Publications by authors named "Riekelt H Houtkooper"

144 Publications

Long noncoding RNAs in cardiometabolic disorders.

FEBS Lett 2022 Jun 26;596(11):1367-1387. Epub 2022 May 26.

Department of Physiology, Amsterdam UMC location Vrije Universiteit Amsterdam, The Netherlands.

The advancement of medical technology has led not only to an increase in life expectancy but also to a rise in aging-related diseases. Aging promotes metabolic disorders, in turn affecting cardiovascular health. Derailment of biological processes in the pancreas, liver, adipose tissue, and skeletal muscle impairs glucose and lipid metabolism, and mitochondrial function, triggering the development of diabetes and lipid-related disorders that inflict damage on cardiac and vascular tissues. Long noncoding RNAs (lncRNAs) regulate a wide range of biological process and are one of the key factors controlling metabolism and mitochondria. Here, we discuss the versatile function of lncRNAs involved in the metabolic regulation of glucose and lipid, and mitochondrial function, and how the dysregulation of lncRNAs induces the development of various metabolic disorders and their cardiovascular consequences.
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http://dx.doi.org/10.1002/1873-3468.14370DOI Listing
June 2022

Polar metabolomics in human muscle biopsies using a liquid-liquid extraction and full-scan LC-MS.

STAR Protoc 2022 Jun 16;3(2):101302. Epub 2022 Apr 16.

Laboratory Genetic Metabolic Diseases, Amsterdam UMC, Location AMC, Meibergdreef 9, AZ 1105 Amsterdam, the Netherlands.

We describe here a user-friendly analysis protocol for semi-targeted polar metabolomics in human muscle biopsies using Zwitterionic Hydrophilic Interaction Liquid Chromatography and high-resolution full-scan mass spectrometry. Previously, this protocol has been used for . Here we show that it can be successfully applied to human muscle biopsies with minor adjustments. Summarized instructions for other matrices are also provided. As peak integration in metabolomics can be challenging, we provide expected retention times and extensive peak descriptions to aid this process. For complete details on the use and execution of this protocol, please refer to Molenaars et al. (2021).
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http://dx.doi.org/10.1016/j.xpro.2022.101302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035783PMC
June 2022

Pharmaceutical and nutraceutical activation of FOXO3 for healthy longevity.

Ageing Res Rev 2022 Jun 11;78:101621. Epub 2022 Apr 11.

Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. Electronic address:

Life expectancy has increased substantially over the last 150 years. Yet this means that now most people also spend a greater length of time suffering from various age-associated diseases. As such, delaying age-related functional decline and extending healthspan, the period of active older years free from disease and disability, is an overarching objective of current aging research. Geroprotectors, compounds that target pathways that causally influence aging, are increasingly recognized as a means to extend healthspan in the aging population. Meanwhile, FOXO3 has emerged as a geroprotective gene intricately involved in aging and healthspan. FOXO3 genetic variants are linked to human longevity, reduced disease risks, and even self-reported health. Therefore, identification of FOXO3-activating compounds represents one of the most direct candidate approaches to extending healthspan in aging humans. In this work, we review compounds that activate FOXO3, or influence healthspan or lifespan in a FOXO3-dependent manner. These compounds can be classified as pharmaceuticals, including PI3K/AKT inhibitors and AMPK activators, antidepressants and antipsychotics, muscle relaxants, and HDAC inhibitors, or as nutraceuticals, including primary metabolites involved in cell growth and sustenance, and secondary metabolites including extracts, polyphenols, terpenoids, and other purified natural compounds. The compounds documented here provide a basis and resource for further research and development, with the ultimate goal of promoting healthy longevity in humans.
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http://dx.doi.org/10.1016/j.arr.2022.101621DOI Listing
June 2022

Genetic, biochemical, and clinical spectrum of patients with mitochondrial trifunctional protein deficiency identified after the introduction of newborn screening in the Netherlands.

J Inherit Metab Dis 2022 Apr 5. Epub 2022 Apr 5.

Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is included in many newborn screening (NBS) programs. Acylcarnitine-based NBS for LCHADD not only identifies LCHADD, but also the other deficiencies of the mitochondrial trifunctional protein (MTP), a multi-enzyme complex involved in long-chain fatty acid β-oxidation. Besides LCHAD, MTP harbors two additional enzyme activities: long-chain enoyl-CoA hydratase (LCEH) and long-chain ketoacyl-CoA thiolase (LCKAT). Deficiency of one or more MTP activities causes generalized MTP deficiency (MTPD), LCHADD, LCEH deficiency (not yet reported), or LCKAT deficiency (LCKATD). To gain insight in the outcomes of MTP-deficient patients diagnosed after the introduction of NBS for LCHADD in the Netherlands, a retrospective evaluation of genetic, biochemical, and clinical characteristics of MTP-deficient patients, identified since 2007, was carried out. Thirteen patients were identified: seven with LCHADD, five with MTPD, and one with LCKATD. All LCHADD patients (one missed by NBS, clinical diagnosis) and one MTPD patient (clinical diagnosis) were alive. Four MTPD patients and one LCKATD patient developed cardiomyopathy and died within 1 month and 13 months of life, respectively. Surviving patients did not develop symptomatic hypoglycemia, but experienced reversible cardiomyopathy and rhabdomyolysis. Five LCHADD patients developed subclinical neuropathy and/or retinopathy. In conclusion, patient outcomes were highly variable, stressing the need for accurate classification of and discrimination between the MTP deficiencies to improve insight in the yield of NBS for LCHADD. NBS allowed the prevention of symptomatic hypoglycemia, but current treatment options failed to treat cardiomyopathy and prevent long-term complications. Moreover, milder patients, who might benefit from NBS, were missed due to normal acylcarnitine profiles.
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http://dx.doi.org/10.1002/jimd.12502DOI Listing
April 2022

Personalized medicine for rare neurogenetic disorders: can we make it happen?

Cold Spring Harb Mol Case Stud 2022 02 24;8(2). Epub 2022 Mar 24.

Department of Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands.

Rare neurogenetic disorders are collectively common, affecting 3% of the population, and often manifest with complex multiorgan comorbidity. With advances in genetic, -omics, and computational analysis, more children can be diagnosed and at an earlier age. Innovations in translational research facilitate the identification of treatment targets and development of disease-modifying drugs such as gene therapy, nutraceuticals, and drug repurposing. This increasingly allows targeted therapy to prevent the often devastating manifestations of rare neurogenetic disorders. In this perspective, successes in diagnosis, prevention, and treatment are discussed with a focus on inherited disorders of metabolism. Barriers for the identification, development, and implementation of rare disease-specific therapies are discussed. New methodologies, care networks, and collaborative frameworks are proposed to optimize the potential of personalized genomic medicine to decrease morbidity and improve lives of these vulnerable patients.
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http://dx.doi.org/10.1101/mcs.a006200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8958924PMC
February 2022

Reduced ech-6 expression attenuates fat-induced lifespan shortening in C. elegans.

Sci Rep 2022 03 1;12(1):3350. Epub 2022 Mar 1.

Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Deregulated energy homeostasis represents a hallmark of aging and results from complex gene-by-environment interactions. Here, we discovered that reducing the expression of the gene ech-6 encoding enoyl-CoA hydratase remitted fat diet-induced deleterious effects on lifespan in Caenorhabditis elegans, while a basal expression of ech-6 was important for survival under normal dietary conditions. Lipidomics revealed that supplementation of fat in ech-6-silenced worms had marginal effects on lipid profiles, suggesting an alternative fat utilization for energy production. Transcriptomics further suggest a causal relation between the lysosomal pathway, energy production, and the longevity effect conferred by the interaction between ech-6 and fat diets. Indeed, enhancing energy production from endogenous fat by overexpressing lysosomal lipase lipl-4 recapitulated the lifespan effects of fat diets on ech-6-silenced worms. Collectively, these results suggest that the gene ech-6 is potential modulator of metabolic flexibility and may be a target for promoting metabolic health and longevity.
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http://dx.doi.org/10.1038/s41598-022-07397-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888598PMC
March 2022

HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia.

Blood 2022 05;139(21):3111-3126

Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands.

The congenital bone marrow failure syndrome Diamond-Blackfan anemia (DBA) is typically associated with variants in ribosomal protein (RP) genes impairing erythroid cell development. Here we report multiple individuals with biallelic HEATR3 variants exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability. These variants destabilize a protein whose yeast homolog is known to synchronize the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5), which are both critical for producing ribosomal subunits and for stabilizing the p53 tumor suppressor when ribosome biogenesis is compromised. Expression of HEATR3 variants or repression of HEATR3 expression in primary cells, cell lines of various origins, and yeast models impairs growth, differentiation, pre-ribosomal RNA processing, and ribosomal subunit formation reminiscent of DBA models of large subunit RP gene variants. Consistent with a role of HEATR3 in RP import, HEATR3-depleted cells or patient-derived fibroblasts display reduced nuclear accumulation of uL18. Hematopoietic progenitor cells expressing HEATR3 variants or small-hairpin RNAs knocking down HEATR3 synthesis reveal abnormal acceleration of erythrocyte maturation coupled to severe proliferation defects that are independent of p53 activation. Our study uncovers a new pathophysiological mechanism leading to DBA driven by biallelic HEATR3 variants and the destabilization of a nuclear import protein important for ribosome biogenesis.
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http://dx.doi.org/10.1182/blood.2021011846DOI Listing
May 2022

HIF-1α Stabilization in Flagellin-Stimulated Human Bronchial Cells Impairs Barrier Function.

Cells 2022 01 24;11(3). Epub 2022 Jan 24.

Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

The respiratory epithelium provides a first line of defense against pathogens. Hypoxia-inducible factor (HIF)1α is a transcription factor which is stabilized in hypoxic conditions through the inhibition of prolyl-hydroxylase (PHD)2, the enzyme that marks HIF1α for degradation. Here, we studied the impact of HIF1α stabilization on the response of primary human bronchial epithelial (HBE) cells to the bacterial component, flagellin. The treatment of flagellin-stimulated HBE cells with the PHD2 inhibitor IOX2 resulted in strongly increased HIF1α expression. IOX2 enhanced the flagellin-induced expression of the genes encoding the enzymes involved in glycolysis, which was associated with the intracellular accumulation of pyruvate. An untargeted pathway analysis of RNA sequencing data demonstrated the strong inhibitory effects of IOX2 toward key innate immune pathways related to cytokine and mitogen-activated kinase signaling cascades in flagellin-stimulated HBE cells. Likewise, the cell-cell junction organization pathway was amongst the top pathways downregulated by IOX2 in flagellin-stimulated HBE cells, which included the genes encoding claudins and cadherins. This IOX2 effect was corroborated by an impaired barrier function, as measured by dextran permeability. These results provide a first insight into the effects associated with HIF1α stabilization in the respiratory epithelium, suggesting that HIF1α impacts properties that are key to maintaining homeostasis upon stimulation with a relevant bacterial agonist.
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http://dx.doi.org/10.3390/cells11030391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8834373PMC
January 2022

Multi-omics analysis identifies essential regulators of mitochondrial stress response in two wild-type strains.

iScience 2022 Feb 5;25(2):103734. Epub 2022 Jan 5.

Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.

The mitochondrial unfolded protein response (UPRmt) is a promising pharmacological target for aging and age-related diseases. However, the integrative analysis of the impact of UPRmt activation on different signaling layers in animals with different genetic backgrounds is lacking. Here, we applied systems approaches to investigate the effect of UPRmt induced by doxycycline (Dox) on transcriptome, proteome, and lipidome in two genetically divergent worm strains, named N2 and CB4856. From the integrated omics datasets, we found that Dox prolongs lifespan of both worm strains through shared and strain-specific mechanisms. Specifically, Dox strongly impacts mitochondria, upregulates defense response, and lipid metabolism, while decreasing triglycerides. We further validated that lipid genes and were required for Dox-induced UPRmt and longevity in N2 and CB4856 worms, respectively. Our data have translational value as they indicate that the beneficial effects of Dox-induced UPRmt on lifespan are consistent across different genetic backgrounds through different regulators.
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http://dx.doi.org/10.1016/j.isci.2022.103734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792074PMC
February 2022

The mouse metallomic landscape of aging and metabolism.

Nat Commun 2022 02 1;13(1):607. Epub 2022 Feb 1.

Université de Lyon, Ecole Normale Supérieure de Lyon, Université de Lyon 1, CNRS, LGL-TPE, Lyon, France.

Organic elements make up 99% of an organism but without the remaining inorganic bioessential elements, termed the metallome, no life could be possible. The metallome is involved in all aspects of life, including charge balance and electrolytic activity, structure and conformation, signaling, acid-base buffering, electron and chemical group transfer, redox catalysis energy storage and biomineralization. Here, we report the evolution with age of the metallome and copper and zinc isotope compositions in five mouse organs. The aging metallome shows a conserved and reproducible fingerprint. By analyzing the metallome in tandem with the phenome, metabolome and proteome, we show networks of interactions that are organ-specific, age-dependent, isotopically-typified and that are associated with a wealth of clinical and molecular traits. We report that the copper isotope composition in liver is age-dependent, extending the existence of aging isotopic clocks beyond bulk organic elements. Furthermore, iron concentration and copper isotope composition relate to predictors of metabolic health, such as body fat percentage and maximum running capacity at the physiological level, and adipogenesis and OXPHOS at the biochemical level. Our results shed light on the metallome as an overlooked omic layer and open perspectives for potentially modulating cellular processes using careful and selective metallome manipulation.
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http://dx.doi.org/10.1038/s41467-022-28060-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807729PMC
February 2022

Time-restricted feeding during the inactive phase abolishes the daily rhythm in mitochondrial respiration in rat skeletal muscle.

FASEB J 2022 02;36(2):e22133

Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Shift-workers show an increased incidence of type 2 diabetes mellitus (T2DM). A possible mechanism is the disruption of the circadian timing of glucose homeostasis. Skeletal muscle mitochondrial function is modulated by the molecular clock. We used time-restricted feeding (TRF) during the inactive phase to investigate how mistimed feeding affects muscle mitochondrial metabolism. Rats on an ad libitum (AL) diet were compared to those that could eat only during the light (inactive) or dark (active) phase. Mitochondrial respiration, metabolic gene expressions, and metabolite concentrations were determined in the soleus muscle. Rats on AL feeding or dark-fed TRF showed a clear daily rhythm in muscle mitochondrial respiration. This rhythm in mitochondrial oxidative phosphorylation capacity was abolished in light-fed TRF animals and overall 24h respiration was lower. The expression of several genes involved in mitochondrial biogenesis and the fission/fusion machinery was altered in light-fed animals. Metabolomics analysis indicated that light-fed animals had lost rhythmic levels of α-ketoglutarate and citric acid. Contrastingly, lipidomics showed that light-fed animals abundantly gained rhythmicity in levels of triglycerides. Furthermore, while the RER shifted entirely with the food intake in the light-fed animals, many measured metabolic parameters (e.g., activity and mitochondrial respiration) did not strictly align with the shifted timing of food intake, resulting in a mismatch between expected metabolic supply/demand (as dictated by the circadian timing system and light/dark-cycle) and the actual metabolic supply/demand (as dictated by the timing of food intake). These data suggest that shift-work impairs mitochondrial metabolism and causes metabolic inflexibility, which can predispose to T2DM.
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http://dx.doi.org/10.1096/fj.202100707RDOI Listing
February 2022

Sitting less elicits metabolic responses similar to exercise and enhances insulin sensitivity in postmenopausal women.

Diabetologia 2021 12 12;64(12):2817-2828. Epub 2021 Sep 12.

Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands.

Aims/hypothesis: In our current society sedentary behaviour predominates in most people and is associated with the risk of developing type 2 diabetes. It has been suggested that replacing sitting time by standing and walking could be beneficial for individuals with type 2 diabetes but the underlying mechanisms are unknown and direct comparisons with exercise are lacking. Our objective was to directly compare metabolic responses of either sitting less or exercising, relative to being sedentary.

Methods: We performed a randomised, crossover intervention study in 12 overweight women who performed three well-controlled 4 day activity regimens: (1) sitting regimen (sitting 14 h/day); (2) exercise regimen (sitting 13 h/day, exercise 1 h/day); and (3) sitting less regimen (sitting 9 h/day, standing 4 h/day and walking 3 h/day). The primary outcome was insulin sensitivity measured by a two-step hyperinsulinaemic-euglycaemic clamp. We additionally performed metabolomics on muscle biopsies taken before the clamp to identify changes at the molecular level.

Results: Replacing sitting time by standing and walking over 4 days resulted in improved peripheral insulin sensitivity, comparable with the improvement achieved by moderate-to-vigorous exercise. Specifically, we report a significant improvement in peripheral insulin sensitivity in the sitting less (~13%) and the exercise regimen (~20%), compared with the sitting regimen. Furthermore, sitting less shifted the underlying muscle metabolome towards that seen with moderate-to-vigorous exercise, compared with the sitting regimen.

Conclusions/interpretations: Replacing sitting time by standing and walking is an attractive alternative to moderate-to-vigorous exercise for improving metabolic health.

Trial Registration: ClinicalTrials.gov NCT03912922.
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http://dx.doi.org/10.1007/s00125-021-05558-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435176PMC
December 2021

An improved functional assay in blood spot to diagnose Barth syndrome using the monolysocardiolipin/cardiolipin ratio.

J Inherit Metab Dis 2022 01 24;45(1):29-37. Epub 2021 Aug 24.

Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.

Barth syndrome is an X-linked disorder characterized by cardiomyopathy, skeletal myopathy, and neutropenia, caused by deleterious variants in TAFAZZIN. This gene encodes a phospholipid-lysophospholipid transacylase that is required for the remodeling of the mitochondrial phospholipid cardiolipin (CL). Biochemically, individuals with Barth syndrome have a deficiency of mature CL and accumulation of the remodeling intermediate monolysocardiolipin (MLCL). Diagnosis typically relies on mass spectrometric measurement of CL and MLCL in cells or tissues, and we previously described a method in blood spot that uses a specific MLCL/CL ratio as diagnostic biomarker. Here, we describe the evolution of our blood spot assay that is based on the implementation of reversed phase-UHPLC separation followed by full scan high resolution mass spectrometry. In addition to the MLCL/CL ratio, our improved method also generates a complete CL spectrum allowing the interrogation of the CL fatty acid composition, which considerably enhances the diagnostic reliability. This addition negates the need for a confirmatory test in lymphocytes thereby providing a shorter turn-around-time while achieving a more certain test result. As one of the few laboratories that offer this assay, we also evaluated the diagnostic yield and performance from 2006 to 2021 encompassing the use of both the original and improved assay. In this period, we performed 796 diagnostic analyses of which 117 (15%) were characteristic of Barth syndrome. In total, we diagnosed 93 unique individuals with Barth syndrome, including three females, which together amounts to about 40% of all reported individuals with Barth syndrome in the world.
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http://dx.doi.org/10.1002/jimd.12425DOI Listing
January 2022

A review of treatment modalities in gyrate atrophy of the choroid and retina (GACR).

Mol Genet Metab 2021 Sep-Oct;134(1-2):96-116. Epub 2021 Jul 26.

Department of Paediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, 1105, AZ, Amsterdam, the Netherlands. Electronic address:

Gyrate atrophy of the choroid and retina (GACR) is a rare inborn error of amino acid metabolism caused by bi-allelic variations in OAT. GACR is characterised by vision decline in early life eventually leading to complete blindness, and high plasma ornithine levels. There is no curative treatment for GACR, although several therapeutic modalities aim to slow progression of the disease by targeting different steps within the ornithine pathway. No international treatment protocol is available. We systematically collected all international literature on therapeutic interventions in GACR to provide an overview of published treatment effects.

Methods: Following the PRISMA guidelines, we conducted a systematic review of the English literature until December 22nd 2020. PubMed and Embase databases were searched for studies related to therapeutic interventions in patients with GACR.

Results: A total of 33 studies (n = 107 patients) met the inclusion criteria. Most studies were designed as case reports (n = 27) or case series (n = 4). No randomised controlled trials or large cohort studies were found. Treatments applied were protein-restricted diets, pyridoxine supplementation, creatine or creatine precursor supplementation, l-lysine supplementation, and proline supplementation. Protein-restricted diets lowered ornithine levels ranging from 16.0-91.2%. Pyridoxine responsiveness was reported in 30% of included mutations. Lysine supplementation decreased ornithine levels with 21-34%. Quality assessment showed low to moderate quality of the articles.

Conclusions: Based primarily on case reports ornithine levels can be reduced by using a protein restricted diet, pyridoxine supplementation (variation-dependent) and/or lysine supplementation. The lack of pre-defined clinical outcome measures and structural follow-up in all included studies impeded conclusions on clinical effectiveness. Future research should be aimed at 1) Unravelling the OAT biochemical pathway to identify other possible pathologic metabolites besides ornithine, 2) Pre-defining GACR specific clinical outcome measures, and 3) Establishing an international historical cohort.
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http://dx.doi.org/10.1016/j.ymgme.2021.07.010DOI Listing
February 2022

The female mouse is resistant to mild vitamin B deficiency.

Eur J Nutr 2022 Feb 2;61(1):329-340. Epub 2021 Aug 2.

Human and Animal Physiology, Wageningen University, PO Box 338, 6700 AH, Wageningen, The Netherlands.

Purpose: Vitamin B provides nicotinamide adenine dinucleotide (NAD), an essential coenzyme in oxidoreductase reactions. Severe vitamin B deficiency leads to the disease Pellagra, while mild vitamin B deficiency has been linked to age-related and metabolic diseases. Mild vitamin B deficiency is understudied, especially in females. Therefore, we examined how female mice responded to a diet that induced mild vitamin B deficiency in male mice.

Methods: Female C57BL/6RccHsd mice were subjected for 18 weeks to a diet without vitamin B and low but sufficient tryptophan (0.115%) (0NR) and were compared to control female mice on the same diet with the reference dose of vitamin B (30NR, 30 mg nicotinamide riboside/ kg diet).

Results: In the female mice, no differences between the two dietary groups were found in liver nicotinamide mononucleotide (NMN) levels, body composition, whole body energy and substrate metabolism measured by indirect calorimetry, or liver triacylglycerol metabolism. Expression of seven genes that previously were shown to respond to mild vitamin B deficiency in male white adipose tissue were not differentially expressed between the female dietary groups, neither was insulin sensitivity.

Conclusion: We concluded that the female 0NR mice were not vitamin B deficient; the role of age, sex and health status is discussed. Demonstrated by clear differences between females and males, the latter showing mild deficiency under the same conditions, this study highlights the importance of studying both sexes.
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http://dx.doi.org/10.1007/s00394-021-02651-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783905PMC
February 2022

Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity.

Aging Cell 2021 08 6;20(8):e13381. Epub 2021 Jul 6.

Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Transcriptome-based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age-related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf-16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in Caenorhabditis elegans. This longevity is dependent on both daf-16 signaling and inhibition of the neuromuscular acetylcholine receptor subunit unc-38. We found unc-38 RNAi to improve healthspan, lifespan, and stimulate DAF-16 nuclear localization, similar to atracurium treatment. Finally, using RNA-seq transcriptomics, we identify atracurium activation of DAF-16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway.
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http://dx.doi.org/10.1111/acel.13381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373276PMC
August 2021

The Role of AMPK Signaling in Brown Adipose Tissue Activation.

Cells 2021 05 6;10(5). Epub 2021 May 6.

Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Obesity is becoming a pandemic, and its prevalence is still increasing. Considering that obesity increases the risk of developing cardiometabolic diseases, research efforts are focusing on new ways to combat obesity. Brown adipose tissue (BAT) has emerged as a possible target to achieve this for its functional role in energy expenditure by means of increasing thermogenesis. An important metabolic sensor and regulator of whole-body energy balance is AMP-activated protein kinase (AMPK), and its role in energy metabolism is evident. This review highlights the mechanisms of BAT activation and investigates how AMPK can be used as a target for BAT activation. We review compounds and other factors that are able to activate AMPK and further discuss the therapeutic use of AMPK in BAT activation. Extensive research shows that AMPK can be activated by a number of different kinases, such as LKB1, CaMKK, but also small molecules, hormones, and metabolic stresses. AMPK is able to activate BAT by inducing adipogenesis, maintaining mitochondrial homeostasis and inducing browning in white adipose tissue. We conclude that, despite encouraging results, many uncertainties should be clarified before AMPK can be posed as a target for anti-obesity treatment via BAT activation.
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http://dx.doi.org/10.3390/cells10051122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148517PMC
May 2021

NAD homeostasis in human health and disease.

EMBO Mol Med 2021 07 27;13(7):e13943. Epub 2021 May 27.

Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism (AGEM), Amsterdam Cardiovascular Sciences (ACS), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Depletion of nicotinamide adenine dinucleotide (NAD ), a central redox cofactor and the substrate of key metabolic enzymes, is the causative factor of a number of inherited and acquired diseases in humans. Primary deficiencies of NAD homeostasis are the result of impaired biosynthesis, while secondary deficiencies can arise due to other factors affecting NAD homeostasis, such as increased NAD consumption or dietary deficiency of its vitamin B3 precursors. NAD depletion can manifest in a wide variety of pathological phenotypes, ranging from rare inherited defects, characterized by congenital malformations, retinal degeneration, and/or encephalopathy, to more common multifactorial, often age-related, diseases. Here, we discuss NAD biochemistry and metabolism and provide an overview of the etiology and pathological consequences of alterations of the NAD metabolism in humans. Finally, we discuss the state of the art of the potential therapeutic implications of NAD repletion for boosting health as well as treating rare and common diseases, and the possibilities to achieve this by means of the different NAD -enhancing agents.
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http://dx.doi.org/10.15252/emmm.202113943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261484PMC
July 2021

Longevity pathways are associated with human ovarian ageing.

Hum Reprod Open 2021 16;2021(2):hoab020. Epub 2021 May 16.

Amsterdam UMC, University of Amsterdam, Center for Reproductive Medicine, Reproductive Biology Laboratory, Amsterdam Reproduction & Development research institute, Amsterdam, The Netherlands.

Study Question: Are genes known to be involved in somatic cell ageing, particularly related to longevity pathways, associated with the accelerated ageing process of the ovary?

Summary Answer: Growth, metabolism, and cell-cycle progression-related pathways that are involved in somatic cell ageing are also associated with ovarian ageing.

What Is Known Already: Ovarian ageing is characterized by a gradual decline in ovarian follicle quantity, a decline in oocyte quality, and lower chances of pregnancy. Genetic pathways modulating the rate of somatic cell ageing have been researched intensively. Ovarian ageing does not follow the same timeline as somatic cell ageing, as signs of ovarian ageing occur at a younger female age, while the somatic cells are still relatively young. It is not known whether the generally recognized somatic cell longevity genes also play a role during ovarian ageing. Looking at somatic cell longevity genes can lead to new hypotheses and possible treatment options for subfertility caused by ovarian ageing.

Study Design Size Duration: In this observational study, we analysed a dataset of individual gene expression profiles of 38 germinal vesicle (GV) oocytes from 38 women aged between 25 and 43 years. We correlated female age (calendar age in years) and biological age (factors known to be associated with ovarian ageing such as dosage of FSH needed for ovarian hyperstimulation, and antral follicle count (AFC)) with gene expression signatures of longevity pathways.

Participants/materials Setting Methods: Transcripts of 38 GV oocytes were used for individual gene expression analysis. R version 3.5.1 was used to process and analyse data. The GeneAge database (build 19) was used to obtain mouse ageing-related genes. Human to mouse orthologues were obtained using the R package biomaRt. Correlations and significance between gene expression data and age were tested for using Pearson's product moment correlation coefficient using ranked expression data. Distributions were compared with an ANOVA, and the Tukey Honest Significant Difference method was used to control for the Type I error rate across multiple comparisons.

Main Results And The Role Of Chance: Of the 136 genes in the GeneAge database, the expression of 15 anti-longevity genes identified in oocytes showed a positive correlation with female calendar age and FSH dosage administered during ICSI treatment, and a negative correlation with AFC. Expression of 32 pro-longevity genes was negatively correlated with calendar age and FSH dosage, and positively correlated with AFC. In general, anti- and pro-longevity genes changed in opposing directions with advancing maternal age in oocytes. Notably, the anti-longevity genes include many 'growth'-related genes involved in the mechanistic target of rapamycin (mTOR) Complex 1 pathway, such as EIF5A2, EIF3H, EIF4E, and mTOR. The pro-longevity genes include many cell-cycle progression-related genes involved in DNA damage repair (e.g. XRCC6, ERCC2, and MSH2) or cell-cycle checkpoint regulation genes (e.g. ATM, BRCA1, TP53, TP63, TP73, and BUB1B).

Limitations Reasons For Caution: Using mature oocytes instead of GV-stage oocytes discarded from ICSI treatments may provide different results. No correction for multiple testing was carried out on individual genes because a small set of longevity-related genes was selected a priori for the analysis. The global trend was corrected for multiple testing and remained significant. This work was an observational study and, as no additional experimental work was performed, the associations described do not directly demonstrate the involvement of such genes in oocyte ageing.

Wider Implications Of The Findings: Growth, metabolism, and cell-cycle progression-related pathways that are known to be involved in somatic cell ageing were associated with ovarian ageing. If experimental data are obtained to support these associations, we suggest that interventions known to modulate these processes could benefit women suffering from ovarian ageing.

Study Funding/competing Interests: G.E.J. is supported by a VENI grant from ZonMw (https://www.zonmw.nl). Work in the Houtkooper group is financially supported by an ERC Starting grant (No. 638290), a VIDI grant from ZonMw (No. 91715305), and the Velux Stiftung (No. 1063). M.G. declares several research and educational grants from Guerbet, Merck and Ferring (all location VUmc), outside the scope of the submitted work. The other authors report no competing interest.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/hropen/hoab020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126403PMC
May 2021

Circadian misalignment disturbs the skeletal muscle lipidome in healthy young men.

FASEB J 2021 06;35(6):e21611

Department of Nutrition and Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.

Circadian misalignment, as seen in shift work, is associated with an increased risk to develop type 2 diabetes. In an experimental setting, we recently showed that a rapid day-night shift for 3 consecutive nights leads to misalignment of the core molecular clock, induction of the PPAR pathway, and insulin resistance in skeletal muscle of young, healthy men. Here, we investigated if circadian misalignment affects the skeletal muscle lipidome and intramyocellular lipid droplet characteristics, explaining the misalignment-induced insulin resistance. Fourteen healthy men underwent one aligned and one circadian misalignment period, both consisting of ~3.5 days. In the misaligned condition, day and night were rapidly shifted by 12 hours leading to opposite eating, sleep, and activity times compared with the aligned condition. For each condition, two muscle biopsies were taken from the m. vastus lateralis in the morning and evening and subjected to semi-targeted lipidomics and confocal microscopy analysis. We found that only 2% of detected lipids were different between morning and evening in the aligned condition, whereas 12% displayed a morning-evening difference upon misalignment. Triacylglycerols, in particular species of a carbon length ≥55, were the most abundant lipid species changed upon misalignment. Cardiolipins were decreased upon misalignment, whereas phosphatidylcholines consistently followed the same morning-evening pattern, suggesting regulation by the circadian clock. Cholesteryl esters adjusted to the shifted behavior. Lipid droplet characteristics remained unaltered upon misalignment. Together, these findings show that simulated shift work disturbs the skeletal muscle lipidome, which may contribute to misalignment-induced insulin resistance.
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http://dx.doi.org/10.1096/fj.202100143RDOI Listing
June 2021

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function.

Int J Mol Sci 2021 Apr 15;22(8). Epub 2021 Apr 15.

Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline-which belongs to the tetracycline class-reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in and in mice. Ampicillin and carbenicillin were used as control antibiotics since these do not interfere with mitochondrial translation. In line with its specific inhibitory effect on mitochondrial translation, doxycycline caused a mitonuclear protein imbalance in doxycycline-treated H9C2 cells, reduced maximal mitochondrial respiration, particularly with complex I substrates, and mitochondria appeared fragmented. Flux measurements using stable isotope tracers showed a shift away from OXPHOS towards glycolysis after doxycycline exposure. Cardiac contractility measurements in adult cardiomyocytes and hearts showed an increased diastolic calcium concentration, and a higher arrhythmicity index. Systolic and diastolic dysfunction were observed after exposure to doxycycline. Mice treated with doxycycline showed mitochondrial complex I dysfunction, reduced OXPHOS capacity and impaired diastolic function. Doxycycline exacerbated diastolic dysfunction and reduced ejection fraction in a diabetes mouse model vulnerable for metabolic derangements. We therefore conclude that doxycycline impairs mitochondrial function and causes cardiac dysfunction.
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http://dx.doi.org/10.3390/ijms22084100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071362PMC
April 2021

Reduced nicotinamide mononucleotide is a new and potent NAD precursor in mammalian cells and mice.

FASEB J 2021 04;35(4):e21456

Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Nicotinamide adenine dinucleotide (NAD ) homeostasis is constantly compromised due to degradation by NAD -dependent enzymes. NAD replenishment by supplementation with the NAD precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) can alleviate this imbalance. However, NMN and NR are limited by their mild effect on the cellular NAD pool and the need of high doses. Here, we report a synthesis method of a reduced form of NMN (NMNH), and identify this molecule as a new NAD precursor for the first time. We show that NMNH increases NAD levels to a much higher extent and faster than NMN or NR, and that it is metabolized through a different, NRK and NAMPT-independent, pathway. We also demonstrate that NMNH reduces damage and accelerates repair in renal tubular epithelial cells upon hypoxia/reoxygenation injury. Finally, we find that NMNH administration in mice causes a rapid and sustained NAD surge in whole blood, which is accompanied by increased NAD levels in liver, kidney, muscle, brain, brown adipose tissue, and heart, but not in white adipose tissue. Together, our data highlight NMNH as a new NAD precursor with therapeutic potential for acute kidney injury, confirm the existence of a novel pathway for the recycling of reduced NAD precursors and establish NMNH as a member of the new family of reduced NAD precursors.
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http://dx.doi.org/10.1096/fj.202001826RDOI Listing
April 2021

Aging selectively dampens oscillation of lipid abundance in white and brown adipose tissue.

Sci Rep 2021 03 15;11(1):5932. Epub 2021 Mar 15.

Laboratory Genetic Metabolic Diseases, Amsterdam UMC-AMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.

Lipid metabolism is under the control of the circadian system and circadian dysregulation has been linked to obesity and dyslipidemia. These factors and outcomes have also been associated to, or affected by, the process of aging. Here, we investigated whether murine white (WAT) and brown (BAT) adipose tissue lipids exhibit rhythmicity and if this is affected by aging. To this end, we have measured the 24 h lipid profiles of WAT and BAT using a global lipidomics analysis of > 1100 lipids. We observed rhythmicity in nearly all lipid classes including glycerolipids, glycerophospholipids, sterol lipids and sphingolipids. Overall, ~ 22% of the analyzed lipids were considered rhythmic in WAT and BAT. Despite a general accumulation of lipids upon aging the fraction of oscillating lipids decreased in both tissues to 14% and 18%, respectively. Diurnal profiles of lipids in BAT appeared to depend on the lipid acyl chain length and this specific regulation was lost in aged mice. Our study revealed how aging affects the rhythmicity of lipid metabolism and could contribute to the quest for targets that improve diurnal lipid homeostasis to maintain cardiometabolic health during aging.
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http://dx.doi.org/10.1038/s41598-021-85455-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961067PMC
March 2021

Metabolomics and lipidomics in Caenorhabditis elegans using a single-sample preparation.

Dis Model Mech 2021 04 27;14(4). Epub 2021 Apr 27.

Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Comprehensive metabolomic and lipidomic mass spectrometry methods are in increasing demand; for instance, in research related to nutrition and aging. The nematode Caenorhabditis elegans is a key model organism in these fields, owing to the large repository of available C. elegans mutants and their convenient natural lifespan. Here, we describe a robust and sensitive analytical method for the semi-quantitative analysis of >100 polar (metabolomics) and >1000 apolar (lipidomics) metabolites in C. elegans, using a single-sample preparation. Our method is capable of reliably detecting a wide variety of biologically relevant metabolic aberrations in, for example, glycolysis and the tricarboxylic acid cycle, pyrimidine metabolism and complex lipid biosynthesis. In conclusion, we provide a powerful analytical tool that maximizes metabolic data yield from a single sample. This article has an associated First Person interview with the joint first authors of the paper.
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http://dx.doi.org/10.1242/dmm.047746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106956PMC
April 2021

Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Do not Improve with Carnitine Supplementation.

Front Pharmacol 2020 12;11:616834. Epub 2021 Jan 12.

Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands.

Patients with a deficiency in very long-chain acyl-CoA dehydrogenase (VLCAD), an enzyme that is involved in the mitochondrial beta-oxidation of long-chain fatty acids, are at risk for developing cardiac arrhythmias. In human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), VLCAD deficiency (VLCADD) results in a series of abnormalities, including: 1) accumulation of long-chain acylcarnitines, 2) action potential shortening, 3) higher systolic and diastolic intracellular Ca concentrations, and 4) development of delayed afterdepolarizations. In the fatty acid oxidation process, carnitine is required for bidirectional transport of acyl groups across the mitochondrial membrane. Supplementation has been suggested as potential therapeutic approach in VLCADD, but its benefits are debated. Here, we studied the effects of carnitine supplementation on the long-chain acylcarnitine levels and performed electrophysiological analyses in VLCADD patient-derived hiPSC-CMs with a gene mutation (p.Val283Ala/p.Glu381del). Under standard culture conditions, VLCADD hiPSC-CMs showed high concentrations of long-chain acylcarnitines, short action potentials, and high delayed afterdepolarizations occurrence. Incubation of the hiPSC-CMs with 400 µM L-carnitine for 48 h led to increased long-chain acylcarnitine levels both in medium and cells. In addition, carnitine supplementation neither restored abnormal action potential parameters nor the increased occurrence of delayed afterdepolarizations in VLCADD hiPSC-CMs. We conclude that long-chain acylcarnitine accumulation and electrophysiological abnormalities in VLCADD hiPSC-CMs are not normalized by carnitine supplementation, indicating that this treatment is unlikely to be beneficial against cardiac arrhythmias in VLCADD patients.
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http://dx.doi.org/10.3389/fphar.2020.616834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883678PMC
January 2021

Quantification of Myocardial Creatine and Triglyceride Content in the Human Heart: Precision and Accuracy of in vivo Proton Magnetic Resonance Spectroscopy.

J Magn Reson Imaging 2021 08 10;54(2):411-420. Epub 2021 Feb 10.

Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: Proton magnetic resonance spectroscopy ( H-MRS) of the human heart is deemed to be a quantitative method to investigate myocardial metabolite content, but thorough validations of in vivo measurements against invasive techniques are lacking.

Purpose: To determine measurement precision and accuracy for quantifications of myocardial total creatine and triglyceride content with localized H-MRS.

Study Type: Test-retest repeatability and measurement validation study.

Subjects: Sixteen volunteers and 22 patients scheduled for open-heart aortic valve replacement or septal myectomy.

Field Strength/sequence: Prospectively ECG-triggered respiratory-gated free-breathing single-voxel point-resolved spectroscopy (PRESS) sequence at 3 T.

Assessment: Myocardial total creatine and triglyceride content were quantified relative to the total water content by fitting the H-MR spectra. Precision was assessed with measurement repeatability. Accuracy was assessed by validating in vivo H-MRS measurements against biochemical assays in myocardial tissue from the same subjects.

Statistical Tests: Intrasession and intersession repeatability was assessed using Bland-Altman analyses. Agreement between H-MRS measurements and biochemical assay was tested with regression analyses.

Results: The intersession repeatability coefficient for myocardial total creatine content was 41.8% with a mean value of 0.083% ± 0.020% of the total water signal, and 36.7% for myocardial triglyceride content with a mean value of 0.35% ± 0.13% of the total water signal. Ex vivo myocardial total creatine concentrations in tissue samples correlated with the in vivo myocardial total creatine content measured with H-MRS: n = 22, r = 0.44; P < 0.05. Likewise, ex vivo myocardial triglyceride concentrations correlated with the in vivo myocardial triglyceride content: n = 20, r = 0.50; P < 0.05.

Data Conclusion: We validated the use of localized H-MRS of the human heart at 3 T for quantitative assessments of in vivo myocardial tissue metabolite content by estimating the measurement precision and accuracy.

Level Of Evidence: 2 TECHNICAL EFFICACY STAGE: 2.
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http://dx.doi.org/10.1002/jmri.27531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277665PMC
August 2021

Adherence Affects Monocyte Innate Immune Function and Metabolic Reprogramming after Lipopolysaccharide Stimulation In Vitro.

J Immunol 2021 02 6;206(4):827-838. Epub 2021 Jan 6.

Center for Experimental and Molecular Medicine, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.

Circulating nonadherent monocytes can migrate to extravascular sites by a process that involves adherence. Alterations in intracellular metabolism shape the immunological phenotype of phagocytes upon activation. To determine the effect of adherence on their metabolic and functional response human monocytes were stimulated with LPS under nonadherent and adherent conditions. Adherent monocytes (relative to nonadherent monocytes) produced less TNF and IL-1β (proinflammatory) and more IL-10 (anti-inflammatory) upon LPS stimulation and had an increased capacity to phagocytose and produce reactive oxygen species. RNA sequencing analysis confirmed that adherence modified the LPS-induced response of monocytes, reducing expression of proinflammatory genes involved in TLR signaling and increasing induction of genes involved in pathogen elimination. Adherence resulted in an increased glycolytic response as indicated by lactate release, gene set enrichment, and [C]-glucose flux analysis. To determine the role of glycolysis in LPS-induced immune responses, this pathway was inhibited by glucose deprivation or the glucose analogue 2-deoxy-d-glucose (2DG). Although both interventions equally inhibited glycolysis, only 2DG influenced monocyte functions, inhibiting expression of genes involved in TLR signaling and pathogen elimination, as well as cytokine release. 2DG, but not glucose deprivation, reduced expression of genes involved in oxidative phosphorylation. Inhibition of oxidative phosphorylation affected TNF and IL-10 release in a similar way as 2DG. Collectively, these data suggest that adherence may modify the metabolic and immunological profile of monocytes and that inhibition of glycolysis and oxidative phosphorylation, but not inhibition of glycolysis alone, has a profound effect on immune functions of monocytes exposed to LPS.
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http://dx.doi.org/10.4049/jimmunol.2000702DOI Listing
February 2021

ARDD 2020: from aging mechanisms to interventions.

Aging (Albany NY) 2020 12 30;12(24):24484-24503. Epub 2020 Dec 30.

Blavatnik Institute, Department of Genetics, Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, Boston, MA 94107, USA.

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7 Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1 to 4 of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8 ARDD meeting that is scheduled for the 31 of August to 3 of September, 2021, at Columbia University, USA.
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http://dx.doi.org/10.18632/aging.202454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803558PMC
December 2020

Metabolic adaptations of human alveolar macrophages upon activation by lipopolysaccharide in vivo.

Scand J Immunol 2021 04 5;93(4):e13011. Epub 2021 Jan 5.

Center of Experimental and Molecular Medicine, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1111/sji.13011DOI Listing
April 2021

Integrating the Hallmarks of Aging Throughout the Tree of Life: A Focus on Mitochondrial Dysfunction.

Front Cell Dev Biol 2020 26;8:594416. Epub 2020 Nov 26.

Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Since the identification and definition of the hallmarks of aging, these aspects of molecular and cellular decline have been most often described as isolated or distinct mechanisms. However, there is significant evidence demonstrating interplay between most of these hallmarks and that they have the capacity to influence and regulate one another. These interactions are demonstrable across the tree of life, yet not all aspects are conserved. Here, we describe an integrative view on the hallmarks of aging by using the hallmark "mitochondrial dysfunction" as a focus point, and illustrate its capacity to both influence and be influenced by the other hallmarks of aging. We discuss the effects of mitochondrial pathways involved in aging, such as oxidative phosphorylation, mitochondrial dynamics, mitochondrial protein synthesis, mitophagy, reactive oxygen species and mitochondrial DNA damage in relation to each of the primary, antagonistic and integrative hallmarks. We discuss the similarities and differences in these interactions throughout the tree of life, and speculate how speciation may play a role in the variation in these mechanisms. We propose that the hallmarks are critically intertwined, and that mapping the full extent of these interactions would be of significant benefit to the aging research community.
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http://dx.doi.org/10.3389/fcell.2020.594416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726203PMC
November 2020
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