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)

The cirrhotic liver is depleted of docosahexaenoic acid (DHA), a key modulator of NF-κB and TGFβ pathways in hepatic stellate cells

Liver cirrhosis results from chronic hepatic damage and is characterized by derangement of the organ architecture with increased liver fibrogenesis and defective hepatocellular function. It frequently evolves into progressive hepatic insufficiency associated with high mortality unless liver transplantation is performed. We have hypothesized that the deficiency of critical nutrients such as essential omega-3 fatty acids might play a role in the progression of liver cirrhosis. Here we evaluated by LC-MS/MS the liver content of omega-3 docosahexaenoic fatty acid (DHA) in cirrhotic patients and investigated the effect of DHA in a murine model of liver injury and in the response of hepatic stellate cells (HSCs) (the main producers of collagen in the liver) to pro-fibrogenic stimuli. We found that cirrhotic livers exhibit a marked depletion of DHA and that this alteration correlates with the progression of the disease. Administration of DHA exerts potent anti-fibrogenic effects in an acute model of liver damage. Studies with HSCs show that DHA inhibits fibrogenesis more intensely than other omega-3 fatty acids. Data from expression arrays revealed that DHA blocks TGFβ and NF-κB pathways. Mechanistically, DHA decreases late, but not early, SMAD3 nuclear accumulation and inhibits p65/RelA-S536 phosphorylation, which is required for HSC survival. Notably, DHA increases ADRP expression, leading to the formation of typical quiescence-associated perinuclear lipid droplets. In conclusion, a marked depletion of DHA is present in the liver of patients with advanced cirrhosis. DHA displays anti-fibrogenic activities on HSCs targeting NF-κB and TGFβ pathways and inducing ADPR expression and quiescence in these cells.This study was supported by European FEDER funding and grants from the Ministry of Economy (SAF2015-70971-R), Gobierno de Navarra 0011-1365-2016-000308, Fundación Echevano, Fundación Unicaja, and Fondo de Investigación Sanitaria (PI16/02081), financed by the Instituto de Salud Carlos III