mTOR Complex 1 Content and Regulation Is Adapted to Animal Longevity

Decreased content and activity of the mechanistic target of rapamycin (mTOR) signalling pathway, as well as the mTOR complex 1 (mTORC1) itself, are key traits for animal species and human longevity. Since mTORC1 acts as a master regulator of intracellular metabolism, it is respon sible, at least in part, for the longevous phenotype. Conversely, increased content and activity of mTOR signalling and mTORC1 are hallmarks of ageing. Additionally, constitutive and aberrant activity of mTORC1 is also found in age-related diseases such as Alzheimer’s disease (AD) and cancer. The downstream processes regulated through this network are diverse, and depend upon nutrient availability. Hence, multiple nutritional strategies capable of regulating mTORC1 activity and, consequently, delaying the ageing process and the development of age-related diseases, are under continuous study. Among these, the restriction of calories is still the most studied and ro bust intervention capable of downregulating mTOR signalling and feasible for application in the human population.Research by the authors was supported by the Spanish Ministry of Science, Innovation, and Universities (Ministerio de Ciencia, Innovación y Universidades, co-financed by FEDER funds from the European Union ‘A way to build Europe’, grant RTI2018-099200-B-I00), the IRBLleida-Diputació de Lleida (PIRS2021), and the Generalitat of Catalonia: Agency for Management of University and Research Grants (2017SGR696) to R.P. IRBLleida is a CERCA Programme/Generalitat of Cataloni

Plasma methionine metabolic profile is associated with longevity in mammals

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)

Up-Regulation of Specific Bioactive Lipids in Celiac Disease

Celiac disease (CD) is an autoimmune enteropathy linked to alterations of metabolism. Currently, limited untargeted metabolomic studies evaluating differences in the plasma metabolome of CD subjects have been documented. We engage in a metabolomic study that analyzes plasma metabolome in 17 children with CD treated with a gluten-free diet and 17 healthy control siblings in order to recognize potential changes in metabolic networks. Our data demonstrates the persistence of metabolic defects in CD subjects in spite of the dietary treatment, affecting a minor but significant fraction (around 4%, 209 out of 4893 molecular features) of the analyzed plasma metabolome. The affected molecular species are mainly, but not exclusively, lipid species with a particular affectation of steroids and derivatives (indicating an adrenal gland affectation), glycerophospholipids (to highlight phosphatidic acid), glycerolipids (with a special affectation of diacylglycerols), and fatty acyls (eicosanoids). Our findings are suggestive of an activation of the diacylglycerol-phosphatidic acid signaling pathway in CD that may potentially have detrimental effects via activation of several targets including protein kinases such as mTOR, which could be the basis of the morbidity and mortality connected with untreated CD. However, more studies are necessary to validate this idea regarding CD.Regional Government of Andalusia, Excellence Research (Project No P12-AGR-2581)Spanish Ministry of Science, Innovation, and Universities (Ministerio de Ciencia, Innovación y Universidades, RTI2018-099200-BI00)Generalitat of Catalonia: Agency for Management of University and Research Grants (2017SGR696)Department of Health (SLT002/16/00250)FEDER - European Union (“A way to build Europe”).IRBLleida - CERCA Programme/Generalitat of Catalonia“Investigation grant program by the Association of Celiacs and Sensitive to Gluten of the Community of Madri

Industrial By-Products As a Novel Circular Source of Biocompatible Extracellular Vesicles

Extracellular vesicles (EVs) constitute an intricate system of molecular exchange that has recently gained tremendous interest. However, sustainable sources of safe biological EVs remain scarce and elusive. This study explores and defines the use of food industry by-products (BP) as a circular source of safe biocompatible EVs. Averaged diameter and molecular compositions indicate a large yield of exosomes and high abundancy of membrane lipids with signaling capacity in these vesicles. Complex proteomes mimicking those circulating in human blood plasma are also identified. Furthermore, BP-EVs do not show relevant cytotoxicity and display excellent oral and intravenous bioavailability together with specific organ targeting capacity. Collectively, it is believed that the novel findings reported here will open substantial venues for the use of BP as an optimal source of biocompatible nanovesicles in manifold applications of the biotechnological and biomedical fields.The authors sincerely thank Gemma Plaza, oenologist at the Castell del Remei winery in Penelles, Lleida, Spain and Juan Carlos Blanco, production manager at Mahou San Miguel in Alovera, Madrid, Spain for their kind and altruistic help on the obtention of their respective industry by-product samples. The authors also thank Dr. Hector Peinado and his research group at the National Center for Oncology Research (CNIO) in Madrid (Spain) for their support on the morphometric characterization of BP-EVs. Support for this work was provided by the Research and Education Council of the Community of Madrid, Spain (2018-T1/ BIO-10633), Ministry of Science and Innovation, Spain (PID2020- 114885RB-C21) and a FIS project by Carlos III Institute of Health (ISCIII), Spain (PI20/00623). A.S. acknowledges a grant from the Talento Program 2018 of the Community of Madrid. X.G.-P. acknowledges grants from Sara Borrell postdoctoral program (CD19/00243) and Miguel Servet tenure track program (CP21/00096) of the Instituto de Salud Carlos III (ISCIII, Spain), respectively awarded on the 2019 and 2021 calls under ISCIII-Health Strategy Actions [These grants are cofunded with European Union Funds (ISCIII Miguel Servet Program 2021 is cofunded by Fondo Social Europeo Plus, FSE+)]. M.V.C. acknowledges a Miguel Servet program contract (CPII20/00007). C.L.’s Ph.D. was funded by the Regional Ministry of Science, Universities and Innovation of the Community of Madrid and the European Social Fund for the recruitment of predoctoral researchers (PEJD-2019-PRE/BIO-16475). IRBLLEIDA and X.G.-P. are co-funded by CERCA Program/Generalitat de Catalunya

The lipidome fingerprint of longevity

Lipids were determinants in the appearance and evolution of life. Recent studies disclose the existence of a link between lipids and animal longevity. Findings from both comparative studies and genetics and nutritional interventions in invertebrates, vertebrates, and exceptionally long-lived animal species—humans included—demonstrate that both the cell membrane fatty acid profile and lipidome are a species-specific optimized evolutionary adaptation and traits associated with longevity. All these emerging observations point to lipids as a key target to study the molecular mechanisms underlying differences in longevity and suggest the existence of a lipidome profile of long life.Research by the authors was supported by the Spanish Ministry of Science, Innovation, and Universities (Ministerio de Ciencia, Innovación y Universidades, RTI2018-099200-BI00), and the Generalitat of Catalonia: Agency for Management of University and Research Grants (2017SGR696) and Department of Health (SLT002/16/00250) to RP. This study was co-financed by FEDER funds from the European Union (“A way to build Europe”). IRBLleida is a CERCA Programme/Generalitat of Catalonia