Publications by authors named "Tilman Grune"

280 Publications

Association between fat-soluble vitamins and self-reported health status: a cross-sectional analysis of the MARK-AGE cohort.

Br J Nutr 2021 Nov 19:1-28. Epub 2021 Nov 19.

Department of Molecular Toxicology, German Institute of Human Nutrition, 14558 Potsdam-Rehbrücke, Germany.

Self-rated health (SRH) is associated with higher risk of death. Since low plasma levels of fat-soluble vitamins are related to mortality, we aimed to assess whether plasma concentrations of vitamins A, D and E were associated with SRH in the MARK-AGE study. We included 3158 participants (52% female) aged between 35-75 years. Cross-sectional data were collected via questionnaires. An enzyme immunoassay quantified 25-hydroxyvitamin D and HPLC determined α-tocopherol and retinol plasma concentrations. The median 25-hydroxyvitamin D and retinol concentrations differed significantly (P<0.001) between SRH categories, and were lower in the combined fair/poor category versus the excellent, very good, good categories (25-hydroxvitamin D: 40.8 vs. 51.9, 49.3, 46.7 nmol/l, respectively; retinol: 1.67 vs. 1.75, 1.74, 1.70 µmol/l, respectively). Both vitamin D and retinol status were independently associated with fair/poor SRH in multiple regression analyses: adjusted ORs (95% CI) for the vitamin D insufficiency, deficiency, severe deficiency categories were 1.33 (1.06-1.68), 1.50 (1.17-1.93), and 1.83 (1.34-2.50) respectively; P=0.015, P=0.001, P<0.001, and for the second/third/fourth retinol quartiles: 1.44 (1.18-1.75), 1.57 (1.28-1.93), 1.49 (1.20-1.84); all P<0.001. No significant associations were reported for α-tocopherol quartiles. Lower vitamin A and D status emerged as independent markers for fair/poor SRH. Further insights into the long-term implications of these modifiable nutrients on health status are warranted.
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http://dx.doi.org/10.1017/S0007114521004633DOI Listing
November 2021

Spontaneous Degenerative Aortic Valve Disease in New Zealand Obese Mice.

J Am Heart Assoc 2021 Nov 15:e023131. Epub 2021 Nov 15.

German Centre for Cardiovascular Research (partner site Berlin) Berlin Germany.

Background Degenerative aortic valve (AoV) disease and resulting aortic stenosis are major clinical health problems. Murine models of valve disease are rare, resulting in a translational knowledge gap on underlying mechanisms, functional consequences, and potential therapies. Naïve New Zealand obese (NZO) mice were recently found to have a dramatic decline of left ventricular (LV) function at early age. Therefore, we aimed to identify the underlying cause of reduced LV function in NZO mice. Methods and Results Cardiac function and pulmonary hemodynamics of NZO and age-matched C57BL/6J mice were monitored by serial echocardiographic examinations. AoVs in NZO mice demonstrated extensive thickening, asymmetric aortic leaflet formation, and cartilaginous transformation of the valvular stroma. Doppler echocardiography of the aorta revealed increased peak velocity profiles, holodiastolic flow reversal, and dilatation of the ascending aorta, consistent with aortic stenosis and regurgitation. Compensated LV hypertrophy deteriorated to decompensated LV failure and remodeling, as indicated by increased LV mass, interstitial fibrosis, and inflammatory cell infiltration. Elevated LV pressures in NZO mice were associated with lung congestion and , evident as right ventricular dilatation, decreased right ventricular function, and increased mean right ventricular systolic pressure, indicative for the development of pulmonary hypertension and ultimately right ventricular failure. Conclusions NZO mice demonstrate as a novel murine model to spontaneously develop degenerative AoV disease, aortic stenosis, and the associated end organ damages of both ventricles and the lung. Closely mimicking the clinical scenario of degenerative AoV disease, the model may facilitate a better mechanistic understanding and testing of novel treatment strategies in degenerative AoV disease.
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http://dx.doi.org/10.1161/JAHA.121.023131DOI Listing
November 2021

CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases.

Circulation 2021 Nov 11. Epub 2021 Nov 11.

Institute of Biochemistry, Charitá - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Many heart diseases can develop a reduced pumping capacity of the heart muscle. A mismatch between ATP demand and ATP production of cardiomyocytes is one of the possible causes. Assessment of the relation between the myocardial ATP production (MV) and cardiac workload is important for better understanding disease development and choice of nutritional or pharmacological treatment strategies. As there is currently no method for the measurement of MV , the use of physiology-based metabolic models in conjunction with protein abundance data is an attractive approach. We developed a comprehensive kinetic model of the cardiac energy metabolism (CARDIOKIN1), which recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts and studies with humans. We used the model to assess the energy status of the left ventricle (LV) of healthy subjects and patients with aortic stenosis (AS) and mitral valve insufficiency (MI). Maximal enzyme activities were individually scaled by means of protein abundances in LV tissue samples. The energy status of the LV was quantified by the ATP consumption at rest (MV (rest)), at maximal workload (MV (max)), and by the myocardial ATP production reserve (MAPR) representing the span between MV (rest) and MV (max). Compared with controls, in both groups of patients, MV (rest) was increased and MV (max) was decreased resulting in a decreased MAPR, although all patients had preserved ejection fraction. Notably, the variance of the energetic status was high ranging from decreased to normal values. In both patient groups, the energetic status was tightly associated with mechanic energy demand. Moreover, a decrease of MV (max) was associated with a decrease of the cardiac output indicating that cardiac functionality and energetic performance of the ventricle are closely coupled. Our analysis suggests that the ATP producing capacity of the LV of patients with valvular dysfunction is generally diminished and correlates positively with mechanic energy demand and cardiac output. However, large differences exist in the energetic state of the myocardium even in patients with similar clinical or image-based markers of hypertrophy and pump function.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055646DOI Listing
November 2021

Fasting concentrations and postprandial response of 1,2-dicarbonyl compounds 3-deoxyglucosone, glyoxal and methylglyoxal are not increased in healthy older adults.

J Gerontol A Biol Sci Med Sci 2021 Nov 2. Epub 2021 Nov 2.

German Institute of Human Nutrition, Potsdam - Rehbrücke, Department of Molecular Toxicology, Nuthetal, Germany.

Dicarbonyl stress describes the increased formation of 1,2-dicarbonyl compounds and is associated with age-related pathologies. The role of dicarbonyl stress in healthy aging is poorly understood. In a preliminary study, we analyzed 1,2-dicarbonyl compounds, namely 3-deoxyglucosone (3-DG), glyoxal (GO) and methylglyoxal (MGO) in plasma of older (25 months, n=11) and younger (5 months, n=14) male C57BL/6J (B6) mice via UPLC-MS/MS. Postprandial 3-DG was higher in younger compared to older mice, whereas no differences were found for GO and MGO. Subsequently, in the main study, we analyzed fasting serum of older (OW, 72.4±6.14 years, n=19) and younger women (YW, 27.0±4.42 years, n=19) as well as older (OM, 74.3±5.20 years, n=15) and younger (YM, 27.0±3.34, n=15) men. Serum glucose, insulin, 1,2-dicarbonyl concentrations and markers of oxidative stress were quantified. In a subgroup of this cohort, an oral dextrose challenge was performed and postprandial response of 1,2-dicarbonyl compounds, glucose and insulin were measured. In women, there were no age differences regarding fasting 1,2-dicarbonyl concentrations nor the response after the oral dextrose challenge. In men, fasting MGO was significantly higher in OM compared to YM (Median: 231 vs.158 nM, p=0.006), whereas no age differences in fasting 3-DG and GO concentrations were found. Glucose (310±71.8 versus 70.8±11.9 min·mmol/L) and insulin (7149±1249 versus 2827±493 min·µIU/mL) response were higher in OM compared to YM, which did not translate into a higher 1,2-dicarbonyl response in older individuals. Overall, aging does not necessarily result in dicarbonyl stress, indicating that strategies to cope with 1,2-dicarbonyl formation can remain intact.
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http://dx.doi.org/10.1093/gerona/glab331DOI Listing
November 2021

Do low molecular weight antioxidants contribute to the Protection against oxidative damage? The interrelation between oxidative stress and low molecular weight antioxidants based on data from the MARK-AGE study.

Arch Biochem Biophys 2021 11 16;713:109061. Epub 2021 Oct 16.

Dept of Physiology and Pharmacology, Sackler Medical School, Tel Aviv University, Tel Aviv, 6997801, Israel; Holon Institute of Technology, Holon, 5810201, Israel. Electronic address:

A redox steady state is important in maintaining vital cellular functions and is therefore homeostatically controlled by a number of antioxidative agents, the most important of which are enzymes. Oxidative Stress (OS) is associated with (or/and caused by) excessive production of damaging reactive oxygen and/or nitrogen species (ROS, RNS), which play a role in many pathologies. Because OS is a risk factor for many diseases, much effort (and money) is devoted to early diagnosis and treatment of OS. The desired benefit of the "identify (OS) and treat (by low molecular weight antioxidants, LMWA)" approach is to enable selective treatment of patients under OS. The present work aims at gaining understanding of the benefit of the antioxidants based on interrelationship between the concentration of different OS biomarkers and LMWA. Both the concentrations of a variety of biomarkers and of LMWA were previously determined and some analyses have been published by the MARK-AGE team. For the sake of simplicity, we assume that the concentration of an OS biomarker is a linear function of the concentration of a LMWA (if the association is due to causal relationship). A negative slope of this dependence (and sign of the correlation coefficient) can be intuitively expected for an antioxidant, a positive slope indicates that the LMWA is pro-oxidative, whereas extrapolation of the OS biomarker to [LMWA] = 0 is an approximation of the concentration of the OS biomarker in the absence of the LMWA. Using this strategy, we studied the effects of 12 LMWA (including tocopherols, carotenoids and ascorbic acid) on the OS status, as observed with 8 biomarkers of oxidative damage (including malondialdehyde, protein carbonyls, 3-nitrotyrosine). The results of this communication show that in a cross-sectional study the LMWA contribute little to the redox state and that different "antioxidants" are very different, so that single LMWA treatment of OS is not scientifically justified assuming our simple model. In view of the difficulty of quantitating the OS and the very different effects of various LMWA, the use of the "identify and treat" approach is questionable.
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http://dx.doi.org/10.1016/j.abb.2021.109061DOI Listing
November 2021

Decreased proteasomal cleavage at nitrotyrosine sites in proteins and peptides.

Redox Biol 2021 10 18;46:102106. Epub 2021 Aug 18.

Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay. Electronic address:

Removal of moderately oxidized proteins is mainly carried out by the proteasome, while highly modified proteins are no longer degradable. However, in the case of proteins modified by nitration of tyrosine residues to 3-nitrotyrosine (NOY), the role of the proteasome remains to be established. For this purpose, degradation assays and mass spectrometry analyses were performed using isolated proteasome and purified fractions of native cytochrome c (Cyt c) and tyrosine nitrated proteoforms (NOY74-Cyt c and NOY97-Cyt c). While Cyt c treated under mild conditions with hydrogen peroxide was preferentially degraded by the proteasome, NOY74- and NOY97-Cyt c species did not show an increased degradation rate with respect to native Cyt c. Peptide mapping analysis confirmed a decreased chymotrypsin-like cleavage at C-terminal of NOY sites within the protein, with respect to unmodified Y residues. Additionally, studies with the proteasome substrate suc-LLVY-AMC (Y-AMC) and its NOY-containing analog, suc-LLVNOY-AMC (NOY-AMC) were performed, both using isolated 20S-proteasome and astrocytoma cell lysates as the proteasomal source. Comparisons of both substrates showed a significantly decreased proteasome activity towards NOY-AMC. Moreover, NOY-AMC, but not Y-AMC degradation rates, were largely diminished by increasing the reaction pH, suggesting an inhibitory influence of the additional negative charge contained in NOY-AMC secondary to nitration. The mechanism of slowing of proteasome activity in NOY-contaning peptides was further substantiated in studies using the phenylalanine and nitro-phenylalanine peptide analog substrates. Finally, degradation rates of Y-AMC and NOY-AMC with proteinase K were the same, demonstrating the selective inability of the proteasome to readily cleave at nitrotyrosine sites. Altogether, data indicate that the proteasome has a decreased capability to cleave at C-terminal of NOY residues in proteins with respect to the unmodified residues, making this a possible factor that decreases the turnover of oxidized proteins, if they are not unfolded, and facilitating the accumulation of nitrated proteins.
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http://dx.doi.org/10.1016/j.redox.2021.102106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403764PMC
October 2021

Microbiome in Blood Samples From the General Population Recruited in the MARK-AGE Project: A Pilot Study.

Front Microbiol 2021 26;12:707515. Epub 2021 Jul 26.

Department of Biology, Ecology and Earth Sciences (DIBEST), University of Calabria, Rende, Italy.

The presence of circulating microbiome in blood has been reported in both physiological and pathological conditions, although its origins, identities and function remain to be elucidated. This study aimed to investigate the presence of blood microbiome by quantitative real-time PCRs targeting the 16S rRNA gene. To our knowledge, this is the first study in which the circulating microbiome has been analyzed in such a large sample of individuals since the study was carried out on 1285 Randomly recruited Age-Stratified Individuals from the General population (RASIG). The samples came from several different European countries recruited within the EU Project MARK-AGE in which a series of clinical biochemical parameters were determined. The results obtained reveal an association between microbial DNA copy number and geographic origin. By contrast, no gender and age-related difference emerged, thus demonstrating the role of the environment in influencing the above levels independent of age and gender at least until the age of 75. In addition, a significant positive association was found with Free Fatty Acids (FFA) levels, leukocyte count, insulin, and glucose levels. Since these factors play an essential role in both health and disease conditions, their association with the extent of the blood microbiome leads us to consider the blood microbiome as a potential biomarker of human health.
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http://dx.doi.org/10.3389/fmicb.2021.707515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350766PMC
July 2021

Altered Adiponectin Response in Older Women Following Dextrose and High-Fat Dietary Challenges.

Mol Nutr Food Res 2021 09 4;65(17):e2100487. Epub 2021 Aug 4.

Department of Nutrition and Gerontology, German Institute of Human Nutrition, Potsdam - Rehbrücke, Nuthetal, Germany.

Scope: Despite its beneficial properties, higher adiponectin concentrations are paradoxically associated with mortality in advanced age. Several mechanisms are being discussed. However, little is known about postprandial regulation of adiponectin in older adults. We assessed age-specific differences of the adiponectin response to different test meals considering potential determinants.

Methods And Results: Older (n = 20) and younger (n = 22) women are randomized to a dextrose (DEX) or high-fat (HF) dietary challenge. Postprandial adiponectin and fibroblast growth factor 21 (FGF21) concentrations are measured before and 60, 120, 240 min after ingestion. We assessed postprandial changes and group differences using linear mixed models controlled for possible determinants. In younger women, postprandial adiponectin remains stable after both test meals. In contrast, adiponectin increases following DEX and decreases after HF in older women, irrespective of control variables. Postprandial adiponectin is positively associated with malondialdehyde and inversely associated with interleukin-6 following DEX and also negatively associated with metabolic parameters after both test meals. In older women, elevated postprandial FGF21 concentrations are associated with a higher adiponectin response (β = 30.7, 95% CI 10.6-50.8, p = 0.007).

Conclusions: Adiponectin response is associated with type of dietary challenge, age, and FGF21 response. Age-group differences are partly attributable to metabolic parameters and oxidative stress.
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http://dx.doi.org/10.1002/mnfr.202100487DOI Listing
September 2021

Special issue on 'Biomarkers of Oxidative Stress, Aging and Nutrition in Human Studies'.

Redox Biol 2021 09 25;45:102059. Epub 2021 Jun 25.

Department of Molecular Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Nuthetal, Germany.

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http://dx.doi.org/10.1016/j.redox.2021.102059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282506PMC
September 2021

Contribution to the ongoing discussion on fluoride toxicity.

Arch Toxicol 2021 07 6;95(7):2571-2587. Epub 2021 Jun 6.

Department of Nutrition and Food Sciences, Nutritional Epidemiology, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany.

Since the addition of fluoride to drinking water in the 1940s, there have been frequent and sometimes heated discussions regarding its benefits and risks. In a recently published review, we addressed the question if current exposure levels in Europe represent a risk to human health. This review was discussed in an editorial asking why we did not calculate benchmark doses (BMD) of fluoride neurotoxicity for humans. Here, we address the question, why it is problematic to calculate BMDs based on the currently available data. Briefly, the conclusions of the available studies are not homogeneous, reporting negative as well as positive results; moreover, the positive studies lack control of confounding factors such as the influence of well-known neurotoxicants. We also discuss the limitations of several further epidemiological studies that did not meet the inclusion criteria of our review. Finally, it is important to not only focus on epidemiological studies. Rather, risk analysis should consider all available data, including epidemiological, animal, as well as in vitro studies. Despite remaining uncertainties, the totality of evidence does not support the notion that fluoride should be considered a human developmental neurotoxicant at current exposure levels in European countries.
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http://dx.doi.org/10.1007/s00204-021-03072-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241794PMC
July 2021

Age, Sex, and BMI Influence on Copper, Zinc, and Their Major Serum Carrier Proteins in a Large European Population Including Nonagenarian Offspring From MARK-AGE Study.

J Gerontol A Biol Sci Med Sci 2021 Nov;76(12):2097-2106

Translational Research Center of Nutrition and Ageing, IRCCS INRCA, Ancona, Italy.

The analysis of copper (Cu) and zinc (Zn) along with their major serum carriers, albumin (Alb) and ceruloplasmin (Cp), could provide information on the capacity of humans to maintain homeostasis of metals (metallostasis). However, their relationship with aging, sex, body mass index, as well as with nutritional and inflammatory markers was never investigated in a large-scale study. Here, we report results from the European large-scale cross-sectional study MARK-AGE in which Cu, Zn, Alb, Cp, as well as nutritional and inflammatory parameters were determined in 2424 age-stratified participants (35-75 years), including the general population (RASIG), nonagenarian offspring (GO), a well-studied genetic model of longevity, and spouses of GO (SGO). In RASIG, Cu to Zn ratio and Cp to Alb ratio were higher in women than in men. Both ratios increased with aging because Cu and Cp increased and Alb and Zn decreased. Cu, Zn, Alb, and Cp were found associated with several inflammatory as well as nutritional biomarkers. GO showed higher Zn levels and higher Zn to Alb ratio compared to RASIG, but we did not observe significant differences with SGO, likely as a consequence of the low sample size of SGO and the shared environment. Our results show that aging, sex, body mass index, and GO status are characterized by different levels of Cu, Zn, and their serum carrier proteins. These data and their relationship with inflammatory biomarkers support the concept that loss of metallostasis is a characteristic of inflammaging.
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http://dx.doi.org/10.1093/gerona/glab134DOI Listing
November 2021

Hepatic Wnt1 Inducible Signaling Pathway Protein 1 (WISP-1/CCN4) Associates with Markers of Liver Fibrosis in Severe Obesity.

Cells 2021 04 29;10(5). Epub 2021 Apr 29.

German Center for Diabetes Research (DZD), 85764 Munich-Neuherberg, Germany.

Liver fibrosis is a critical complication of obesity-induced fatty liver disease. Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4), a novel adipokine associated with visceral obesity and insulin resistance, also contributes to lung and kidney fibrosis. The aim of the present study was to investigate the role of CCN4 in liver fibrosis in severe obesity. For this, human liver biopsies were collected from 35 severely obese humans (BMI 42.5 ± 0.7 kg/m, age 46.7 ± 1.8 y, 25.7% males) during bariatric surgery and examined for the expression of CCN4, fibrosis, and inflammation markers. Hepatic stellate LX-2 cells were treated with human recombinant CCN4 alone or in combination with LPS or transforming growth factor beta (TGF-β) and examined for fibrosis and inflammation markers. CCN4 mRNA expression in the liver positively correlated with BMI and expression of fibrosis markers COL1A1, COL3A1, COL6A1, αSMA, TGFB1, extracellular matrix turnover enzymes TIMP1 and MMP9, and the inflammatory marker ITGAX/CD11c. In LX-2 cells, the exposure to recombinant CCN4 caused dose-dependent induction of MMP9 and MCP1. CCN4 potentiated the TGF-β-mediated induction of COL3A1, TIMP1, and MCP1 but showed no interaction with LPS treatment. Our results suggest a potential contribution of CCN4 to the early pathogenesis of obesity-associated liver fibrosis.
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http://dx.doi.org/10.3390/cells10051048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146455PMC
April 2021

Hypertrophy-Reduced Autophagy Causes Cardiac Dysfunction by Directly Impacting Cardiomyocyte Contractility.

Cells 2021 04 4;10(4). Epub 2021 Apr 4.

DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany.

Cardiac remodeling and contractile dysfunction are leading causes in hypertrophy-associated heart failure (HF), increasing with a population's rising age. A hallmark of aged and diseased hearts is the accumulation of modified proteins caused by an impaired autophagy-lysosomal-pathway. Although, autophagy inducer rapamycin has been described to exert cardioprotective effects, it remains to be shown whether these effects can be attributed to improved cardiomyocyte autophagy and contractility. In vivo hypertrophy was induced by transverse aortic constriction (TAC), with mice receiving daily rapamycin injections beginning six weeks after surgery for four weeks. Echocardiographic analysis demonstrated TAC-induced HF and protein analyses showed abundance of modified proteins in TAC-hearts after 10 weeks, both reduced by rapamycin. In vitro, cardiomyocyte hypertrophy was mimicked by endothelin 1 (ET-1) and autophagy manipulated by silencing Atg5 in neonatal cardiomyocytes. ET-1 and siAtg5 decreased Atg5-Atg12 and LC3-II, increased natriuretic peptides, and decreased amplitude and early phase of contraction in cardiomyocytes, the latter two evaluated using ImageJ macro Myocyter recently developed by us. ET-1 further decreased cell contractility in control but not in siAtg5 cells. In conclusion, ET-1 decreased autophagy and cardiomyocyte contractility, in line with siAtg5-treated cells and the results of TAC-mice demonstrating a crucial role for autophagy in cardiomyocyte contractility and cardiac performance.
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http://dx.doi.org/10.3390/cells10040805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065800PMC
April 2021

Network analysis in aged C. elegans reveals candidate regulatory genes of ageing.

Biogerontology 2021 06 19;22(3):345-367. Epub 2021 Apr 19.

Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 116 35, Athens, Greece.

Ageing is a biological process guided by genetic and environmental factors that ultimately lead to adverse outcomes for organismal lifespan and healthspan. Determination of molecular pathways that are affected with age and increase disease susceptibility is crucial. The gene expression profile of the ideal ageing model, namely the nematode Caenorhabditis elegans mapped with the microarray technology initially led to the identification of age-dependent gene expression alterations that characterize the nematode's ageing process. The list of differentially expressed genes was then utilized to construct a network of molecular interactions with their first neighbors/interactors using the interactions listed in the WormBase database. The subsequent network analysis resulted in the unbiased selection of 110 candidate genes, among which well-known ageing regulators appeared. More importantly, our approach revealed candidates that have never been linked to ageing before, thus suggesting promising potential targets/ageing regulators.
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http://dx.doi.org/10.1007/s10522-021-09920-3DOI Listing
June 2021

Ageing affects subtelomeric DNA methylation in blood cells from a large European population enrolled in the MARK-AGE study.

Geroscience 2021 06 19;43(3):1283-1302. Epub 2021 Apr 19.

Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.

Ageing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give promising insights into this issue. Previously reported associations between susceptibility to age-related diseases and epigenetic instability at subtelomeres suggest that the DNA methylation profile of subtelomeres undergoes remodelling during ageing. In the present work, this hypothesis has been tested in the context of the European large-scale project MARK-AGE. In this cross-sectional study, we profiled the DNA methylation of chromosomes 5 and 21 subtelomeres, in more than 2000 age-stratified women and men recruited in eight European countries. The study included individuals from the general population as well as the offspring of nonagenarians and Down syndrome subjects, who served as putative models of delayed and accelerated ageing, respectively. Significant linear changes of subtelomeric DNA methylation with increasing age were detected in the general population, indicating that subtelomeric DNA methylation changes are typical signs of ageing. Data also show that, compared to the general population, the dynamics of age-related DNA methylation changes are attenuated in the offspring of centenarian, while they accelerate in Down syndrome individuals. This result suggests that subtelomeric DNA methylation changes reflect the rate of ageing progression. We next attempted to trace the age-related changes of subtelomeric methylation back to the influence of diverse variables associated with methylation variations in the population, including demographics, dietary/health habits and clinical parameters. Results indicate that the effects of age on subtelomeric DNA methylation are mostly independent of all other variables evaluated.
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http://dx.doi.org/10.1007/s11357-021-00347-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190237PMC
June 2021

Microbiota profiling in aging-associated inflammation and liver degeneration.

Int J Med Microbiol 2021 May 29;311(4):151500. Epub 2021 Mar 29.

Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria. Electronic address:

Background: The number of people above the age of 60 years is raising world-wide being associated with an increase in the prevalence of aging-associated impairments and even diseases. Recent studies suggest that aging is associated with alterations in bacterial endotoxin levels and that these changes may add to low-grade inflammation, the so-called 'inflammaging', and aging-associated liver degeneration. However, mechanisms involved, and especially, the interaction of intestinal microbiota and barrier in the development of aging-associated inflammation and liver degeneration have not been fully understood.

Objective: The aim of the present study was to determine if intestinal microbiota composition changes with age and if these alterations are associated with changes of markers of intestinal barrier function and the development of inflammation and liver degeneration.

Methods: Blood, liver, small and large intestinal tissue of male 2-, 15-, 24- and 30-months old C57BL/6 mice fed standard chow were obtained. Intestinal microbiota composition, expression levels of antimicrobial peptides in small intestine and markers of intestinal barrier function were measured. Furthermore, indices of liver damage, inflammation and expression levels of lipopolysaccharide binding protein (Lbp) as well as of toll-like receptors (Tlr) 1-9 in liver tissue were assessed.

Results: Pairwise comparisons of the microbial community in the small intestine showed differences between 2- and 24-, 15- and 24-, as well as 15- and 30-months old animals while Shannon's diversity, species richness and evenness indexes did not differ in both small and large intestine, respectively, between age groups. Concentrations of nitric oxide were significantly lower in small intestine of 15-, 24- and 30-months old mice compared to 2-months old mice while mRNA expression of the antimicrobial peptides defensin alpha 1 and lysozyme 1 was unchanged. In contrast, in liver tissue, older age of animals was associated with increasing inflammation and the development of fibrosis in 24- and 30-months old mice. Numbers of inflammatory foci and neutrophils in livers of 24- and 30-months old mice were significantly higher compared to 2-months old mice. These alterations were also associated with higher endotoxin levels in plasma as well as an increased mRNA expression of Lbp and Tlr1, Tlr2, Tlr4, Tlr6 and Tlr9 in livers in older mice.

Conclusion: Despite no consistent and robust changes of microbiota composition in small and/or large intestine of mice of different age were observed, our data suggest that alterations of markers of intestinal barrier function in small intestine are associated with an induction of several Tlrs and beginning hepatic inflammation in older mice and increase with age.
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http://dx.doi.org/10.1016/j.ijmm.2021.151500DOI Listing
May 2021

Reduced Liver Autophagy in High-Fat Diet Induced Liver Steatosis in New Zealand Obese Mice.

Antioxidants (Basel) 2021 Mar 24;10(4). Epub 2021 Mar 24.

Department of Molecular Toxicology, German Institute of Human Nutrition, Potsdam-Rehbruecke, 14558 Nuthetal, Germany.

Non-alcoholic fatty liver disease (NAFLD), as a consequence of overnutrition caused by high-calorie diets, results in obesity and disturbed lipid homeostasis leading to hepatic lipid droplet formation. Lipid droplets can impair hepatocellular function; therefore, it is of utmost importance to degrade these cellular structures. This requires the normal function of the autophagic-lysosomal system and the ubiquitin-proteasomal system. We demonstrated in NZO mice, a polygenic model of obesity, which were compared to C57BL/6J (B6) mice, that a high-fat diet leads to obesity and accumulation of lipid droplets in the liver. This was accompanied by a loss of autophagy efficiency whereas the activity of lysosomal proteases and the 20S proteasome remained unaffected. The disturbance of cellular protein homeostasis was further demonstrated by the accumulation of 3-nitrotyrosine and 4-hydroxynonenal modified proteins, which are normally prone to degradation. Therefore, we conclude that fat accumulation in the liver due to a high-fat diet is associated with a failure of autophagy and leads to the disturbance of proteostasis. This might further contribute to lipid droplet stabilization and accumulation.
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http://dx.doi.org/10.3390/antiox10040501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063826PMC
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

A robust machine learning framework to identify signatures for frailty: a nested case-control study in four aging European cohorts.

Geroscience 2021 06 18;43(3):1317-1329. Epub 2021 Feb 18.

German Institute for Human Nutrition, Potsdam, Germany.

Phenotype-specific omic expression patterns in people with frailty could provide invaluable insight into the underlying multi-systemic pathological processes and targets for intervention. Classical approaches to frailty have not considered the potential for different frailty phenotypes. We characterized associations between frailty (with/without disability) and sets of omic factors (genomic, proteomic, and metabolomic) plus markers measured in routine geriatric care. This study was a prevalent case control using stored biospecimens (urine, whole blood, cells, plasma, and serum) from 1522 individuals (identified as robust (R), pre-frail (P), or frail (F)] from the Toledo Study of Healthy Aging (R=178/P=184/F=109), 3 City Bordeaux (111/269/100), Aging Multidisciplinary Investigation (157/79/54) and InCHIANTI (106/98/77) cohorts. The analysis included over 35,000 omic and routine laboratory variables from robust and frail or pre-frail (with/without disability) individuals using a machine learning framework. We identified three protective biomarkers, vitamin D3 (OR: 0.81 [95% CI: 0.68-0.98]), lutein zeaxanthin (OR: 0.82 [95% CI: 0.70-0.97]), and miRNA125b-5p (OR: 0.73, [95% CI: 0.56-0.97]) and one risk biomarker, cardiac troponin T (OR: 1.25 [95% CI: 1.23-1.27]). Excluding individuals with a disability, one protective biomarker was identified, miR125b-5p (OR: 0.85, [95% CI: 0.81-0.88]). Three risks of frailty biomarkers were detected: pro-BNP (OR: 1.47 [95% CI: 1.27-1.7]), cardiac troponin T (OR: 1.29 [95% CI: 1.21-1.38]), and sRAGE (OR: 1.26 [95% CI: 1.01-1.57]). Three key frailty biomarkers demonstrated a statistical association with frailty (oxidative stress, vitamin D, and cardiovascular system) with relationship patterns differing depending on the presence or absence of a disability.
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http://dx.doi.org/10.1007/s11357-021-00334-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190217PMC
June 2021

Sensitivity of Osteosarcoma Cells to Concentration-Dependent Bioactivities of Lipid Peroxidation Product 4-Hydroxynonenal Depend on Their Level of Differentiation.

Cells 2021 01 29;10(2). Epub 2021 Jan 29.

Laboratory for Oxidative Stress (LabOS), Division of Molecular Medicine, Rudjer Boskovic Institute, HR-10000 Zagreb, Croatia.

4-Hydroxynonenal (HNE) is a major aldehydic product of lipid peroxidation known to exert several biological effects. Normal and malignant cells of the same origin express different sensitivity to HNE. We used human osteosarcoma cells (HOS) in different stages of differentiation in vitro, showing differences in mitosis, DNA synthesis, and alkaline phosphatase (ALP) staining. Differentiated HOS cells showed decreased proliferation (H-thymidine incorporation), decreased viability (thiazolyl blue tetrazolium bromide-MTT), and increased apoptosis and necrosis (nuclear morphology by staining with 4',6-diamidino-2-phenylindole-DAPI). Differentiated HOS also had less expressed c-MYC, but the same amount of c-FOS (immunocytochemistry). When exposed to HNE, differentiated HOS produced more reactive oxygen species (ROS) in comparison with undifferentiated HOS. To clarify this, we measured HNE metabolism by an HPLC method, total glutathione (GSH), oxidized GSH (ox GSH), glutathione transferase activity (GST), proteasomal activity by enzymatic methods, HNE-protein adducts by genuine ELISA and fatty acid composition by GC-MS in these cell cultures. Differentiated HOS cells had less GSH, lower HNE metabolism, increased formation of HNE-protein adducts, and lower proteasomal activity, in comparison to undifferentiated counterpart cells, while GST and oxGSH were the same. Fatty acids analyzed by GC-MS showed that there is an increase in C20:3 in differentiated HOS while the amount of C20:4 remained the same. The results showed that the cellular machinery responsible for protection against toxicity of HNE was less efficient in differentiated HOS cells. Moreover, differentiated HOS cells contained more C20:3 fatty acid, which might make them more sensitive to free radical-initiated oxidative chain reactions and more vulnerable to the effects of reactive aldehydes such as HNE. We propose that HNE might act as natural promotor of decay of malignant (osteosarcoma) cells in case of their differentiation associated with alteration of the lipid metabolism.
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http://dx.doi.org/10.3390/cells10020269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912392PMC
January 2021

Sarcopenia - Molecular mechanisms and open questions.

Ageing Res Rev 2021 01 29;65:101200. Epub 2020 Oct 29.

German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, 13347 Berlin, Germany; University of Potsdam, Institute of Nutritional Science, Nuthetal, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Nuthetal, Germany. Electronic address:

Sarcopenia represents a muscle-wasting syndrome characterized by progressive and generalized degenerative loss of skeletal muscle mass, quality, and strength occurring during normal aging. Sarcopenia patients are mainly suffering from the loss in muscle strength and are faced with mobility disorders reducing their quality of life and are, therefore, at higher risk for morbidity (falls, bone fracture, metabolic diseases) and mortality. Several molecular mechanisms have been described as causes for sarcopenia that refer to very different levels of muscle physiology. These mechanisms cover e. g. function of hormones (e. g. IGF-1 and Insulin), muscle fiber composition and neuromuscular drive, myo-satellite cell potential to differentiate and proliferate, inflammatory pathways as well as intracellular mechanisms in the processes of proteostasis and mitochondrial function. In this review, we describe sarcopenia as a muscle-wasting syndrome distinct from other atrophic diseases and summarize the current view on molecular causes of sarcopenia development as well as open questions provoking further research efforts for establishing efficient lifestyle and therapeutic interventions.
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http://dx.doi.org/10.1016/j.arr.2020.101200DOI Listing
January 2021

Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: Role of thioredoxin-interacting protein (TXNIP).

Redox Biol 2020 10 7;37:101748. Epub 2020 Oct 7.

Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, Muenchen-Neuherberg, Germany. Electronic address:

Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetes-prone NZO mice.
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http://dx.doi.org/10.1016/j.redox.2020.101748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589534PMC
October 2020

Long-term effects of a food pattern on cardiovascular risk factors and age-related changes of muscular and cognitive function.

Medicine (Baltimore) 2020 Sep;99(39):e22381

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin.

Introduction: The mean age of the German population increased over the last years, which resulted in a higher prevalence of cardiovascular diseases, type 2 diabetes, cognitive impairment, sarcopenia and bone fractures. Current evidence indicates a preservation of human wellbeing in the elderly by a healthy diet, although the recommended macronutrient composition and quality remains unclear and needs further long-term investigation. In this context we investigate the effect of a specific dietary pattern on age-related disorders in a randomized controlled multi-center trial (RCT).

Methods: We assess the effect of a specific dietary pattern (NutriAct) with a high proportion of unsaturated fat, plant proteins and fibres (fat 35%-40% of total energy (%E) of which 15%E-20%E monounsaturated fatty acids (MUFA) and 10%E-15%E polyunsaturated fatty acids (PUFA), 15%E-25%E proteins, ≥30 g fibres per day and 35%E-45%E carbohydrates) on age-related impairment of health within a 36-months RCT conducted in the region of Berlin and Potsdam. 502 eligible men (n = 183) and women (n = 319), aged 50 to 80 years, with an increased risk to develop age-related diseases were randomly assigned to either an intervention group focusing on NutriAct dietary pattern or a control group focusing on usual care and dietary recommendations in accordance to the German Nutrition Society (DGE). In the intervention group, 21 nutrition counsellings as well as supplementation of rapeseed oil, oil cake and specific designed foods are used to achieve the intended NutriAct dietary pattern.The primary outcome is a composite endpoint of age-related disorders, including cardiovascular morbidity, decline of cognitive function as well as clinical features of sarcopenia. Secondary outcomes include diet-induced effects on quality of life, depression, frailty, cardiovascular function, bone density, fat distribution pattern, glucose, lipid and energy metabolism, as well as the identification of biomarkers linked with age-related disorders.

Discussion: The findings of this trial will provide clinically relevant information regarding dietary effects on age-related impairment of health and will contribute to the definition of the optimal macronutrient composition in the context of healthy aging in the German population.
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http://dx.doi.org/10.1097/MD.0000000000022381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523819PMC
September 2020

Punicalagin Attenuates Palmitate-Induced Lipid Droplet Content by Simultaneously Improving Autophagy in Hepatocytes.

Mol Nutr Food Res 2020 10 28;64(20):e2000816. Epub 2020 Sep 28.

Department of Molecular Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Nuthetal, 14558, Germany.

Scope: Several studies show that excessive lipid intake can cause hepatic steatosis. To investigate lipotoxicity on cellular level, palmitate (PA) is often used to highly increase lipid droplets (LDs). One way to remove LDs is autophagy, while it is controversially discussed if autophagy is also affected by PA. It is aimed to investigate whether PA-induced LD accumulation can impair autophagy and punicalagin, a natural autophagy inducer from pomegranate, can improve it.

Methods And Results: To verify the role of autophagy in LD degradation, HepG2 cells are treated with PA and analyzed for LD and perilipin 2 content in presence of autophagy inducer Torin 1 and inhibitor 3-Methyladenine. PA alone seems to initially induce autophagy-related proteins but impairs autophagic-flux in a time-dependent manner, considering 6 and 24 h PA. To examine whether punicalagin can prevent autophagy impairment, cells are cotreated for 24 h with PA and punicalagin. Results show that punicalagin preserves expression of autophagy-related proteins and autophagic flux, while simultaneously decreasing LDs and perilipin 2.

Conclusion: Data provide new insights into the role of PA-induced excessive LD content on autophagy and suggest autophagy-inducing properties of punicalagin, indicating that punicalagin can be a health-beneficial compound for future research on lipotoxicity in liver.
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http://dx.doi.org/10.1002/mnfr.202000816DOI Listing
October 2020

Accumulation of polyubiquitinated proteins: A consequence of early inactivation of the 26S proteasome.

Free Radic Biol Med 2020 11 18;160:293-302. Epub 2020 Aug 18.

Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbrücke, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany; German Center for Cardiovascular Research (DZHK), 10117, Berlin, Germany; University of Potsdam, Institute of Nutritional Science, 14558, Nuthetal, Germany. Electronic address:

The proteasomal degradation system is one of the most important protein degradation systems in the cytosol and nucleus. This system is present in two major forms: the ATP-stimulated 26S/30 S proteasome or the ATP-independent 20S core proteasome. While the first recognize ubiquitin-tagged target proteins and degrade them, the 20S proteasome works also independent from ATP, but requires partially unfolded substrates. While the role of the proteasome in the selective removal of oxidized proteins is undoubted, the debate about a selective ubiquitination of oxidized proteins is still ongoing. Here we demonstrate, that under some conditions of oxidative stress an accumulation of oxidized and of K48-ubiquitinated proteins occurs. However, the removal of oxidized proteins seems not to be linked to ubiquitination. In further experiments, we could show that the accumulation of ubiquitinated proteins under certain oxidative stress conditions is rather a result of a different sensitivity of the 26S proteasome and the ubiquitination machinery towards oxidants.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.08.008DOI Listing
November 2020

Age-Related Maintenance of the Autophagy-Lysosomal System Is Dependent on Skeletal Muscle Type.

Oxid Med Cell Longev 2020 24;2020:4908162. Epub 2020 Jul 24.

Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany.

The skeletal muscle plays an important role in maintaining whole-body mechanics, metabolic homeostasis, and interorgan crosstalk. However, during aging, functional and structural changes such as fiber integrity loss and atrophy can occur across different species. A commonly observed hallmark of aged skeletal muscle is the accumulation of oxidatively modified proteins and protein aggregates which point to an imbalance in proteostasis systems such as degradation machineries. Recently, we showed that the ubiquitin-proteasomal system was impaired. Specifically, the proteasomal activity, which was declining in aged (SOL) and (EDL). Therefore, in order to understand whether another proteolytic system would compensate the decline in proteasomal activity, we aimed to investigate age-related changes in the autophagy-lysosomal system (ALS) in SOL, mostly consisting of slow-twitch fibers, and EDL, mainly composed of fast-twitch fibers, from young (4 months) and old (25 months) C57BL/6JRj mice. Here, we focused on changes in the content of modified proteins and the ALS. Our results show that aged SOL and EDL display high levels of protein modifications, particularly in old SOL. While autophagy machinery appears to be functional, lysosomal activity declines gradually in aged SOL. In contrast, in old EDL, the ALS seems to be affected, demonstrated by an increased level of key autophagy-related proteins, which are known to accumulate when their delivery or degradation is impaired. In fact, lysosomal activity was significantly decreased in old EDL. Results presented herein suggest that the ALS can compensate the high levels of modified proteins in the more oxidative muscle, SOL, while EDL seems to be more prone to ALS age-related alterations.
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http://dx.doi.org/10.1155/2020/4908162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396090PMC
May 2021

High-protein diet more effectively reduces hepatic fat than low-protein diet despite lower autophagy and FGF21 levels.

Liver Int 2020 12 21;40(12):2982-2997. Epub 2020 Jul 21.

Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany.

Background And Aims: Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent and nutrition intervention remains the most important therapeutic approach for NAFLD. Our aim was to investigate whether low- (LP) or high-protein (HP) diets are more effective in reducing liver fat and reversing NAFLD and which mechanisms are involved.

Methods: 19 participants with morbid obesity undergoing bariatric surgery were randomized into two hypocaloric (1500-1600 kcal/day) diet groups, a low protein (10E% protein) and a high protein (30E% protein), for three weeks prior to surgery. Intrahepatic lipid levels (IHL) and serum fibroblast growth factor 21 (FGF21) were measured before and after the dietary intervention. Autophagy flux, histology, mitochondrial activity and gene expression analyses were performed in liver samples collected during surgery.

Results: IHL levels decreased by 42.6% in the HP group, but were not significantly changed in the LP group despite similar weight loss. Hepatic autophagy flux and serum FGF21 increased by 66.7% and 42.2%, respectively, after 3 weeks in the LP group only. Expression levels of fat uptake and lipid biosynthesis genes were lower in the HP group compared with those in the LP group. RNA-seq analysis revealed lower activity of inflammatory pathways upon HP diet. Hepatic mitochondrial activity and expression of β-oxidation genes did not increase in the HP group.

Conclusions: HP diet more effectively reduces hepatic fat than LP diet despite of lower autophagy and FGF21. Our data suggest that liver fat reduction upon HP diets result primarily from suppression of fat uptake and lipid biosynthesis.
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http://dx.doi.org/10.1111/liv.14596DOI Listing
December 2020

Medication Intake Is Associated with Lower Plasma Carotenoids and Higher Fat-Soluble Vitamins in the Cross-Sectional MARK-AGE Study in Older Individuals.

J Clin Med 2020 Jul 1;9(7). Epub 2020 Jul 1.

Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany.

The regular use of medication may interfere with micronutrient metabolism on several levels, such as absorption, turnover rate, and tissue distribution, and this might be amplified during aging. This study evaluates the impact of self-reported medication intake on plasma micronutrients in the MARK-AGE Project, a cross-sectional observational study in 2217 subjects (age- and sex-stratified) aged 35-75 years from six European countries that were grouped according to age. Polypharmacy as possible determinant of micronutrient concentrations was assessed using multiple linear regression models adjusted for age-group, dietary fruit, vegetables, and juice intake, and other confounders. Younger participants reported taking fewer drugs than older participants. Inverse associations between medication intake and lutein (-3.31% difference per increase in medication group), β-carotene (-11.44%), α-carotene (-8.50%) and positive associations with retinol (+2.26%), α-tocopherol/cholesterol (+2.89%) and γ-tocopherol/cholesterol (+1.36%) occurred in multiple adjusted regression models. Combined usage of a higher number of medical drugs was associated with poorer status of carotenoids on the one hand and higher plasma concentrations of retinol, α- and γ-tocopherol on the other hand. Our results raise concerns regarding the safety of drug combinations via the significant and surprisingly multifaceted disturbance of the concentrations of relevant micronutrients.
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http://dx.doi.org/10.3390/jcm9072072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408954PMC
July 2020

Aging affects sex- and organ-specific trace element profiles in mice.

Aging (Albany NY) 2020 07 3;12(13):13762-13790. Epub 2020 Jul 3.

Department of Molecular Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany.

A decline of immune responses and dynamic modulation of the redox status are observed during aging and are influenced by trace elements such as copper, iodine, iron, manganese, selenium, and zinc. So far, analytical studies have focused mainly on single trace elements. Therefore, we aimed to characterize age-specific profiles of several trace elements simultaneously in serum and organs of adult and old mice. This allows for correlating multiple trace element levels and to identify potential patterns of age-dependent alterations. In serum, copper and iodine concentrations were increased and zinc concentration was decreased in old as compared to adult mice. In parallel, decreased copper and elevated iron concentrations were observed in liver. The age-related reduction of hepatic copper levels was associated with reduced expression of copper transporters, whereas the increased hepatic iron concentrations correlated positively with proinflammatory mediators and Nrf2-induced ferritin H levels. Interestingly, the age-dependent inverse regulation of copper and iron was unique for the liver and not observed in any other organ. The physiological importance of alterations in the iron/copper ratio for liver function and the aging process needs to be addressed in further studies.
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http://dx.doi.org/10.18632/aging.103572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377894PMC
July 2020

Arterial structure and function during and after long-duration spaceflight.

J Appl Physiol (1985) 2020 07 11;129(1):108-123. Epub 2020 Jun 11.

NASA Johnson Space Center, Houston, Texas.

Spaceflight missions expose astronauts to increased risk of oxidative stress and inflammatory damage that might accelerate the development of asymptomatic cardiovascular disease. The purpose of this investigation was to determine whether long-duration spaceflight (>4 mo) results in structural and functional changes in the carotid and brachial arteries. Common carotid artery (CCA) intima-media thickness (cIMT), CCA distensibility and stiffness, and brachial artery endothelium-dependent and -independent vasodilation were measured in 13 astronauts (10 men, 3 women) ~180 and 60 days before launch, during the mission on ~15, 60, and 160 days of spaceflight, and within 1 wk after landing. Biomarkers of oxidative stress and inflammation were measured at corresponding times in fasting blood samples and urine samples from 24- or 48-h pools. Biomarkers of oxidative stress and inflammation increased during spaceflight, but most returned to preflight levels within 1 wk of landing. Mean cIMT, CCA stiffness, and distensibility were not significantly different from preflight at any time. As a group, neither mean endothelium-dependent nor -independent vasodilation changed from preflight to postflight, but changes within individuals in endothelial function related to some biomarkers of oxidative stress. Whereas biomarkers of oxidative stress and inflammation are elevated during spaceflight, CCA and brachial artery structure and function were not changed by spaceflight. It is unclear whether future exploration missions, with an extended duration in altered gravity fields and higher radiation exposure, may be problematic. Carotid artery structure and stiffness did not change on average in astronauts during long-duration spaceflight (<12 mo), despite increased oxidative stress and inflammation. Most oxidative stress and inflammation biomarkers returned to preflight levels soon after landing. Brachial artery structure and function also were unchanged by spaceflight. In this group of healthy middle-aged male and female astronauts, spaceflight in low Earth orbit does not appear to increase long-term cardiovascular health risk.
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http://dx.doi.org/10.1152/japplphysiol.00550.2019DOI Listing
July 2020
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