Suchergebnisse

Methionine metabolism arises as a key target to elucidate the molecular adaptations underlying animal longevity due to the negative association between longevity and methionine content. The present study follows a comparative approach to analyse plasma methionine metabolic profile using a LC-MS/MS platform from 11 mammalian species with a longevity ranging from 3.5 to 120 years. Our findings demonstrate the existence of a species-specific plasma profile for methionine metabolism associated with longevity characterised by: i) reduced methionine, cystathionine and choline; ii) increased non-polar amino acids; iii) reduced succinate and malate; and iv) increased carnitine. Our results support the existence of plasma longevity features that might respond to an optimised energetic metabolism and intracellular structures found in long-lived species. ; This work was supported by the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), and the Generalitat of Catalonia (Agency for Management of University and Research Grants (2017SGR696) and Department of Health (SLT002/16/00250)) to R.P. This study has been co-financed by FEDER funds from the European Union ("A way to build Europe"). IRBLleida is a CERCA Programme/Generalitat of Catalonia. M.J. is a 'Serra Hunter' Fellow. N.M.M. received a predoctoral fellowship from the Generalitat of Catalonia (AGAUR, ref 2018FI_B2_00104).

Maximum longevity (ML) varies significantly across animal species, but the underlying molecular mechanisms remain poorly understood. Recent studies and omics approaches suggest that phenotypic traits of ML could to converge in the mammalian target of rapamycin (mTOR) signalling pathway. The present study is a comparative approach using heart tissue from 8 mammalian species with a ML ranging from 3.5 to 46 years. Gene expression, protein content, and concentration of regulatory metabolites of the mTOR complex 1 (mTORC1) were measured using droplet digital PCR, western blot and mass spectrometry, respectively. Our results demonstrate 1) the existence of differences species-specific in gene expression and protein content of mTORC1; 2) that the achievement of a longevity phenotype requires decreased and inhibited mTORC1; 3) decreased content of mTORC1 activators in long-lived animals, and 4) independence of phylogeny relationships on these changes. Altogether, our findings support mTORC1 down-regulation to achieve a longevous phenotype. ; This work was supported by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (grant number PI14/00328), the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), and the Generalitat of Catalonia, Agency for Management of University and Research Grants (2017SGR696) and Department of Health (SLT002/16/00250) to R.P. This study has been co-financed by FEDER funds from the European Union ("A way to build Europe").

Scope: Diets with low content in advanced glycation end products (AGEs) lead to beneficial properties in highly prevalent age-related diseases. To shed light on the mechanisms behind, the changes induced by a low AGE dietary intervention in the circulating metabolome are analyzed. Methods and Results: To this end, 20 non-diabetic patients undergoing peritoneal dialysis are randomized to continue their usual diet or to one with a low content of AGEs for 1 month. Then, plasmatic metabolome and lipidomes are analyzed by liquid-chromatography coupled to mass spectrometry. The levels of defined AGE structures are also quantified by ELISA and by mass-spectrometry. The results show that the low AGE diet impinged significant changes in circulating metabolomes (166 molecules) and lipidomes (91 lipids). Metabolic targets of low-AGE intake include sphingolipid, ether-lipids, and glycerophospholipid metabolism. Further, it reproduces some of the plasma characteristics of healthy aging. Conclusion : The finding of common pathways induced by low-AGE diets with previous metabolic traits implicated in aging, insulin resistance, and obesity suggest the usefulness of the chosen approach and supports the potential extension of this study to other populations. ; The authors acknowledge funding from the Spanish Ministry of Economy and Competitiveness (PRX15/00613), Institute of Health Carlos III (P.I. 17–00134, PI20-00155) to M.P.-O.; and the Generalitat of Catalonia, Agency for Management of University and Research Grants (2017SGR696) to R.P. R.B. is a fellow from Program "Impuls"-Santander. R.R.-M. is a fellow from CONACYT. This study has been co-financed by FEDER funds from the European Union ("A way to build Europe"). M.J. is a professor under the "Serra Hunter" program (Generalitat de Catalunya).

This study aimed to determine how the microbiota profile might be predisposed to a better response in blood lipid profiles due to dietary fibre supplementation. A three-arm intervention study that included three different fibre types (mainly insoluble, soluble, and antioxidant fibre) supplemented (19.2 g/day) during 2 months in individuals with hypercholesterolemia was developed. Changes in faecal microbiota and blood lipid profile after fibre supplementation were determined. In all volunteers, regardless of fibre type, an increase in the abundance of Bifidobacterium was observed, and similarly, an inverse relationship between faecal propionic acid and blood LDL-cholesterol, LDL particle size, and LDL/HDL particle ratio (p-values 0.0067, 0.0002, and 0.0067, respectively) was observed. However, not all volunteers presented an improvement in lipid profile. The non-responders to fibre treatment showed a decrease in microbiota diversity (Shannon and Simpson diversity index p-values of 0.0110 and 0.0255, respectively) after the intervention; where the reduction in short-chain fatty acids (SCFAs) producing bacterial genera such as Clostridium XIVa and Ruminococcus after dietary fibre treatment was the main difference. It was concluded that the non-responsiveness to dietary fibre treatment might be mediated by the lack of ability to maintain a stable SCFA producing bacteria diversity and composition after extra fibre intake. ; The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the Seventh Framework Programme of the European Union (FP7/2007-2013) under REA grant agreement no. 600388 (TECNIOspring Progamme) and from the Agency for Business Competitiveness of the Government of Catalonia ACCIÓ that support the fellowship given to Ana Belén Granado-Serrano (TECSPR14-0-0023)

Gut microbiota has been suggested to affect lipid metabolism. The objective of this study was to characterize the faecal microbiota signature and both short chain fatty acids (SCFAs) and bile acids (BA) profile of hypercholesterolemic subjects. Microbiota composition, SCFAs, BA and blood lipid profile from male volunteers with hypercholesterolemia (HC) and normocholesterolemia (NC) were determined by 16S rDNA sequencing, HPLC, GC and NMR, respectively. HC subjects were characterized by having lower relative abundance of Anaeroplasma (0.002% vs 0.219%, p-value = 0.026) and Haemophilus (0.041% vs 0.078%, p-value = 0.049), and higher of Odoribacter (0.51% vs 0.16%; p-value = 0.044). Correlation analysis revealed that Anaeroplasma and Haemophilus were associated to an unfavourable lipid profile: they correlated negatively to cholesterol and triglycerides related biomarkers and the ratio total to high density lipoprotein (HDL) cholesterol, and positively to HDL size. Odoribacter displayed an opposite behaviour. Faecal SCFAs profile revealed higher abundance of isobutyric (2.76% vs 0.82%, p-value = 0.049) and isovaleric acid (1.32% vs 0.06%, p-value = 0.016) in HC. Isobutyric acid correlated positively with Odoribacter and lipid parameters indicative of an unfavourable profile. BA profile did not show differences between groups. It was concluded that HC subjects showed a particular faecal bacterial signature and SCFAs profile associated with their lipid profile. ; The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the Seventh Framework Programme of the European Union (FP7/2007-2013) under REA grant agreement No. 600388 (TECNIOspring Progamme) and from the Agency for Business Competitiveness of the Government of Catalonia ACCIÓ that support the fellowship given to Ana Belén Granado-Serrano (TECSPR14-0-0023). I.A.L enjoys a post-doctoral contract (2017PMF-POST2-19) from the European Union's Horizon 2020 research and innovation programme under the Marie ...

PGC-1α controls, to a large extent, the capacity of cells to respond to changing nutritional requirements and energetic demands. The key role of metabolic reprogramming in tumor development has highlighted the potential role of PGC-1α in cancer. To investigate how loss of PGC-1α activity in primary cells impacts the oncogenic characteristics of spontaneously immortalized cells, and the mechanisms involved, we used the classic 3T3 protocol to generate spontaneously immortalized mouse embryonic fibroblasts (iMEFs) from wild-type (WT) and PGC-1α knockout (KO) mice and analyzed their oncogenic potential in vivo and in vitro. We found that PGC-1α KO iMEFs formed larger and more proliferative primary tumors than WT counterparts, and fostered the formation of lung metastasis by B16 melanoma cells. These characteristics were associated with the reduced capacity of KO iMEFs to respond to cell contact inhibition, in addition to an increased ability to form colonies in soft agar, an enhanced migratory capacity, and a reduced growth factor dependence. The mechanistic basis of this phenotype is likely associated with the observed higher levels of nuclear β-catenin and c-myc in KO iMEFs. Evaluation of the metabolic adaptations of the immortalized cell lines identified a decrease in oxidative metabolism and an increase in glycolytic flux in KO iMEFs, which were also more dependent on glutamine for their survival. Furthermore, glucose oxidation and tricarboxylic acid cycle forward flux were reduced in KO iMEF, resulting in the induction of compensatory anaplerotic pathways. Indeed, analysis of amino acid and lipid patterns supported the efficient use of tricarboxylic acid cycle intermediates to synthesize lipids and proteins to support elevated cell growth rates. All these characteristics have been observed in aggressive tumors and support a tumor suppressor role for PGC-1α, restraining metabolic adaptations in cancer. ; This work was funded by grants from the Spanish "Ministerio de Ciencia, Innovación y Universidades" (MICINN) and ERDF/FEDER funds, SAF2012-37693, SAF2015-63904-R, SAF2015-71521-REDC, RTI2018-093864-B-I00 to M.M., SAF2017-83043-R and B2017/BMD-3724 to S·C., PI15/00107 to A.M.R, the University of the Basque Country UPV/EHU grant GIU16/62) to J.l.R.S. and M.B.R.L., and the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 721236-TREATMENT to M.M.

Brain neurons offer diverse responses to stresses and detrimental factors during development and aging, and as a result of both neurodegenerative and neuropsychiatric disorders. This multiplicity of responses can be ascribed to the great diversity among neuronal populations. Here we have determined the metabolomic profile of three healthy adult human brain regions—entorhinal cortex, hippocampus, and frontal cortex—using mass spectrometry-based technologies. Our results show the existence of a lessened energy demand, mitochondrial stress, and lower one-carbon metabolism (particularly restricted to the methionine cycle) specifically in frontal cortex. These findings, along with the better antioxidant capacity and lower mTOR signaling also seen in frontal cortex, suggest that this brain region is especially resistant to stress compared to the entorhinal cortex and hippocampus, which are more vulnerable regions. Globally, our results show the presence of specific metabolomics adaptations in three mature, healthy human brain regions, confirming the existence of cross-regional differences in cell vulnerability in the human cerebral cortex. ; This research was funded by the Spanish Ministry of Economy and Competitiveness, Institute Carlos III (FIS grants PI14/00757 and PI14/00328), and the Autonomous Government of Catalonia (2014SGR69 and 2014SGR168) to IF and RP. This study was co-financed by FEDER funds from the European Union ('A way to build Europe'). RC received predoctoral fellowships from the Autonomous Government of Catalonia. We thank T. Yohannan for editorial help.