Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

Mitochondrial metabolism and autophagy are two of the most metabolically active cellular processes, playing a crucial role in regulating organism longevity. In fact, both mitochondrial dysfunction or autophagy decline compromise cellular homeostasis and induce inflammation. Calorie restriction (CR) is the oldest strategy known to promote healthspan, and a plethora of CR mimetics have been used to emulate its beneficial effects. Herein, we discuss how CR and CR mimetics, by modulating mitochondrial metabolism or autophagic flux, prevent inflammatory processes, protect the intestinal barrier function, and dampen both inflammaging and neuroinflammation. We outline the effects of some compounds classically known as modulators of autophagy and mitochondrial function, such as NAD+ precursors, metformin, spermidine, rapamycin, and resveratrol, on the control of the inflammatory cascade and how these anti-inflammatory properties could be involved in their ability to increase resilience to age-associated diseasesThis research was funded by the H2020-EU.1.1. European Research Council (ERC-2016-StG 715322-EndoMitTalk), and Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI16/188, PI19/855), Fondo Europeo de Desarrollo Regional (FEDER). M.M. is supported by the Miguel Servet program from Instituto de Salud Carlos III (CPII19/00014, Instituto de Investigación del Hospital 12 de Octubre

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Nicotinamide adenine dinucleotide metabolism in the immune response, autoimmunity and inflammageing

Metabolism is dynamically regulated to accompany immune cell function, and altered immunometabolism can result in impaired immune responses. Concomitantly, the pharmacological manipulation of metabolic processes offers an opportunity for therapeutic intervention in inflammatory disorders. The nicotinamide adenine dinucleotide (NAD+) is a critical metabolic intermediate that serves as enzyme cofactor in redox reactions, and is also used as a co-substrate by many enzymes such as sirtuins, adenosine diphosphate ribose transferases and synthases. Through these activities, NAD+ metabolism regulates a broad spectrum of cellular functions such as energy metabolism, DNA repair, regulation of the epigenetic landscape and inflammation. Thus, the manipulation of NAD+ availability using pharmacological compounds such as NAD+ precursors can have immune-modulatory properties in inflammation. Here, we discuss how the NAD+ metabolism contributes to the immune response and inflammatory conditions, with a special focus on multiple sclerosis, inflammatory bowel diseases and inflammageingSpanish Ministry of Science and Innovation (PID2019-110511RB-I00) to M.N.N, and the H2020-EU.1.1, European Research Council (ERC-2016-StG 715322-EndoMitTalk), Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI19/855) to M.M, Fondo Europeo de Desarrollo Regional (FEDER) to M.M and M.N.N. M.M.GH was funded by the Spanish Ministry of Science, Innovation and Universities (FPU19/02576). M.M. is supported by the Miguel Servet program (CPII19/00014, Fundación de Investigación del Hospital 12 de Octubre). Institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSO are also acknowledged

Glycolysis – a key player in the inflammatory response

The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro-inflammatory phenotype, including signalling events, epigenetic remodelling, post-transcriptional regulation and post-translational modifications. Inflammatory processes are a common feature of many age-associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation-related pathologies through the manipulation of the vascular and immune cell metabolism.European Research Council (ERC-2016-StG 715322-EndoMitTalk), and Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI16/188, PI19/855), Fondo Europeo de Desarrollo Regional (FEDER). GS-H was funded by a FPIUAM grant (Universidad Autonoma de Madrid). MMGH was funded by ERC. EG-R was funded by a Juan de la Cierva grant (IJC2018-036850-I; Universidad Autónoma de Madrid). JO was funded by a Juan de la Cierva grant (FJCI-2017-33855; Universidad Autónoma de Madrid)

Glycolysis – a key player in the inflammatory response

The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro-inflammatory phenotype, including signalling events, epigenetic remodelling, post-transcriptional regulation and post-translational modifications. Inflammatory processes are a common feature of many age-associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation-related pathologies through the manipulation of the vascular and immune cell metabolism.European Research Council (ERC-2016-StG 715322-EndoMitTalk), and Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI16/188, PI19/855), Fondo Europeo de Desarrollo Regional (FEDER). GS-H was funded by a FPIUAM grant (Universidad Autonoma de Madrid). MMGH was funded by ERC. EG-R was funded by a Juan de la Cierva grant (IJC2018-036850-I; Universidad Autónoma de Madrid). JO was funded by a Juan de la Cierva grant (FJCI-2017-33855; Universidad Autónoma de Madrid)

Changes in ecosystem properties after post-fire management strategies in wildfire-affected Mediterranean forests

11 páginas.- 4 figuras.- 2 tablas.- referencias.- Additional supporting information may be found online in the Supporting Information section. https://doi.org/10.1111/1365-2664.13819Forest are highly vulnerable to global change drivers, such as an increase in wildfire events. Learning more about how and why different post-fire management strategies regulate the ability of forest ecosystem properties (e.g. plant diversity and function) to simultaneously recover after wildfire and provide multiple ecosystem functions is of critical importance. This study aims to evaluate how unburned, burned managed and burned unmanaged plots regulate the responses of multiple forest ecosystem properties (e.g. plant diversity, nutrient cycling, soil carbon stocks, water regulation, decomposition and wood production) and overall multifunctionality to wildfires. In September 2017, we selected two post-fire management strategies in a 3-km2 watershed previously affected by a wildfire in July 2012: contour-felled log debris (CFD), log erosion barriers area (LEB), and also unburned and unmanaged plots (BNA). We randomly distributed 12 plots among the three post-fire management strategies (three plots per treatment) and unburned. The results showed that multiple forest ecosystem properties were significantly affected by wildfire and that specific post-fire management treatment (e.g. LEB and CFD) can be used to efficiently support plant diversity and ecosystem functioning. Our results revealed that the general indicators of ecosystem functions decreased in Mediterranean forests after wildfires and post-fire management strategies (LEB and CFD) significantly helped to recover the ecosystems’ short-term community-level properties and ecosystem functions (5 years after a wildfire event) to pre-fire levels. Synthesis and applications. These findings demonstrate that multiple ecosystem functions are affected by wildfires in Mediterranean forests and show that post-fire management treatments can promote multifunctionality and plant diversity. Our results unfold the potential of log erosion barriers (LEB) and contour-felled log debris (CFD) as effective strategies for recovering community-level properties and forest functions in the short term.M.D.-B. is supported by a Ramón y Cajal grant from the Spanish government (agreement nº RYC2018-025483-I). M.M.-R. is supported by an Australian Research Council Discovery Early Career Research Award (DE180100570)Peer reviewe

SilvAdapt.Net: A Site-Based Network of Adaptive Forest Management Related to Climate Change in Spain

Adaptive forest management (AFM) is an urgent need because of the uncertainty regarding how changes in the climate will affect the structure, composition and function of forests during the next decades. Current research initiatives for the long-term monitoring of impacts of silviculture are scattered and not integrated into research networks, with the consequent losses of opportunities and capacity for action. To increase the scientific and practical impacts of these experiences, it is necessary to establish logical frameworks that harmonize the information and help us to define the most appropriate treatments. In this context, a number of research groups in Spain have produced research achievements and know-how during the last decades that can allow for the improvement in AFM. These groups address the issue of AFM from different fields, such as ecophysiology, ecohydrology and forest ecology, thus resulting in valuable but dispersed expertise. The main objective of this work is to introduce a comprehensive strategy aimed to study the implementation of AFM in Spain. As a first step, a network of 34 experimental sites managed by 14 different research groups is proposed and justified. As a second step, the most important AFM impacts on Mediterranean pines, as one of the most extended natural and planted forest types in Spain, are presented. Finally, open questions dealing with key aspects when attempting to implement an AFM framework are discussed. This study is expected to contribute to better outlining the procedures and steps needed to implement regional frameworks for AFM.A.J. Molina is beneficiary of an “APOSTD” fellowship (APOSTD/2019/111) funded by the Generalitat Valenciana. M. Moreno-de las Heras is beneficiary of a Serra Hunter fellowship (UB-LE-9055) funded by the Generalitat de Catalunya. F.J. Ruiz-Gómez is supported by a postdoctoral fellowship of the Junta de Andalucía (Sevilla, Spain), and the European Social Fund 2014–2020 Program (DOC_0055). The authors received national and international funding through the following projects: SILVADAPT.NET (RED2018-102719-T), ESPECTRAMED (CGL2017-86161-R), Life-FOREST CO2 (LIFE14 CCM/ES/001271), ALTERACLIM (CGL2015-69773-C2-1-P), INERTIA (PID2019-111332RB-C22-BDV), CEHYRFO-MED (CGL2017-86839-C3-2-R), DEHESACLIM (IB16185), RESILIENTFORESTS (LIFE17 CCA/ES/000063), Rhysotto (PID2019-106583RB-I00), AGL2017-83828-C2-2-R, RTI2018-096884-B-C31, ESPAS (CGL2015-65569-R), and caRRRascal (RTI2018-095037-B-I00)

Range Contraction and Population Decline of the European Dupont’s Lark Population

The Dupont’s lark (Chersophilus duponti) is an endangered passerine typical of Mediterranean shrub-steppes, whose European distribution is restricted to Spain. Here, we update the population size and distribution range of the species at a European scale and evaluate (i) the current status; (ii) the change in population size and distribution range of the species from 2004 to 2009 to the current period (2017–2022); and (iii) the effectiveness of the current network of special protection areas (SPAs) for protecting the Dupont’s lark. The European Dupont’s lark population showed a decrease of 29.9%, declining from ca. 3267 to 2289 territorial males from 2004 to 2009 to the current period. Moreover, the species has suffered a contraction in its distribution range of 35.9%, with only 39.3% of the species’ territories located within the current network of SPAs. Our findings agree with the previously described decline of the Dupont’s lark in Europe. The population decline was even larger in peripheral regions, which suggests that the species is suffering a centripetal process of contraction and extinction. These results indicate that if there is no change in present-day declining forces, several peripheral populations will reach extinction in a few decades and the overall population size of the species will continue decreasing. Our study should be considered as a last call for action and used for implementing urgent conservation measures to protect the species and its habitat. Future studies should focus on analyzing and managing the factors driving the species’ extinction and future actions for the conservation of the species should focus on increasing the percentage of the Dupont’s lark territories within protected areas, since the data are alarmingly low for a species that is facing clear risk of extinction

Metabolic syndrome criteria and severity and carbon dioxide (CO2) emissions in an adult population

Background: Metabolic syndrome (MetS) has become a growing risk factor of some non-communicable diseases. Increase of greenhouse gas emissions affects the planet. Aims: To assess the association between MetS severity and amount of carbon dioxide (CO2) emitted in an adult population. Design: Cross-sectional study (n = 6646; 55-76-year-old-men; 60-75-year-old-women with MetS). Methods: Dietary habits were assessed using a pre-validated semi quantitative 143-item food frequency questionnaire. The amount of CO2 emitted due to the production of food consumed by person and day was calculated using a European database, and the severity of the MetS was calculated with the MetS Severity Score. Results: Higher glycaemia levels were found in people with higher CO2 emissions. The risk of having high severe MetS was related to high CO2 emissions. Conclusions: Low CO2 emissions diet would help to reduce MetS severity. Advantages for both health and the environment were found following a more sustainable diet. Trial registration: ISRCTN, ISRCTN89898870 . Registered 05 September 2013