Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile

Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here, we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR induces dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans, CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis, and inflammation. Furthermore, our data identify promising pathways for therapeutic targets to combat age-related diseases and promote health in humans.American Federation for Aging ResearchNational Center for Research Resources (U.S.) (Grant UL1 RR024992)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (Grant P30DK056341

RXRs control serous macrophage neonatal expansion and identity and contribute to ovarian cancer progression

Tissue-resident macrophages (TRMs) populate all tissues and play key roles in homeostasis, immunity and repair. TRMs express a molecular program that is mostly shaped by tissue cues. However, TRM identity and the mechanisms that maintain TRMs in tissues remain poorly understood. We recently found that serous-cavity TRMs (LPMs) are highly enriched in RXR transcripts and RXR-response elements. Here, we show that RXRs control mouse serous-macrophage identity by regulating chromatin accessibility and the transcriptional regulation of canonical macrophage genes. RXR deficiency impairs neonatal expansion of the LPM pool and reduces the survival of adult LPMs through excess lipid accumulation. We also find that peritoneal LPMs infiltrate early ovarian tumours and that RXR deletion diminishes LPM accumulation in tumours and strongly reduces ovarian tumour progression in mice. Our study reveals that RXR signalling controls the maintenance of the serous macrophage pool and that targeting peritoneal LPMs may improve ovarian cancer outcomes.This work was supported by a HFSP fellowship to M.C-A. (LT000110/2015-L/1), grants from the Spanish Ministerio de Ciencia e Innovación (MCI) (SAF2015-64287R, SAF2017-90604-REDT-NurCaMein, RTI2018-095928-B100), La Marató de TV3 Foundation (201605-32) and Comunidad de Madrid (MOIR-B2017/BMD-3684) to M.R, and the Formación de Profesorado Universitario (FPU17/01731) programme (MCI) to J.P. The CNIC is supported by the MCI and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome.

Clonal hematopoiesis of indeterminate potential (CHIP), defined as the presence of somatic mutations in cancer-related genes in blood cells in the absence of hematological cancer, has recently emerged as an important risk factor for several age-related conditions, especially cardiovascular disease. CHIP is strongly associated with normal aging, but its role in premature aging syndromes is unknown. Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare genetic condition driven by the accumulation of a truncated form of the lamin A protein called progerin. HGPS patients exhibit several features of accelerated aging and typically die from cardiovascular complications in their early teens. Previous studies have shown normal hematological parameters in HGPS patients, except for elevated platelets, and low levels of lamin A expression in hematopoietic cells relative to other cell types in solid tissues, but the prevalence of CHIP in HGPS remains unexplored. To investigate the potential role of CHIP in HGPS, we performed high-sensitivity targeted sequencing of CHIP-related genes in blood DNA samples from a cohort of 47 HGPS patients. As a control, the same sequencing strategy was applied to blood DNA samples from middle-aged and elderly individuals, expected to exhibit a biological age and cardiovascular risk profile similar to HGPS patients. We found that CHIP is not prevalent in HGPS patients, in marked contrast to our observations in individuals who age normally. Thus, our study unveils a major difference between HGPS and normal aging and provides conclusive evidence that CHIP is not frequent in HGPS and, therefore, is unlikely to contribute to the pathophysiology of this accelerated aging syndrome.This work was supported by Fundación “la Caixa” (grant number LCF/PR/HR17/52150007 to VF, and JJF). JJF is supported by a Ramón y Cajal award (RYC2016–20026) from the Spanish Ministerio de Ciencia e Innovación (MICIN)/Agencia Estatal de Investigación (AEI)/10.13039/501100011033 and Fondo Social Europeo “El FSE invierte en tu futuro”. VA’s lab is supported by MICIN/ AEI/10.13039/501100011033 and Fondo Social Europeo “El FSE invierte en tu futuro” (grant number PID2019-108489RBI00), the Progeria Research Foundation (Award PRF 2019–77), and a donation from Asociación Progeria Alexandra Peraut. LBG is supported by The Progeria Research Foundation. MDD is supported by a predoctoral FPI fellowship from the Spanish MICIN/AEI/10.13039/501100011033 and Fondo Social Europeo “El FSE invierte en tu futuro” (PRE2019-087463), and MA-P is supported by a predoctoral FPU contract from the Ministerio de Educación, Cultura y Deporte (FPU18/02913). The CNIC is supported by the MICIN, the Instituto de Salud Carlos III, the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant number CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033).S

Conserved and species-specific molecular denominators in mammalian skeletal muscle aging

Aging is a complex phenomenon involving functional decline in multiple physiological systems. We undertook a comparative analysis of skeletal muscle from four different species, i.e. mice, rats, rhesus monkeys, and humans, at three different representative stages during their lifespan (young, middle, and old) to identify pathways that modulate function and healthspan. Gene expression profiling and computational analysis revealed that pathway complexity increases from mice to humans, and as mammals age, there is predominantly an upregulation of pathways in all species. Two downregulated pathways, the electron transport chain and oxidative phosphorylation, were common among all four species in response to aging. Quantitative PCR, biochemical analysis, mitochondrial DNA measurements, and electron microscopy revealed a conserved age-dependent decrease in mitochondrial content, and a reduction in oxidative phosphorylation complexes in monkeys and humans. Western blot analysis of key proteins in mitochondrial biogenesis discovered that (i) an imbalance toward mitochondrial fusion occurs in aged skeletal muscle and (ii) mitophagy is not overtly affected, presumably leading to the observed accumulation of abnormally large, damaged mitochondria with age. Select transcript expression analysis uncovered that the skeletal inflammatory profile differentially increases with age, but is most pronounced in humans, while increased oxidative stress (as assessed by protein carbonyl adducts and 4-hydroxynonenal) is common among all species. Expression studies also found that there is unique dysregulation of the nutrient sensing pathways among the different species with age. The identification of conserved pathways indicates common molecular mechanisms intrinsic to health and lifespan, whereas the recognition of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process

Conserved and species-specific molecular denominators in mammalian skeletal muscle aging

Aging is a complex phenomenon involving functional decline in multiple physiological systems. We undertook a comparative analysis of skeletal muscle from four different species, i.e. mice, rats, rhesus monkeys, and humans, at three different representative stages during their lifespan (young, middle, and old) to identify pathways that modulate function and healthspan. Gene expression profiling and computational analysis revealed that pathway complexity increases from mice to humans, and as mammals age, there is predominantly an upregulation of pathways in all species. Two downregulated pathways, the electron transport chain and oxidative phosphorylation, were common among all four species in response to aging. Quantitative PCR, biochemical analysis, mitochondrial DNA measurements, and electron microscopy revealed a conserved age-dependent decrease in mitochondrial content, and a reduction in oxidative phosphorylation complexes in monkeys and humans. Western blot analysis of key proteins in mitochondrial biogenesis discovered that (i) an imbalance toward mitochondrial fusion occurs in aged skeletal muscle and (ii) mitophagy is not overtly affected, presumably leading to the observed accumulation of abnormally large, damaged mitochondria with age. Select transcript expression analysis uncovered that the skeletal inflammatory profile differentially increases with age, but is most pronounced in humans, while increased oxidative stress (as assessed by protein carbonyl adducts and 4-hydroxynonenal) is common among all species. Expression studies also found that there is unique dysregulation of the nutrient sensing pathways among the different species with age. The identification of conserved pathways indicates common molecular mechanisms intrinsic to health and lifespan, whereas the recognition of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process.This research was funded in part by the Intramural Research Program of the NIA/NIH. E.M.M was supported by a postdoctoral grant of the Research Foundation—Flanders (FWO/12R2415N—http://www.fwo.be/en/). I.W. was supported by the Bundesministerium für Bildung und Forschung (BMBF 01GM1113B; mitoNET—Deutsches Netzwerk für mitochondriale Erkrankungen), by the Cluster of Excellence Frankfurt Macromolecular Complexes at the Goethe University Frankfurt DFG project EXC 115 and by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 815, project Z1 (Redox-Proteomics). And partly by the European Union’s Seventh Framework Programme (FP7) under Grant agreement no.. 223576 (MYOAGE) to C.F. J.M.V. was supported by the Spanish Ministerio de Economía y Competitividad (grants BFU2011-23578 and BFU2015-64630-R). We thank the personnel from the Servicio Centralizado de Apoyo a la Investigación (SCAI, University of Córdoba) for technical support.Peer reviewe

O espaço literário ibérico na última década: Hipóteses para o estudo das fronteiras e das relações entre sistemas

[Resumo] O capítulo desenvolve um quadro metodológico para a análise das relações entre sistemas literários na península Ibérica. Propõe combinar metodologias sociológicas, sistémicas e espaciais. Sem esquecer os processos históricos, estuda a atuonomia das unidades sistémicas, as planificações literárias, culturais e identitárias, a constituição de centros e periferias, as interferências e os conflitos entre sistemas, ou a definição de fronteiras. Coloca em foco alguns processos e práticas das última década, como uma nova planificação institucional das relações galego-portuguesas, as mudanças no modelo Galeusca ou o reconhecimento da poesia galega no campo literário espanhol.[Abstract] This chapter develops a methodological framework for the analysis of the relationships between literary systems in the Iberian Peninsula. This proposal combines sociological, systemic and spatial methodologies. Without neglecting historical processes, it studies the autonomy of systemic units, literary, cultural and identity planning, the constitution of centres and peripheries, interferences and conflicts between systems, or the definition of boundaries. It focuses on some processes and practices of the last decade, such as new institutional planning for Galician-Portuguese relationships, the changes in the Galeusca model, or the recognition of Galician poetry in the Spanish literary field

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Catalonia's Library System Law from the perspective of a university library

Des de la perspectiva dels quatre anys transcorreguts des de l'aprovacióde la Llei del sistema bibliotecari de Catalunya, les autores d'aquest article reflexionen sobre el valor i l'efecte de la promulgació d'un text legal en general, i d'aquesta llei en particular. Es fa al·lusió a la legislació sobre biblioteques dels EUA com a model de legislació amb un to marcadament promotor més que no pas impositiu i, finalment, s'analitzen sumàriament les referències de la Llei a les biblioteques universitàries.Four years have passed since the approval of the Library System Law in Catalonia and the authors of this article discuss on the value and effect of  enacting a legal text and this law in particular. They refer to the U.S. legislation on North American university libraries and think of it as a legislative model having a marked promotive tendency rather than an impositive one. They summarily analyze the law effects on university libraries

Optimisation of benzalkonium chloride treatment in the disinfection of Listeria monocytogenes in the food industry

Poster.-- 11th International Conference on Predictive Modelling in Food, Bragança, Portugal, 17-20 September 2019Peer reviewe