Dietary Inflammatory Index and Cross-Sectional Associations with Inflammation, Muscle Mass and Function in Healthy Old Adults.

IMPORTANCE: Inflammaging is considered a driver of age-related loss of muscle mass and function (sarcopenia). As nutrition might play a role in this process, the Dietary Inflammatory Index® (DII) has been developed to quantify the inflammatory potential of an individual diet. OBJECTIVES: We aimed to examine associations between the DII, inflammation, oxidative stress and sarcopenia-related parameters in healthy old compared to young adults. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included data of 79 community-dwelling, healthy old adults (65-85 years) and 59 young adults (18-35 years) who participated in a randomized controlled trial from April to December 2019. MEASUREMENTS: The DII was computed with dietary data collected from 24-h recall interviews. Associations between the DII, inflammatory and oxidative stress markers as well as bioimpedance-derived body composition, handgrip strength and gait speed were determined with multiple linear regression analyses adjusted for age, sex, physical activity and insulin resistance. RESULTS: Regression analyses revealed significant relationships between a higher interleukin (IL) 6 and IL-6:IL-10-ratio and higher percentage fat mass (%FM), waist-to-height-ratio (WHtR) as well as lower percentage skeletal muscle mass (%SMM) and gait speed exclusively in old adults. Subsequent analyses showed that IL-6 was associated with a pro-inflammatory diet as indicated by a higher DII, again exclusively in old adults (beta coefficient (ß)= 0.027, standard error (SE) 0.013, p=0.037). While the DII was not related with handgrip strength or oxidative stress in neither old nor young adults, linear models confirmed that a higher DII was inversely associated with gait speed in old participants (ß= -0.022, SE 0.006, p<0.001). Finally, a pro-inflammatory diet was significantly associated with higher %FM, WHtR and lower %SMM in both age groups. CONCLUSION AND RELEVANCE: A pro-inflammatory diet reflected by the DII is associated with higher systemic inflammation, slower gait speed as well as lower muscle mass in old adults. Intervention studies are needed to examine whether anti-inflammatory dietary approaches can help to improve muscle mass and function and thus minimize the risk for sarcopenia in the long-term.

Self-rated health in individuals with and without disease is associated with multiple biomarkers representing multiple biological domains.

Self-rated health (SRH) is one of the most frequently used indicators in health and social research. Its robust association with mortality in very different populations implies that it is a comprehensive measure of health status and may even reflect the condition of the human organism beyond clinical diagnoses. Yet the biological basis of SRH is poorly understood. We used data from three independent European population samples (N approx. 15,000) to investigate the associations of SRH with 150 biomolecules in blood or urine (biomarkers). Altogether 57 biomarkers representing different organ systems were associated with SRH. In almost half of the cases the association was independent of disease and physical functioning. Biomarkers weakened but did not remove the association between SRH and mortality. We propose three potential pathways through which biomarkers may be incorporated into an individual's subjective health assessment, including (1) their role in clinical diseases; (2) their association with health-related lifestyles; and (3) their potential to stimulate physical sensations through interoceptive mechanisms. Our findings indicate that SRH has a solid biological basis and it is a valid but non-specific indicator of the biological condition of the human organism.

Effects of isoflavones on breast tissue and the thyroid hormone system in humans: a comprehensive safety evaluation.

Isoflavones are secondary plant constituents of certain foods and feeds such as soy, linseeds, and red clover. Furthermore, isoflavone-containing preparations are marketed as food supplements and so-called dietary food for special medical purposes to alleviate health complaints of peri- and postmenopausal women. Based on the bioactivity of isoflavones, especially their hormonal properties, there is an ongoing discussion regarding their potential adverse effects on human health. This review evaluates and summarises the evidence from interventional and observational studies addressing potential unintended effects of isoflavones on the female breast in healthy women as well as in breast cancer patients and on the thyroid hormone system. In addition, evidence from animal and in vitro studies considered relevant in this context was taken into account along with their strengths and limitations. Key factors influencing the biological effects of isoflavones, e.g., bioavailability, plasma and tissue concentrations, metabolism, temporality (pre- vs. postmenopausal women), and duration of isoflavone exposure, were also addressed. Final conclusions on the safety of isoflavones are guided by the aim of precautionary consumer protection.

Posttranslational protein modifications by reactive nitrogen and chlorine species and strategies for their prevention and elimination.

Proteins are subject to various posttranslational modifications, some of them being undesired from the point of view of metabolic efficiency. Prevention of such modifications is expected to provide new means of therapy of diseases and decelerate the process of aging. In this review, modifications of proteins by reactive nitrogen species and reactive halogen species, is briefly presented and means of prevention of these modifications and their sequelae are discussed, including the denitrase activity and inhibitors of myeloperoxidase.

Oxidative stress markers and micronutrients in maternal and cord blood in relation to neonatal outcome.

BACKGROUND/OBJECTIVES: Oxidative stress and micronutrient deficiencies have been related to lower birth weight (BW), small for gestational age (SGA) offspring and preterm delivery. SUBJECTS/METHODS: The relation between neonatal outcome (BW, head circumference, SGA, preterm delivery) with markers of oxidative stress and micronutrients in maternal and cord blood was to be examined. Oxidative stress markers (protein carbonyls (PrCarb), 3-nitrotyrosine (3NT), malondialdehyde (MDA)), total protein concentration and lipid-soluble micronutrients (carotenoids, retinol, tocopherols) were measured in 200 newborns (11% preterms, 13% SGA) and 151 mothers. Associations between target parameters in cord plasma and maternal serum with BW, head circumference and risk of being SGA or preterm were explored. RESULTS: Maternal protein concentration, PrCarb, MDA and all lipid-soluble micronutrients were significantly higher compared with newborns, except for 3NT, which was significantly elevated in newborns. Newborn parameters correlated positively with those of mothers. Preterms had lower proteins and retinol but higher PrCarb than terms. Maternal PrCarb and retinol were inversely associated with BW and head circumference. Mothers with PrCarb, MDA and retinol in the highest quintile had a 3.3-fold (0.9; 12.1), 2.1-fold (0.7; 6.4) and 3.3-fold (1.2; 9.4) risk, respectively, for delivering an SGA newborn, whereas the lowest quintile of retinol in cord blood was associated with an increased risk for preterm delivery. CONCLUSIONS: Oxidative stress (elevated PrCarb) was associated with lower BW/head circumference and SGA. Inadequate hemodilution may explain the inverse relation of maternal retinol with BW and head circumference, and the association between highest maternal retinol and risk for SGA.

5-Methyltetrahydrofolate and thiamine diphosphate in cord-blood erythrocytes of preterm versus term newborns.

BACKGROUND/OBJECTIVES: A low folate or low thiamine status may be associated with the risk of preterm delivery, small for gestational age (SGA) offspring and adverse pregnancy outcomes. SUBJECTS/METHODS: 5-Methyltetrahydrofolate (5MTHF) and thiamine diphosphate (TDP) were measured directly in cord-blood erythrocytes (CBEs) of early preterm (n=26; <32 weeks gestational age; including 50% multiple births), late preterm (n=38; 32 to <37 weeks; including 24% multiple births) and term newborns (n=60, 37-42 weeks) via high-performance liquid chromatography and fluorescence detection. Associations between 5MTHF and TDP with gestational age, newborn anthropometrics (birth weight, newborn's length and head circumference) and risk of being SGA were explored. RESULTS: Group comparison as well as multivariate linear regression analysis of cord-blood vitamins revealed that 5MTHF was significantly lower in late preterms compared with terms but did not differ between singletons and multiples. TDP tended to be higher in preterms than in terms and lower in multiples than in singletons in both early and late preterms. Multivariate analysis on birth outcomes showed that 5MTHF was significantly positively associated with gestational age, birth weight and newborn's length. 5MTHF, increasing gestational age and parity were associated with a significantly reduced risk for being SGA, while TDP, multiple births and gender were not associated with the risk for being SGA. CONCLUSIONS: Higher CBE concentrations of 5MTHF were associated with improved birth outcomes. Lower TDP concentrations were observed in multiple births. Future studies evaluating cord-blood vitamin concentrations and their associations with birth outcomes should additionally include dietary intakes and maternal blood concentrations at different stages of pregnancy.

Molecular effects of advanced glycation end products on cell signalling pathways, ageing and pathophysiology.

Advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed by the Maillard chemical process of non- enzymatic glycation of free amino groups of proteins, lipids and nucleic acids. This chemical modification of biomolecules is triggered by endogeneous hyperglycaemic or oxidative stress-related processes. Additionally, AGEs can derive from exogenous, mostly diet-related, sources. Considering that AGE accumulation in tissues correlates with ageing and is a hallmark in several age-related diseases it is not surprising that the role of AGEs in ageing and pathology has become increasingly evident. The receptor for AGEs (RAGE) is a single transmembrane protein being expressed in a wide variety of human cells. RAGE binds a broad repertoire of extracellular ligands and mediates responses to stress conditions by activating multiple signal transduction pathways being mostly responsible for acute and/or chronic inflammation. RAGE activation has been implicated in ageing as well as in a number of age-related diseases, including atherosclerosis, neurodegeneration, arthritis, stoke, diabetes and cancer. Here we present a synopsis of findings that relate to AGEs-reported implication in cell signalling pathways and ageing, as well as in pathology. Potential implications and opportunities for translational research and the development of new therapies are also discussed.

Oxidative protein damage and the proteasome.

Protein damage, caused by radicals, is involved in many diseases and in the aging process. Therefore, it is crucial to understand how protein damage can be limited, repaired or removed. To degrade damaged proteins, several intracellular proteolytic systems exist. One of the most important contributors in intracellular protein degradation of oxidized, aggregated and misfolded proteins is the proteasomal system. The proteasome is not a simple, unregulated structure. It is a more complex proteolytic composition that undergoes diverse regulation in situations of oxidative stress, aging and pathology. In addition to that, numerous studies revealed that the proteasome activity is altered during life time, contributing to the aging process. In addition, in the nervous system, the proteasome plays an important role in maintaining neuronal protein homeostasis. However, alterations in the activity may have an impact on the onset of neurodegenerative diseases. In this review, we discuss what is presently known about protein damage, the role of the proteasome in the degradation of damaged proteins and how the proteasome is regulated. Special emphasis was laid on the role of the proteasome in neurodegenerative diseases.

Protein pool maintenance during oxidative stress.

The production of reactive species causes oxidative modifications of proteins accompanied by a loss of protein function. By protein oxidation all cellular compartments and any amino acid are effected. This might result in a defect of cellular homeostasis. Therefore, the degradation of non-functional, oxidized proteins is an essential function of the proteolytic branch of the antioxidant defense machinery. The major proteolytic system responsible for the removal of oxidized proteins is the proteasomal system. Whereas moderately oxidized proteins are more sensitive to proteolytic attack, severely oxidized ones are often poor substrates and might, however, inhibit the proteasome. This paper reviews the data available on protein modifications following oxidative stress, the cellular responses and the role of proteasome in this process.

Strong associations of psoriasis with antigen processing LMP and transport genes TAP differ by gender and phenotype.

Psoriasis, a skin disease with autoimmune features, can be triggered and exacerbated by genetic and environmental factors. Chemicals can break tolerance to self-antigens by interfering with antigen processing and presentation; therefore, proteins involved in antigen processing may affect susceptibility. We test here whether variants of immunoproteasome subunits LMP2 and LMP7, or antigen peptide transport proteins TAP1 (transporters associated with antigen presentation) and TAP2 are associated with psoriasis. We analyzed 7 single-nucleotide polymorphisms in 321 Caucasian (German) psoriasis patients and 235 unrelated controls by time-of-flight mass spectrometry, using the Sequenom platform. We found strong associations of psoriasis with variant alleles of LMP and TAP (OR(TAP_687): 3.3, 95% CI: 1.9-5.7). Genotype effects were generally stronger for males and LMP effects were mainly seen for psoriasis arthropathica. Our results will help define behavioral or drug treatment suggestions to patients and contribute to a better understanding of the role of low molecular weight chemicals in genetic susceptibility to autoimmune diseases.

The nuclear proteasome and the degradation of oxidatively damaged proteins.

The accumulation of oxidized proteins is known to be linked to some severe neurodegenerative diseases like Alzheimer's, Parkinson's and Huntington's disease. Furthermore, the aging process is also accompanied by an ongoing aggregation of misfolded and damaged proteins. Therefore, mammalian cells have developed potent degradation systems, which selectively degrade damaged and misfolded proteins. The proteasomal system is largely responsible for the removal of oxidatively damaged proteins form the cellular environment. Not only cytosolic proteins are prone to oxidative stress, also nuclear proteins are readily oxidized. The nuclear proteasomal system is responsible for the degradation of these proteins. This review is focused on the specific degradation of oxidized nuclear proteins, the role of the proteasome in this process and the regulation of the nuclear proteasomal system under oxidative conditions.

Having it all: historical energy intakes do not generate the anticipated trade-offs in fecundity.

An axiom of life-history theory, and fundamental to our understanding of ageing, is that animals must trade-off their allocation of resources since energy and nutrients are limited. Therefore, animals cannot "have it all"--combine high rates of fecundity with extended lifespans. The idea of life-history trade-offs was recently challenged by the discovery that ageing may be governed by a small subset of molecular processes independent of fitness. We tested the "trade-off" and "having it all" theories by examining the fecundities of C57BL/6J mice placed onto four different dietary treatments that generated caloric intakes from -21 to +8.6% of controls. We predicted body fat would be deposited in relation to caloric intake. Excessive body fat is known to cause co-morbidities that shorten lifespan, while caloric restriction enhances somatic protection and increases longevity. The trade-off model predicts that increased fat would be tolerated because reproductive gain offsets shortened longevity, while animals on a restricted intake would sacrifice reproduction for lifespan extension. The responses of body fat to treatments followed our expectations, however, there was a negative relationship between reproductive performance (fecundity, litter mass) and historical intake/body fat. Our dietary restricted animals had lower protein oxidative damage and appeared able to combine life-history traits in a manner contrary to traditional expectations by having increased fecundity with the potential to have extended lifespans.

[Protein oxidation and proteolysis during cellular senescence]. / Proteinoxidation und Proteolyse während der zellulären Alterung.

One of the hallmarks of the aging process is the accumulation of oxidized proteins. Therefore, the accumulation of oxidized proteins is one of the key factors in the aging process. Oxidized proteins are normally repaired or degraded by the proteasomal system. This system is the most important intracellular protein degradation machinery, responsible for the degradation of oxidized proteins. For unknown reasons the removal of oxidized proteins is disturbed in aged cells. This leads to the accumulation of non-functional proteins. Further studies are needed for a better understanding of the changes in the proteasomal system and the interference with these changes.

[Protein oxidation in the aging of skin fibroblasts]. / Proteinoxidation in der Alterung von Hautfibroblasten.

The ageing process is accompanied by enhanced oxidative damage. All cellular components including proteins are affected by oxidation. Within the cell, the proteasome is responsible for the degradation of these oxidised proteins. During the ageing process this function of the proteasome is increasingly diminished, therefore oxidised proteins accumulate. Furthermore lipofuscin, a highly cross-linked and modified protein aggregate, is formed. This aggregate accumulates within cells and is able to inhibit the proteasome. The nucleus of the cells is less affected by these changes due to the lack of intranuclear lipofuscin accumulation.

Effects of different steroid treatment on reperfusion-associated production of reactive oxygen species and arrhythmias during coronary surgery.

BACKGROUND: During conventional cardiac surgery ischemia and reperfusion may cause excessive production of reactive oxygen species leading to tissue damage including early arrhythmias. We therefore assessed the kinetics of markers of radical stress including oxidized and reduced glutathione (GSSG/GSH), oxidized proteins (PCG) and malondialdehyde (MDA), and tested the hypothesis that different steroid treatments inhibit these markers and early reperfusion-associated supraventricular and ventricular extrasystolic beats. METHODS: In a randomized, controlled, blinded, prospective trial 36 patients received a preoperative infusion of methylprednisolone (MP, 15 mg kg-1, n = 12), tirilazad mesylate (TM, 10 mg kg-1, n = 12) or placebo (PL, NaCl, n = 12). Coronary sinus and arterial blood was drawn at baseline and 2, 5, 15, 30, 60 and 240 min after aortic declamping. Holter-ECG analysis was used to identify arrhythmias. RESULTS: Cardiac GSSG release occurred very early (< 15 min) and was not significantly attenuated by either drug treatment. Cardiac PCG production showed biphasic increases, lasted > 4 h and was significantly reduced only by TM. Cardiac MDA release was short (< 30 min) and significantly reduced by MP and TM. Neither treatment had a significant influence on the early occurrence of ventricular or supraventricular arrhythmias. The number of patients needing cardioversions or defibrillations also were not different. CONCLUSIONS: The results indicate that cardiac production of reactive oxygen species occurs after reperfusion in humans and is not inhibited by steroid treatment. Steroid treatment effectively reduces lipid peroxidation during cardiac surgery but has no influence on arrhythmias.

Hohenheimer Consensus Talk. Oxidative and premature skin ageing.

To elucidate the scientific state of the art with respect to the role of nutrition in skin ageing, nine experts from different disciplines discussed the role of micronutrients on 'oxidative and premature skin ageing'. In this 25th Hohenheim Consensus Meeting, 13 questions were discussed and, based on published valid data, answered by mutual agreement. The consensus answers achieved during the meeting are justified by a scientific background text. The importance of in vitro and in vivo models regarding oxidative and premature skin ageing was critically evaluated. There was a special focus on prevention and intervention of skin ageing with nutrition. Finally, the paper summarizes the scientific background from different areas related to oxidative and premature skin ageing.

Oxidative stress in chronic lymphoedema.

BACKGROUND: Chronic lymphoedema is one of the most frequent and debilitating complications after surgical and radiological tumour treatment. Prevention and therapy of lymphoedema is therefore an important problem of the rehabilitation of those patients. AIM: To investigate whether chronic lymphoedema results in increased oxidative stress. DESIGN: Prospective case-control study. METHODS: We obtained venous blood samples from patients (n=38) with chronic lymphoedema and determined biomarkers of prooxidative reactions and of antioxidative defense system in the erythrocytes or blood plasma: reduced and oxidized glutathione (GSH and GSSG), and lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE). Healthy volunteers (n=90) and patients who had undergone surgical and/or radiotherapeutic treatment of tumours without consequent lymphoedema (n=20) acted as controls. RESULTS: The blood of patients with chronic lymphoedema contained lower concentrations of GSH and higher levels of GSSG and of MDA and HNE, compared with the control group. MDA was increased by about three-fold in the serum of the lymphoedema patients. Accelerated free radical formation and lipid peroxidation processes were further demonstrated by the liberation of MDA and HNE into the blood serum after manual lymph drainage. DISCUSSION: Our data demonstrate enhanced formation of reactive oxygen species (ROS) and accelerated lipid peroxidation processes in chronic lymphoedematous tissue. The strengthening of antioxidative defense mechanisms could be useful in the therapy of chronic lymphoedema.

Elevated serum concentration of cardiotoxic lipid peroxidation products in chronic renal failure in relation to severity of renal anemia.

Patients with end-stage renal disease undergoing hemodialysis (HD) are exposed to oxidative stress. Increased levels of malondialdehyde (MDA) and 4-hydroxylnonenal (HNE) were found in plasma of uremic patients indicating accelerated lipid peroxidation (LPO) as a consequence of multiple pathogenetic factors. The catabolism and action of those products was already intensively studied. As highly reactive metabolites they are able to bind to proteins, nucleic acids, and other molecules. Doing so, they exert molecular signal effects in cells and are able to exacerbate tissue and organ damage, e.g. cardiotoxic effects. Since renal anemia was shown to promote oxidative stress as well, the aim of our investigation was to examine its role in HD patients. Therefore, two groups of HD patients were investigated (group I Hb < 10 g/dl, group II Hb > 10 g/dl) and serum concentrations of MDA, HNE, and of protein carbonyls, a marker for protein oxidation, were determined. All HD patients had significantly higher levels of the LPO products MDA and HNE compared with controls. However, group I patients showed higher MDA and HNE concentrations compared to group II patients. The same result could be seen for protein carbonyls. During HD concentration of both LPO products decreased. However, this was not the case for protein carbonyls. These results lead to the conclusion that optimized correction of the renal anemia may result in a significant reduction of oxidative stress and therefore in the reduction of organ tissue damage. In this way correction of renal anemia will reduce the cardiovascular risk and comorbidity of HD patients improving their prognosis.