbal memory, plasma c-reactive protein (CRP) and plasma vitamin B12. On average, baseline CRP levels were significantly lower in the acute EBV infection group as compared to healthy controls. Authors conclude that development of fatigue is to a larger extent predicted by baseline variables related to symptoms and functions than to baseline variables reflecting infectious and immune processes.
Abstract
INTRODUCTION Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue and Chronic Fatigue Syndrome (CFS). This study investigated baseline predictors of chronic fatigue six months after an acute EBV infection. MATERIALS AND METHODS A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed for 149 possible baseline predictors and followed prospectively. We performed linear regression to assess possible associations between baseline predictors and fatigue (Chalder Fatigue Questionnaire total score) six months after the acute EBV infection. A total of 70 healthy controls were included for cross-sectional reference. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents). RESULTS In the final multiple linear regression model, fatigue six months after acute EBV infection was significantly and independently predicted by the following baseline variables (regression coefficient B[95% CI]): Sensory sensitivity (0.8[0.09-1.6]), pain severity (0.2[0.02-0.3]), functional impairment (1000 steps/day) (-0.3[-0.5 to -0.08]), negative emotions (anxiety) (0.4[0.2-0.6]), verbal memory (correct word recognition) (1.7[0.1-3.3]), plasma C-reactive protein (2.8[1.1-4.4] for CRP values >0.86) and plasma Vitamin B12 (-0.005[-0.01 to -0.001]). CONCLUSIONS Development of fatigue after acute EBV infection is to a larger extent predicted by baseline variables related to symptoms and functions than to baseline variables reflecting infectious and immune processes. TRIAL REGISTRATION ClinicalTrials, ID: NCT02335437, https://clinicaltrials.gov/ct2/show/NCT02335437.
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Rhodiola/Cordyceps-Based Herbal Supplement Promotes Endurance Training-Improved Body Composition But Not Oxidative Stress and Metabolic Biomarkers: A Preliminary Randomized Controlled Study.
Liao, YH, Chao, YC, Sim, BY, Lin, HM, Chen, MT, Chen, CY
Nutrients. 2019;11(10)
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Physical inactivity has negative health consequences. Such consequences include muscle loss, weight gain, low-grade inflammation, oxidative stress and increased disease risk for metabolic disorders such as type 2 diabetes and cardiovascular diseases. The development of such chronic metabolic disorders often starts at a much younger age, long before it manifests as clinical disease decades later. Endurance exercise is one way to reduce the development and progression of metabolic disease. In addition, the herb Rhodiola crenulata (RC) and fungus Cordyceps sinensis (CS) have shown to bear benefits on metabolic disease parameters. Both have long been used in Chinese medicine for their health-promoting, antioxidant and anti-inflammatory effects. This study sought to assess whether the benefits of regular endurance training can be futher enhanced with the supplementation of RC and CS. This randomized, double-blind, placebo-controlled trial enrolled 14 young sedentary adults who received an 8-week endurance training program. They also received either supplements or a placebo. Measurements and markers of body composition, oxidative stress and metabolic function were obtained before and after the intervention. The results found no difference in blood fats and oxidative stress markers between groups. In fact endurance training alone improved endurance capacity and glycemic control, but again with no particular difference between control and intervention. However, the supplementation group showed improvement in body composition with reduced body fat and increased muscle mass compared to the control group. Larger studies are needed to strengthen the results.
Abstract
Rhodiola crenulata (R) and Cordyceps sinensis (C) are commonly used herbs that promote health in traditional Chinese medicine. These two herbs have also been shown to exhibit anti-inflammation and antioxidant functions. Regular endurance training reveals potent endurance capacity, body composition improvement, and metabolic-related biomarker benefits. However, it is not known whether the combination of Rhodiola crenulata and Cordyceps sinensis (RC) supplementation during endurance training provides additive health benefits. The purpose of this study was to investigate the effects of 8-week endurance training plus RC supplementation on body composition, oxidative stress, and metabolic biomarkers in young sedentary adults. METHODS Fourteen young sedentary adults (8M/6F) participated in this double-blind randomized controlled study. Participants were assigned to exercise training with placebo groups (PLA, n = 7, 4M/3F; age: 21.4 ± 0.4 years) and exercise training with the RC group (RC, 20 mg/kg/day; n = 7, 4M/3F; age: 21.7 ± 0.4 years). Both groups received identical exercise training for eight weeks. The body composition, circulating oxidative stress, and blood metabolic biomarkers were measured before and after the 8-week intervention. RESULTS Improvement in body composition profiles were significantly greater in the RC group (body weight: p = 0.044, BMI: p = 0.003, upper extremity fat mass: p = 0.032, lower extremity muscle mass: p = 0.029, trunk fat mass: p = 0.011) compared to the PLA group after training. The blood lipid profile and systemic oxidative stress makers (thiobarbituric reactive substanceand total antioxidant capacity) did not differ between groups. Although endurance training markedly improved endurance capacity and glycemic control ability (i.e., fast blood glucose, insulin, and HOMA index), there were no differences in these variables between treatments. CONCLUSIONS In this preliminary investigation, we demonstrated that an 8-week RC supplementation (20 mg/kg/day) faintly enhanced endurance training-induced positive adaptations in body composition in young sedentary individuals, whereas the blood lipid profile and systemic oxidative stress states were not altered after such intervention.
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Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome.
Nagy-Szakal, D, Williams, BL, Mishra, N, Che, X, Lee, B, Bateman, L, Klimas, NG, Komaroff, AL, Levine, S, Montoya, JG, et al
Microbiome. 2017;5(1):44
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, swollen lymph glands and irritable bowel syndrome (IBS). It is associated with gut bacterial dysbiosis, systemic inflammation and both gastro intestinal (GI) and neurological disturbances. The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. This experiment looked at fecal bacterial samples and metabolic pathway markers in 50 ME/CFS patients and 50 healthy controls. In ME/CFS subgroups, measures of symptom severity including pain, fatigue, and reduced motivation were correlated with the amounts and types of gut bacteria and certain metabolic pathways. Future prospective studies should consider more detailed exploration of IBS subtypes, associated GI symptoms, and their relationship to ME/CFS dysbiosis. This may enable more accurate diagnosis and the development of specific therapeutic strategies.
Abstract
BACKGROUND Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling. RESULTS Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways. CONCLUSIONS Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.
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Reversal of cognitive decline: a novel therapeutic program.
Bredesen, DE
Aging. 2014;6(9):707-17
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Alzheimer’s Disease (AD) is estimated to affect 30 million individuals globally, with projections as high as 150 million by 2050 if no effective treatment is found. This report describes a personalised, multi-modal, therapeutic programme used with 10 individuals with various degrees of cognitive decline. The goal was to optimise metabolic parameters and lifestyle factors and was personalised based on laboratory test results. 9 out of 10 of the case study patients experienced improvement in cognitive abilities, beginning within 3-6 months of starting the programme. These effects were sustained at 2.5 year follow up. The 1 patient who did not benefit had advanced AD, in comparison to the other patients with subjective or mild cognitive decline. The authors call for a more extensive trial of the therapeutic programme.
Abstract
This report describes a novel, comprehensive, and personalized therapeutic program that is based on the underlying pathogenesis of Alzheimer's disease, and which involves multiple modalities designed to achieve metabolic enhancement for neurodegeneration (MEND). The first 10 patients who have utilized this program include patients with memory loss associated with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI). Nine of the 10 displayed subjective or objective improvement in cognition beginning within 3-6 months, with the one failure being a patient with very late stage AD. Six of the patients had had to discontinue working or were struggling with their jobs at the time of presentation, and all were able to return to work or continue working with improved performance. Improvements have been sustained, and at this time the longest patient follow-up is two and one-half years from initial treatment, with sustained and marked improvement. These results suggest that a larger, more extensive trial of this therapeutic program is warranted. The results also suggest that, at least early in the course, cognitive decline may be driven in large part by metabolic processes. Furthermore, given the failure of monotherapeutics in AD to date, the results raise the possibility that such a therapeutic system may be useful as a platform on which drugs that would fail as monotherapeutics may succeed as key components of a therapeutic system.