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1.
Plasma acylcarnitines and gut-derived aromatic amino acids as sex-specific hub metabolites of the human aging metabolome.
Sol, J, Obis, È, Mota-Martorell, N, Pradas, I, Galo-Licona, JD, Martin-Garí, M, Fernández-Bernal, A, Ortega-Bravo, M, Mayneris-Perxachs, J, Borrás, C, et al
Aging cell. 2023;(6):e13821
Abstract
Aging biology entails a cell/tissue deregulated metabolism that affects all levels of biological organization. Therefore, the application of "omic" techniques that are closer to phenotype, such as metabolomics, to the study of the aging process should be a turning point in the definition of cellular processes involved. The main objective of the present study was to describe the changes in plasma metabolome associated with biological aging and the role of sex in the metabolic regulation during aging. A high-throughput untargeted metabolomic analysis was applied in plasma samples to detect hub metabolites and biomarkers of aging incorporating a sex/gender perspective. A cohort of 1030 healthy human adults (45.9% females, and 54.1% males) from 50 to 98 years of age was used. Results were validated using two independent cohorts (1: n = 146, 53% females, 30-100 years old; 2: n = 68, 70% females, 19-107 years old). Metabolites related to lipid and aromatic amino acid (AAA) metabolisms arose as the main metabolic pathways affected by age, with a high influence of sex. Globally, we describe changes in bioenergetic pathways that point to a decrease in mitochondrial β-oxidation and an accumulation of unsaturated fatty acids and acylcarnitines that could be responsible for the increment of oxidative damage and inflammation characteristic of this physiological process. Furthermore, we describe for the first time the importance of gut-derived AAA catabolites in the aging process describing novel biomarkers that could contribute to better understand this physiological process but also age-related diseases.
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2.
Metabolomic Profiling in Children with Celiac Disease: Beyond the Gluten-Free Diet.
Martín-Masot, R, Jiménez-Muñoz, M, Herrador-López, M, Navas-López, VM, Obis, E, Jové, M, Pamplona, R, Nestares, T
Nutrients. 2023;(13)
Abstract
Celiac disease (CD) is included in the group of complex or multifactorial diseases, i.e., those caused by the interaction of genetic and environmental factors. Despite a growing understanding of the pathophysiological mechanisms of the disease, diagnosis is still often delayed and there are no effective biomarkers for early diagnosis. The only current treatment, a gluten-free diet (GFD), can alleviate symptoms and restore intestinal villi, but its cellular effects remain poorly understood. To gain a comprehensive understanding of CD's progression, it is crucial to advance knowledge across various scientific disciplines and explore what transpires after disease onset. Metabolomics studies hold particular significance in unravelling the complexities of multifactorial and multisystemic disorders, where environmental factors play a significant role in disease manifestation and progression. By analyzing metabolites, we can gain insights into the reasons behind CD's occurrence, as well as better comprehend the impact of treatment initiation on patients. In this review, we present a collection of articles that showcase the latest breakthroughs in the field of metabolomics in pediatric CD, with the aim of trying to identify CD biomarkers for both early diagnosis and treatment monitoring. These advancements shed light on the potential of metabolomic analysis in enhancing our understanding of the disease and improving diagnostic and therapeutic strategies. More studies need to be designed to cover metabolic profiles in subjects at risk of developing the disease, as well as those analyzing biomarkers for follow-up treatment with a GFD.
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3.
Lipid Adaptations against Oxidative Challenge in the Healthy Adult Human Brain.
Jové, M, Mota-Martorell, N, Obis, È, Sol, J, Martín-Garí, M, Ferrer, I, Portero-Otín, M, Pamplona, R
Antioxidants (Basel, Switzerland). 2023;(1)
Abstract
It is assumed that the human brain is especially susceptible to oxidative stress, based on specific traits such as a higher rate of mitochondrial free radical production, a high content in peroxidizable fatty acids, and a low antioxidant defense. However, it is also evident that human neurons, although they are post-mitotic cells, survive throughout an entire lifetime. Therefore, to reduce or avoid the impact of oxidative stress on neuron functionality and survival, they must have evolved several adaptive mechanisms to cope with the deleterious effects of oxidative stress. Several of these antioxidant features are derived from lipid adaptations. At least six lipid adaptations against oxidative challenge in the healthy human brain can be discerned. In this work, we explore the idea that neurons and, by extension, the human brain is endowed with an important arsenal of non-pro-oxidant and antioxidant measures to preserve neuronal function, refuting part of the initial premise.
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Hakuna MAM-Tata: Investigating the role of mitochondrial-associated membranes in ALS.
Bernal, AF, Mota, N, Pamplona, R, Area-Gomez, E, Portero-Otin, M
Biochimica et biophysica acta. Molecular basis of disease. 2023;(6):166716
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant heterogeneity in pathogenic and clinical terms, MN demise ultimately unifies patients. Across the many disturbances in neuronal biology present in the disease and its models, two common trends are loss of calcium homeostasis and dysregulations in lipid metabolism. Since both mitochondria and endoplasmic reticulum (ER) are essential in these functions, their intertwin through the so-called mitochondrial-associated membranes (MAMs) should be relevant in this disease. In this review, we present a short overview of MAMs functional aspects and how its dysfunction could explain a substantial part of the cellular disarrangements in ALS's natural history. MAMs are hubs for lipid synthesis, integrating glycerophospholipids, sphingolipids, and cholesteryl ester metabolism. These lipids are essential for membrane biology, so there should be a close coupling to cellular energy demands, a role that MAMs may partially fulfill. Not surprisingly, MAMs are also host part of calcium signaling to mitochondria, so their impairment could lead to mitochondrial dysfunction, affecting oxidative phosphorylation and enhancing the vulnerability of MNs. We present data supporting that MAMs' maladaptation could be essential to MNs' vulnerability in ALS.
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5.
Gut microbiota links to serum ferritin and cognition.
Rosell-Díaz, M, Santos-González, E, Motger-Albertí, A, Ramió-Torrentà, L, Garre-Olmo, J, Pérez-Brocal, V, Moya, A, Jové, M, Pamplona, R, Puig, J, et al
Gut microbes. 2023;(2):2290318
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Abstract
Iron is required for the replication and growth of almost all bacterial species and in the production of myelin and neurotransmitters. Increasing clinical studies evidence that the gut microbiota plays a critical role in iron metabolism and cognition. However, the understanding of the complex iron-microbiome-cognition crosstalk remains elusive. In a recent study in the Aging Imageomics cohort (n = 1,030), we identified a positive association of serum ferritin (SF) with executive function (EF) as inferred from the semantic verbal fluency (SVF,) the total digit span (TDS) and the phonemic verbal fluency tests (PVF). Here, we explored the potential mechanisms by analyzing the gut microbiome and plasma metabolome using shotgun metagenomics and HPLC-ESI-MS/MS, respectively. Different bacterial species belonging to the Proteobacteria phylum (Klebsiella pneumoniae, Klebsiella michiganensis, Unclassified Escherichia) were negatively associated both with SF and executive function. At the functional level, an enrichment of microbial pathways involved in phenylalanine, arginine, and proline metabolism was identified. Consistently, phenylacetylglutamine, a metabolite derived from microbial catabolism of phenylalanine, was negatively associated with SF, EF, and semantic memory. Other metabolites such as ureidobutyric acid and 19,20-DiHDPA, a DHA-derived oxylipin, were also consistently and negatively associated with SF, EF, and semantic memory, while plasma eicosapentaenoic acid was positively associated. The associations of SF with cognition could be mediated by the gut microbiome through microbial-derived metabolites.
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Weak Association between Skin Autofluorescence Levels and Prediabetes with an ILERVAS Cross-Sectional Study.
Sánchez, E, Kerkeni, M, Hernández, M, Gavaldà, R, Rius, F, Sauret, A, Torres, G, Bermúdez-López, M, Fernández, E, Castro-Boqué, E, et al
Nutrients. 2022;(5)
Abstract
A large body of evidence demonstrates a relationship between hyperglycemia and increased concentrations of advanced glycation end-products (AGEs). However, there is little information about subcutaneous AGE accumulation in subjects with prediabetes, and whether or not this measurement could assist in the diagnosis of prediabetes is unclear. A cross-sectional study was conducted in 4181 middle-aged subjects without diabetes. Prediabetes (n = 1444) was defined as a glycosylated hemoglobin (HbA1c) level between 39 and 47 mmol/mol (5.7 to 6.4%), and skin autofluorescence (SAF) measurement was performed to assess AGEs. A multivariable logistic regression model and receiver operating characteristic curve were used. The cohort consisted of 50.1% women with an age of 57 [52;62] years, a BMI of 28.3 [25.4;31.6] kg/m2, and a prevalence of prediabetes of 34.5%. Participants with prediabetes showed higher SAF than control participants (2.0 [1.7;2.2] vs. 1.9 [1.7;2.2], p < 0.001). However, HbA1c was not significantly correlated with SAF levels (r = 0.026, p = 0.090). In addition, the SAF level was not independently associated with prediabetes (OR = 1.12 (0.96 to 1.30)). Finally, there was no good cutoff point for SAF to identify patients with prediabetes (AUC = 0.52 (0.50 to 0.54), sensitivity = 0.61, and 1-specificity = 0.56). Given all of this evidence, we can conclude that although there is an increase in SAF levels in participants with prediabetes, the applicability and clinical relevance of the results is low in this population.
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Metabolomic Analysis Points to Bioactive Lipid Species and Acireductone Dioxygenase 1 (ADI1) as Potential Therapeutic Targets in Poor Prognosis Endometrial Cancer.
Gatius, S, Jove, M, Megino-Luque, C, Albertí-Valls, M, Yeramian, A, Bonifaci, N, Piñol, M, Santacana, M, Pradas, I, Llobet-Navas, D, et al
Cancers. 2022;(12)
Abstract
Metabolomic profiling analysis has the potential to highlight new molecules and cellular pathways that may serve as potential therapeutic targets for disease treatment. In this study, we used an LC-MS/MS platform to define, for the first time, the specific metabolomic signature of uterine serous carcinoma (SC), a relatively rare and aggressive variant of endometrial cancer (EC) responsible for 40% of all endometrial cancer-related deaths. A metabolomic analysis of 31 ECs (20 endometrial endometrioid carcinomas (EECs) and 11 SCs) was performed. Following multivariate statistical analysis, we identified 232 statistically different metabolites among the SC and EEC patient samples. Notably, most of the metabolites identified (89.2%) were lipid species and showed lower levels in SCs when compared to EECs. In addition to lipids, we also documented metabolites belonging to amino acids and purine nucleotides (such as 2-Oxo-4-methylthiobutanoic acid, synthesised by acireductone dioxygenase 1 (ADI1) enzyme), which showed higher levels in SCs. To further investigate the role of ADI1 in SC, we analysed the expression protein levels of ADI1 in 96 ECs (67 EECs and 29 SCs), proving that the levels of ADI1 were higher in SCs compared to EECs. We also found that ADI1 mRNA levels were higher in p53 abnormal ECs compared to p53 wild type tumours. Furthermore, elevated ADI1 mRNA levels showed a statistically significant negative correlation with overall survival and progression-free survival among EEC patients. Finally, we tested the ability of ADI1 to induce migration and invasion capabilities in EC cell lines. Altogether, these results suggest that ADI1 could be a potential therapeutic target in poor-prognosis SCs and other Ecs with abnormal p53 expression.
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Is There a Link between Obesity Indices and Skin Autofluorescence? A Response from the ILERVAS Project.
Sánchez, E, Sánchez, M, López-Cano, C, Bermúdez-López, M, Valdivielso, JM, Farràs-Sallés, C, Pamplona, R, Torres, G, Mauricio, D, Castro, E, et al
Nutrients. 2022;(1)
Abstract
There is controversial information about the accumulation of advanced glycation end-products (AGEs) in obesity. We assessed the impact of total and abdominal adiposity on AGE levels via a cross-sectional investigation with 4254 middle-aged subjects from the ILERVAS project. Skin autofluorescence (SAF), a non-invasive assessment of subcutaneous AGEs, was measured. Total adiposity indices (BMI and Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE)) and abdominal adiposity (waist circumference and body roundness index (BRI)) were assessed. Lean mass was estimated using the Hume index. The area under the receiver operating characteristic (ROC) curve was evaluated for each index. Different cardiovascular risk factors (smoking, prediabetes, hypertension and dyslipidemia) were evaluated. In the study population, 26.2% showed elevated SAF values. No differences in total body fat, visceral adiposity and lean body mass were detected between patients with normal and high SAF values. SAF levels showed a very slight but positive correlation with total body fat percentage (estimated by the CUN-BAE formula) and abdominal adiposity (estimated by the BRI). However, none of them had sufficient power to identify patients with high SAF levels (area under the ROC curve <0.52 in all cases). Finally, a progressive increase in SAF levels was observed in parallel with cardiovascular risk factors in the entire population and when patients with normal weight, overweight and obesity were evaluated separately. In conclusion, total obesity and visceral adiposity are not associated with a greater deposit of AGE. The elevation of AGE in obesity is related to the presence of cardiometabolic risk.
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Development and Validation of a Personalized, Sex-Specific Prediction Algorithm of Severe Atheromatosis in Middle-Aged Asymptomatic Individuals: The ILERVAS Study.
Bermúdez-López, M, Martí-Antonio, M, Castro-Boqué, E, Bretones, MDM, Farràs, C, Torres, G, Pamplona, R, Lecube, A, Mauricio, D, Valdivielso, JM, et al
Frontiers in cardiovascular medicine. 2022;:895917
Abstract
BACKGROUND Although European guidelines recommend vascular ultrasound for the assessment of cardiovascular risk in low-to-moderate risk individuals, no algorithm properly identifies patients who could benefit from it. The aim of this study is to develop a sex-specific algorithm to identify those patients, especially women who are usually underdiagnosed. METHODS Clinical, anthropometrical, and biochemical data were combined with a 12-territory vascular ultrasound to predict severe atheromatosis (SA: ≥ 3 territories with plaque). A Personalized Algorithm for Severe Atheromatosis Prediction (PASAP-ILERVAS) was obtained by machine learning. Models were trained in the ILERVAS cohort (n = 8,330; 51% women) and validated in the control subpopulation of the NEFRONA cohort (n = 559; 47% women). Performance was compared to the Systematic COronary Risk Evaluation (SCORE) model. RESULTS The PASAP-ILERVAS is a sex-specific, easy-to-interpret predictive model that stratifies individuals according to their risk of SA in low, intermediate, or high risk. New clinical predictors beyond traditional factors were uncovered. In low- and high-risk (L&H-risk) men, the net reclassification index (NRI) was 0.044 (95% CI: 0.020-0.068), and the integrated discrimination index (IDI) was 0.038 (95% CI: 0.029-0.048) compared to the SCORE. In L&H-risk women, PASAP-ILERVAS showed a significant increase in the area under the curve (AUC, 0.074 (95% CI: 0.062-0.087), p-value: < 0.001), an NRI of 0.193 (95% CI: 0.162-0.224), and an IDI of 0.119 (95% CI: 0.109-0.129). CONCLUSION The PASAP-ILERVAS improves SA prediction, especially in women. Thus, it could reduce the number of unnecessary complementary explorations selecting patients for a further imaging study within the intermediate risk group, increasing cost-effectiveness and optimizing health resources. CLINICAL TRIAL REGISTRATION [www.ClinicalTrials.gov], identifier [NCT03228459].
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10.
DPP9 as a Potential Novel Mediator in Gastrointestinal Virus Infection.
Del Castillo-Izquierdo, Á, Moreno-Navarrete, JM, Latorre, J, Arnoriaga-Rodríguez, M, Ballanti, M, Monteleone, G, Alessandro Paoluzi, O, Mingrone, G, Puig, J, Ramos, R, et al
Antioxidants (Basel, Switzerland). 2022;(11)
Abstract
Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family. Inhibition of DPP9 has recently been shown to activate the nucleotide-binding domain leucine-rich repeat 1 (NLRP1) inflammasome. NLRP1 is known to bind nucleic acids with high affinity and directly interact with double stranded RNA, which plays a key role in viral replication. DPP9 has also recently emerged as a key gene related to lung-inflammation in critical SARS-CoV-2 infection. Importantly, DPP9 activity is strongly dependent on the oxidative status. Here, we explored the potential role of DPP9 in the gastrointestinal tract. We performed transcriptomics analyses of colon (microarray, n = 37) and jejunal (RNA sequencing, n = 31) biopsies from two independent cohorts as well as plasma metabolomics analyses in two independent cohorts (n = 37 and n = 795). The expression of DPP9 in the jejunum, colon, and blood was significantly associated with circulating biomarkers of oxidative stress (uric acid, bilirubin). It was also associated positively with the expression of transcription factors (NRF-2) and genes (SOD, CAT, GPX) encoding for antioxidant enzymes, but negatively with that of genes (XDH, NOX) and transcription factors (NF-KB) involved in ROS-generating enzymes. Gene co-expression patterns associated with DPP9 identified several genes participating in antiviral pathways in both tissues. Notably, DPP9 expression in the colon and plasma was strongly positively associated with several circulating nucleotide catabolites (hypoxanthine, uric acid, 3-ureidopropionic acid) with important roles in the generation of ROS and viral infection, as well as other metabolites related to oxidative stress (Resolvin D1, glutamate-containing dipeptides). Gene-drug enrichment analyses identified artenimol, puromycin, anisomycin, 3-phenyllactic acid, and linezolid as the most promising drugs targeting these DPP9-associated genes. We have identified a novel potential pathogenic mechanism of viral infection in the digestive tract and promising existing drugs that can be repositioned against viral infection.