Metformin induces lipid changes on sphingolipid species and oxidized lipids in polycystic ovary syndrome women

Metformin is one of the treatments used for pcoS pathology decreasing body weight, plasma androgen, FSH and glucose levels. Unfortunately, there is little known about metformin’s effects on lipid metabolism, a crucial process in pcoS pathology. We have employed a lipidomic approach to explore alterations in the plasma lipid profile of patients with PCOS following metformin treatment. The aim is to offer new insights about the effect of metformin in PCOS patients. Plasma samples were obtained from 27 subjects prior to and following 12 weeks of metformin treatment. A detailed biochemical characterization and lipidomic profile was performed. Metformin reduces BMI, HOMA-IR, fSH and androstenedione and increases DHeA-S but no changes were found in glucose levels after treatment. Multivariate statistics revealed a specific lipidomic signature due to the effect of 12 weeks of metformin treatment in pcoS patients. this signature includes changes in sphingolipid metabolism suggesting a crosstalk between these lipid species and the androgenic metabolism and a decrease in oxidized lipids reinforcing that metformin treatment improves oxidative stress status. our study confirms the specific effect of metformin in lipid metabolism on women with PCOS after 12 weeks of treatment.We thank Maria Rosa Gomez and David Argiles for technical support. This research was funded by grants from Carlos III Health Institute (ISCIII) (PI16/1083, PI16/0301) to V.M.V and M.R, respectively and CIBERehd (CB06/04/0071)−initiatives of the ISCIII to M.R and V.M.V, the European Regional Development Fund (ERDF “A way to build Europe”). Unrestricted grant from Menarini S.A to M.R. V.M.V. and M.R. are recipients of contracts from the Ministry of Health of the Valencian Regional Government and Carlos III Health Institute (CES10/030 and CP10/0360, respectively). R. P. is recipient of contracts from the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (grant number PI14/00328); Spanish Ministry of Science, Innovation and Universities (grant number RTI2018-099200-B-I00), and the Generalitat of Catalonia, Department of Health (grant number SLT002/16/00250) and Department of Business and Knowledge (grant number 2017SGR696). This study has been co-financed by FEDER funds from the European Union (‘A way to build Europe’). I.P. received a predoctoral fellowship from the Lleida University. S.R-LL. is recipient of a Juan de la Cierva contract from Spanish Ministry of Economy and Competitiveness (FJCI-2015-25040). C.B. is recipient of a Sara Borrell contract from Institute of Health Carlos III (CD14/00043). M.J is a Serra Húnter Fellow

Membrane lipid unsaturation as physiological adaptation to animal longevity

The appearance of oxygen in the terrestrial atmosphere represented an important selective pressure for ancestral living organisms and contributed toward setting up the pace of evolutionary changes in structural and functional systems. The evolution of using oxygen for efficient energy production served as a driving force for the evolution of complex organisms. The redox reactions associated with its use were, however, responsible for the production of reactive species (derived from oxygen and lipids) with damaging effects due to oxidative chemical modifications of essential cellular components. Consequently, aerobic life required the emergence and selection of antioxidant defense systems. As a result, a high diversity in molecular and structural antioxidant defenses evolved. In the following paragraphs, we analyze the adaptation of biological membranes as a dynamic structural defense against reactive species evolved by animals. In particular, our goal is to describe the physiological mechanisms underlying the structural adaptation of cellular membranes to oxidative stress and to explain the meaning of this adaptive mechanism, and to review the state of the art about the link between membrane composition and longevity of animal species.Investigations of the author of this review have been supported in part by I+D grants from the Spanish Ministry of Science and Innovation (BFU2011-23888), and BSCH-UCM (2009-2010) to Gustavo Barja; and grants from the Spanish Ministry of Education and Science (BFU2009-11879/BFI), the Spanish Ministry of Economy and Competitiveness-Institute of Health Carlos III (PI13/00584) and the Generalitat of Catalunya (2009SGR735) to Reinald Pamplona

Regulation of membrane unsaturation as antioxidant adaptive mechanism in long-lived animal species

Oxidative stress resulting from biomolecular oxidative damage due to the imbalance between reactive species production and antioxidant response has become an universal constraint of life-history evolution in animals and a modulator of phenotypic development and trade-offs. Redox balance is an important selective pressure faced by most organisms, and a myriad of mechanisms have evolved to regulate and adjust this balance. This diversity of mechanisms means that organisms have a great deal of flexibility in how they deal with reactive species challenges across time, conditions, and tissue types, as well as that different organisms may evolve different strategies for dealing with similar challenges. In the following paragraphs, we review the adaption of biological membranes as structural antioxidant defense against reactive species evolved by animals. In particular, it is our goal to describe the physiological mechanisms underlying the structural adaption of cellular membranes to oxidative stress, to explain the meaning of this adaptive mechanism, and to review the state of the art about the link between membrane composition and longevity of animal species.Investigations of the author of this review have been supported in part by I + D grants from the Spanish Ministry of Science and Innovation (BFU2008-00335/ BFI and BFU2011-23888), and BSCH-UCM (2009-2010) to G.B; and grants from the Spanish Ministry of Education and Science (BFU2009-11879/BFI), the Spanish Ministry of Health (RD06/0013/0012), and the Generalitat of Catalunya (2009SGR735) to R.P

Biosíntesis de novo de glicerofosfolípidos y longevidad

Introducción. Entre los principales componentes lipídicos de las membranas celulares se encuentran los glicerofosfolípidos (GFL), que se sintetizan en una vía de novo a partir del diacilglicerol (DAG). El perfil lipídico es una característica optimizada asociada con la longevidad animal. En este contexto, hipotetizamos que la tasa de biosíntesis de DAGs y, por extensión, de GFL, guarda una relación con la longevidad de una especie animal. Material y métodos. Se realiza un análisis lipidómico basado en espectrometría de masas del plasma de 11 especies de mamíferos que cubren un rango de longevidad máxima de 3,5 a 120 años. La identificación de especies lipídicas se basa en masa exacta, tiempo de retención y distribución isotópica. Se aplica un test ANOVA para obtener las especies lipídicas diferenciales entre las especies y la correlación de Spearman para establecer su asociación con la longevidad. Los análisis estadísticos se realizaron con el programa SPSS y el software para el análisis metabolómico Metaboanalyst. Resultados. Entre las 1061 especies moleculares lipídicas diferenciales se identifican 47 DAGs, 14 de los cuales presentan una correlación significativa y negativa con la longevidad animal. El análisis multivariante muestra que solamente con estos 14 DAGs somos capaces de discriminar una especie animal y su longevidad máxima. Conclusiones. Éstos resultados sugieren que las especies longevas tienen una menor tasa de biosíntesis de novo de GFL, posiblemente asociada a una menor tasa de recambio de los lípidos de membrana, lo que conllevaría un menor coste energético.El trabajo ha sido financiado, en parte, por una ayuda del Ministerio Español de Economía y Competitividad (ref. FIS-PI1400328), y por la Generalitat de Catalunya (2017SGR696 y SLT002/00250) a R. Pamplona. El estudio ha sido cofinanciado por los Fondos de la Unión Europea (“Una manera de hacer Europa”)

Non-enzymatic modification of aminophospholipids by carbonyl-amine reactions

Non-enzymatic modification of aminophospholipids by lipid peroxidation-derived aldehydes and reducing sugars through carbonyl-amine reactions are thought to contribute to the age-related deterioration of cellular membranes and to the pathogenesis of diabetic complications. Much evidence demonstrates the modification of aminophospholipids by glycation, glycoxidation and lipoxidation reactions. Therefore, a number of early and advanced Maillard reaction-lipid products have been detected and quantified in different biological membranes. These modifications may be accumulated during aging and diabetes, introducing changes in cell membrane physico-chemical and biological properties

Target of rapamycin activation predicts lifespan in fruit flies

Aging and age-related diseases are one of the most important health issues that the world will confront during the 21st century. Only by understanding the proximal causes will we be able to find treatments to reduce or delay the onset of degenerative diseases associated with aging. Currently, the prevalent paradigm in the field is the accumulation of damage. However, a new theory that proposes an alternative explanation is gaining momentum. The hyperfunction theory proposes that aging is not a consequence of a wear and tear process, but a result of the continuation of developmental programs during adulthood. Here we use Drosophila melanogaster, where evidence supporting both paradigms has been reported, to identify which parameters that have been previously related with lifespan best predict the rate of aging in wild type flies cultured at different temperatures. We find that mitochondrial function and mitochondrial reactive oxygen species (mtROS) generation correlates with metabolic rate, but not with the rate of aging. Importantly, we find that activation of nutrient sensing pathways (i.e. insulin-PI3K/Target of rapamycin (Tor) pathway) correlates with lifespan, but not with metabolic rate. Our results, dissociate metabolic rate and lifespan in wild type flies and instead link nutrient sensing signaling with longevity as predicted by the hyperfunction theory.This study was supported by the European Research Council (ERC Starting Grant to A.S.), the Academy of Finland (Research Academy Fellowship to A.S), the Spanish Ministry of Economy and Competitiveness (BFU2009-11879/BFI; RD12/0043/0018 and PI1400328 to R.P.), and the Autonomous Government of Catalonia (2014SGR168 to R.P)

Plasma long-chain free fatty acids predict mammalian longevity

determination of their longevity. In the present work, the use of high-throughput technologies allowed us to determine the plasma lipidomic profile of 11 mammalian species ranging in maximum longevity from 3.5 to 120 years. The non-targeted approach revealed a specie-specific lipidomic profile that accurately predicts the animal longevity. The regression analysis between lipid species and longevity demonstrated that the longer the longevity of a species, the lower is its plasma long-chain free fatty acid (LC-FFA) concentrations, peroxidizability index, and lipid peroxidation-derived products content. The inverse association between longevity and LC-FFA persisted after correction for body mass and phylogenetic interdependence. These results indicate that the lipidomic signature is an optimized feature associated with animal longevity, emerging LC-FFA as a potential biomarker of longevityWe acknowledge funding from the Spanish Ministry of Science and Innovation (CGL2010-18124) to J.C.A.; from the Spanish Ministry of Health (PI11-01532) to M.P.O.; and from the Spanish Ministry of Science and Innovation (BFU2009-11879/BFI), the Generalitat of Catalonia (2009SGR735), and the La MaratoTV3 Foundation to R.P. R.C. was supported by a Generalitat of Catalonia Predoctoral Fellowship. We thank David Argiles for excellent technical assistance. We thank Dr. Montserrat Rué for her support in statistical analyses

mTORC1 and longevit

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”)

The biological basis of the aging process

El procés biològic bàsic subjacent de l’envelliment va ésser avançat per la teoria de l’envelliment basada en els radicals lliures l’any 1954: la reacció dels radicals lliures actius, produïts fisiològicament en l’organisme, amb els constituents cel·lulars inicia els canvis associats a l’envelliment. La implicació dels radicals lliures en l’envelliment està relacionada amb el seu paper clau en l’origen i l’evolució de la vida. La informació disponible avui en dia ens mostra que la composició específica de les macromolècules cel·lulars (proteïnes, àcids nucleics, lípids i carbohidrats) en les espècies animals longeves tenen intrínsicament una resistència elevada a la modificació oxidativa, la qual cosa probablement contribueix a la longevitat superior d’aquestes espècies. Les espècies longeves també mostren unes taxes reduïdes de producció de radicals lliures i de lesió oxidativa. D’altra banda, la restricció dietària disminueix la producció de radicals lliures i la lesió molecular oxidativa. Aquests canvis estan directament associats a la reducció de la ingesta de proteïnes dels animals sotmesos a restricció, que alhora sembla que són deguts específicament a la reducció de la ingesta de metionina. En aquesta revisió s’emfatitza que una taxa baixa de generació de lesió endògena i una resistència intrínsecament elevada a la modificació de les macromolècules cel·lulars són trets clau de la longevitat de les espècies animals.The basic chemical process underlying aging was first put forward by the free radical theory of aging in 1956; the reaction of active free radicals (normally produced within an organism itself) with cellular constituents initiates the changes associated with aging. The involvement of free radicals in aging is related to their key role in the origin and evolution of life. The specific composition of tissue macromolecules (proteins, nucleic acids, lipids and carbohydrates) in long-lived animal species gives them an intrinsically high resistance to modification that probably contributes to the superior longevity of these species. Long-lived species also show low rates of reactive oxygen species (ROS) generation and oxidative damage to their mitochondria. Dietary restriction further decreases mitochondrial ROS production and oxidative molecular damage due to the decreased intake of dietary proteins. These effects of protein restriction seem to be specifically due to the lowered methionine intake of protein and dietary restricted animals. Both a low rate of generation of endogenous damage and an intrinsically high resistance to the modification of tissue macromolecules are key traits of animal longevity

Lipidomics reveals altered biosynthetic pathways of glycerophospholipids and cell signaling as biomarkers of the polycystic ovary syndrome

Purpose: In this work, a non-targeted approach was used to unravel changes in the plasma lipidome of PCOS patients. The aim is to offer new insights in PCOS patients strictly selected in order to avoid confounding factors such as dyslipemia, obesity, altered glucose/insulin metabolism, cardiovascular disease, or cancer. Results: Multivariate statistics revealed a specific lipidomic signature for PCOS patients without associated pathologies. This signature implies changes, mainly by down-regulation, in glycerolipid, glycerophospholipid and sphingolipid metabolism suggesting an altered biosynthetic pathway of glycerophospholipids and cell signaling as second messengers in women with PCOS. Conclusions: Our study confirms that a lipidomic approach discriminates a specific phenotype from PCOS women without associated pathologies from healthy controls. Methods: In a cross-sectional pilot study, data were obtained from 34 subjects, allocated to one of two groups: a) lean, healthy controls (n = 20), b) PCOS patients (n = 14) with diagnosis based on hyperandrogenaemia, oligo-anovulation and abnormal ovaries with small follicular cysts. A detailed biochemical characterization was made and lipidomic profiling was performed via an untargeted approach using LC-ESI-QTOF MS/MS.We acknowledge funding from the Fund for Health Research (FIS) and co-funding from the European Regional Development Fund of the European Union (FEDER, ‘Una manera de hacer Europa’): PI15/1424, PI16/1083, PI16/0301 and UGP15-193 by FISABIO, to A.H.M, M.R. and V.M.V, respectively. This research was also in part funded by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (FIS grants PI14/00328), and the Autonomous Government of Catalonia (2017SGR and SLT002/16/00250) to R.P. This study was co-financed by FEDER funds from the European Union (‘Una manera de hacer Europa’)