Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging

24 páginas, 7 figuras. Borras C, et al. Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging. Aging (Albany NY). 2016 Oct 28;8(12):3185-3208. doi: 10.18632/aging.101078.Centenarians not only enjoy an extraordinary aging, but also show a compression of morbidity. Using functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC) we identified 1721 mRNAs differentially expressed by centenarians when compared with septuagenarians and young people. Sub-network analysis led us to identify Bcl-xL as an important gene up-regulated in centenarians. It is involved in the control of apoptosis, cellular damage protection and also in modulation of immune response, all associated to healthy aging. Indeed, centenarians display lower plasma cytochrome C levels, higher mitochondrial membrane potential and also less cellular damage accumulation than septuagenarians. Leukocyte chemotaxis and NK cell activity are significantly impaired in septuagenarians compared with young people whereas centenarians maintain them. To further ascertain the functional role of Bcl-xL in cellular aging, we found that lymphocytes from septuagenarians transduced with Bcl-xL display a reduction in senescent-related markers. Finally, to demonstrate the role of Bcl-xL in longevity at the organism level, C. elegans bearing a gain of function mutation in the Bcl-xL ortholog ced-9, showed a significant increase in mean and maximal life span. These results show that mRNA expression in centenarians is unique and reveals that Bcl-xL plays an important role in exceptional aging.This work was supported by grants SAF2013-44663-R, from the Spanish Ministry of Education and Science (MEC); ISCIII2012-RED-43-029 from the “Red Tematica de investigacion cooperative en envejecimiento y fragilidad” (RETICEF); PROMETEOII/2014/056 from "Conselleria d’Educació, Cultura I Esport de la Generalitat Valenciana"; and EU Funded CM1001 and FRAILOMIC-HEALTH.2012.2.1.1-2 (To J.V) APM-03/15 from Conselleria de Sanitat, AICO/2016/067 and from Conselleria d’Educació, Cultura i Esport de la Generalitat Valenciana, Intramural Grant from INCLIVA (to C.B.),VAL i+d Fellowship from Generalitat Valenciana (to C.L.-F.) and Marie Curie Career Integration Grant (to N.F). This study has been co-financed by FEDER funds from the European Union.Peer reviewe

Estimación del factor de propagación R0 del COVID-19 por medio del modelo de Kermack-McKendrick

Abstract: The SIR epidemic model is useful to measure the speed of spread of the COVID-19 infection in terms of the epidemiological threshold R0 over time. An ordinary differential mathematical model was developed to measure the behavior of COVID-19 in Peru, based on the experience in the control of Kermack – McKendrick infections. The rate of infected β and of recovered or eliminated γ was also estimated, using the official data sets of the World Health Organization, starting from the historical between March 07 and September 24, 2020 and; projected until October 28, 2021. Explaining that the lowest rate of infected will occur from June 30, 2021 β = 0.24. Evidence of an eradication prognosis for October 28, 2021 with a rate of infected (β = 0.21) and threshold (R0 = 0.03), in addition the accuracy of the model was quantified in 93.012%, with a 6.988% error COVID-19 mitigation mean percentage, with the temporal average value being R0 <1, so each person who contracts the disease will infect less than one person before dying or recovering, so the outbreak will disappear. Keywords: infected, recovered, spread, mitigation, epidemiological threshold.El modelo epidémico SIR, es útil para medir la rapidez de propagación de la infección COVID-19 en términos de umbral epidemiológico R0 a lo largo del tiempo. Se desarrolló un modelo matemático diferencial ordinario para medir el comportamiento del COVID-19 en el Perú, partiendo de la experiencia en el control de infecciones Kermack–McKendrick. Se estimó además la tasa de infectados β y de recuperados o eliminados γ, haciendo uso del conjuntos de datos oficiales de la Organización Mundial de la Salud, partiendo del histórico entre el 07 de Marzo y el 24 de Septiembre de 2020 y; proyectado hasta el 28 de Octubre de 2021. Explicando que la menor tasa de infectados ocurrirá a partir del 30 de Junio de 2021 β=0,24. Evidenciando un pronóstico de erradicación para el 28 de Octubre de 2021 con una tasa de infectados (β=0,21) y umbral (R0=0,03), además se cuantificó la exactitud del modelo en 93,012%, con 6,988 % de error porcentual medio de mitigación COVID-19, siendo el valor promedio temporal R0 <1, así que cada persona que contrae la enfermedad infectará a menos de una persona antes de morir o recuperarse, por lo que el brote desaparecerá. Palabras Clave: infectado; recuperado; propagación; mitigación: umbral epidemiológico

8-Propyl-6H-[1,3]dioxolo[4,5-g]chromen-6-one: A new coumarin with monoamine oxidase B inhibitory activity and possible anti-parkinsonian effects

Parkinson’s disease is a common neurodegenerative disorder. In this study, the monoamine oxidase inhibitory activity and potential anti-parkinsonian effects of 8-propyl-6H-[1,3]dioxolo[4,5-g]chromen-6-one (FCS303), a new synthetic coumarin, were evaluated. To do this, we used the reserpine model of Parkinson’s disease, an assay of levodopa/carbidopa potentiation, the catalepsy model of haloperidol, and an in vitro assay against monoamine oxidase (MAO) activity. Additionally, lipid peroxidation and protein carbonyl group quantification was performed in mice brain homogenates previously treated with haloperidol. FCS303 inhibited monoamine oxidase B (MAO-B) with an IC50 of 5.46 ± 0.36 µM; however, there was no effect on monoamine oxidase A (MAO-A). The oral administration of FCS303 led to a significant reversal of hypokinesia in the reserpine model (at 24 h, doses of 100 and 200 mg/kg) and in the levodopa/carbidopa potentiation assay (at 2 and 24 h, dose of 200 mg/kg). In addition, FCS303 (100 mg/kg) showed anti-cataleptic activity against haloperidol. FCS303 (50 mg/kg) significantly decreased lipid peroxidation and protein carbonyl quantification. These results suggest that FCS303 could present anti-parkinsonian activity related to MAO-B inhibitory activity.This work was conducted with funding from Universidad Nacional de Colombia, Bogotá (VRI/DIB, Project: 13668)S

Safety and feasibility of percutaneous retrograde coronary sinus delivery of autologous bone marrow mononuclear cell transplantation in patients with chronic refractory angina

<p>Abstract</p> <p>Background</p> <p>Chronic refractory angina is a challenging clinical problem with limited treatment options. The results of early cardiovascular stem cell trials using ABMMC have been promising but have utilized intracoronary or intramyocardial delivery. The goal of the study was to evaluate the safety and early efficacy of autologous bone marrow derived mononuclear cells (ABMMC) delivered via percutaneous retrograde coronary sinus perfusion (PRCSP) to treat chronic refractory angina (CRA).</p> <p>Methods</p> <p>From May 2005 to October 2006, 14 patients, age 68 +/- 20 years old, with CRA and ischemic stress-induced myocardial segments assessed by SPECT received a median 8.19*10⁸± 4.3*10⁸mononuclear and 1.65*10⁷± 1.42*10⁷CD34⁺cells by PRCSP..</p> <p>Results</p> <p>ABMMC delivery was successful in all patients with no arrhythmias, elevated cardiac enzymes or complications related to the delivery. All but one patient improved by at least one Canadian Cardiovascular Society class at 2 year follow-up compared to baseline (p < 0.001). The median baseline area of ischemic myocardium by SPECT of 38.2% was reduced to 26.5% at one year and 23.5% at two years (p = 0.001). The median rest left ventricular ejection fraction by SPECT at baseline was 31.2% and improved to 35.5% at 2 year follow up (p = 0.019).</p> <p>Conclusions</p> <p>PRCSP should be considered as an alternative method of delivery for cell therapy with the ability to safely deliver large number of cells regardless of coronary anatomy, valvular disease or myocardial dysfunction. The clinical improvement in angina, myocardial perfusion and function in this phase 1 study is encouraging and needs to be confirmed in randomized placebo controlled trials.</p

Mixed Th2 and non-Th2 inflammatory pattern in the asthma-COPD overlap : a network approach

Altres ajuts: The authors are grateful to all the patients who participated in the study. A number of investigators contributed to the study logistics and they are listed in the Supplementary materials. The project was endorsed by the COPD and Asthma Research Board (PII de EPOC y asma) of the Spanish Society of Pneumology and Thoracic Surgery (SEPAR).The asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a clinical condition that combines features of those two diseases, and that is difficult to define due to the lack of understanding of the underlying mechanisms. Determining systemic mediators may help clarify the nature of inflammation in patients with ACO. We aimed at investigating the role and interaction of common markers of systemic inflammation (IL-6, IL-8, and tumor necrosis factor-α), Th2-related markers (periostin, IL-5, and IL-13), and IL-17 in asthma, COPD, and ACO. This is a cross-sectional study of patients aged ≥40 years with a post-bronchodilator forced expiratory volume in the first second/forced vital capacity 10 pack-years in a patient with a previous diagnosis of asthma or by the presence of eosinophilia in a patient with a previous diagnosis of COPD. Clinical, functional, and inflammatory parameters were compared between categories using discriminant and network analysis. In total, 109 ACO, 89 COPD, and 94 asthma patients were included. Serum levels (median [interquartile range]) of IL-5 were higher in asthma patients than in COPD patients (2.09 [0.61-3.57] vs 1.11 [0.12-2.42] pg/mL, respectively; p =0.03), and IL-8 levels (median [interquartile range]) were higher in COPD patients than in asthma patients (9.45 [6.61-13.12] vs 7.03 [4.69-10.44] pg/mL, respectively; p <0.001). Their values in ACO were intermediate between those in asthma and in COPD. Principal component and network analysis showed a mixed inflammatory pattern in ACO in between asthma and COPD. IL-13 was the most connected node in the network, with different weights among the three conditions. Asthma and COPD are two different inflammatory conditions that may overlap in some patients, leading to a mixed inflammatory pattern. IL-13 could be central to the regulation of inflammation in these conditions

Targeting Alzheimer's disease with multimodal polypeptide-based nanoconjugates

Alzheimer’s disease (AD), the most prevalent form of dementia, remains incurable mainly due to our failings in the search for effective pharmacological strategies. Here, we describe the development of targeted multimodal polypeptide-based nanoconjugates as potential AD treatments. Treatment with polypeptide nanoconjugates bearing propargylamine moieties and bisdemethoxycurcumin or genistein afforded neuroprotection and displayed neurotrophic effects, as evidenced by an increase in dendritic density of pyramidal neurons in organotypic hippocampal culture. The additional conjugation of the Angiopep-2 targeting moiety enhanced nanoconjugate passage through the blood-brain barrier and modulated brain distribution with nanoconjugate accumulation in neurogenic areas, including the olfactory bulb. Nanoconjugate treatment effectively reduced neurotoxic β amyloid aggregate levels and rescued impairments to olfactory memory and object recognition in APP/PS1 transgenic AD model mice. Overall, this study provides a description of a targeted multimodal polyglutamate-based nanoconjugate with neuroprotective and neurotrophic potential for AD treatment

Genistein effect on cognition in prodromal Alzheimer's disease patients. The GENIAL clinical trial

Background: Delaying the transition from minimal cognitive impairment to Alzheimer’s dementia is a major concern in Alzheimer’s disease (AD) therapeutics. Pathological signs of AD occur years before the onset of clinical dementia. Thus, long-term therapeutic approaches, with safe, minimally invasive, and yet efective substances are recommended. There is a need to develop new drugs to delay Alzheimer’s dementia. We have taken a nutritional supplement approach with genistein, a chemically defned polyphenol that acts by multimodal specifc mechanisms. Our group previously showed that genistein supplementation is efective to treat the double transgenic (APP/PS1) AD animal model. Methods: In this double-blind, placebo-controlled, bicentric clinical trial, we evaluated the efect of daily oral supplementation with 120 mg of genistein for 12 months on 24 prodromal Alzheimer’s disease patients. The amyloidbeta deposition was analyzed using 18F-futemetamol uptake. We used a battery of validated neurocognitive tests: Mini-Mental State Exam (MMSE), Memory Alteration Test (M@T), Clock Drawing Test, Complutense Verbal Learning Test (TAVEC), Barcelona Test-Revised (TBR), and Rey Complex Figure Test. Results: We report that genistein treatment results in a signifcant improvement in two of the tests used (dichotomized direct TAVEC, p=0.031; dichotomized delayed Centil REY copy p=0.002 and a tendency to improve in all the rest of them. The amyloid-beta deposition analysis showed that genistein-treated patients did not increase their uptake in the anterior cingulate gyrus after treatment (p=0.878), while placebo-treated did increase it (p=0.036). We did not observe signifcant changes in other brain areas studied. Conclusions: This study shows that genistein may have a role in therapeutics to delay the onset of Alzheimer’s dementia in patients with prodromal Alzheimer’s disease. These encouraging results indicate that this should be followed up by a new study with more patients to further validate the conclusion that arises from this study.This work was supported by the following grants: CB16/10/00435 (CIBERFES) from Instituto de Salud Carlos III, (PID2019-110906RB-I00/ AEI/10.13039/501100011033) and RED2018-102576-T from the Spanish Ministry of Innovation and Science, PROMETEO/2019/097 from “Consellería de Innovación, Universidades, Ciencia y Sociedad Digital de la Generalitat Valen ciana” and EU Funded H2020- DIABFRAIL-LATAM (Ref: 825546), European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL) and of the ERA-NET Cofund ERA-HDHL (GA N° 696295 of the EU Horizon 2020 Research and Innovation Programme) and Fundación Ramón Areces y Fundación Soria Melguizo. to J.V. and Grant PID2020-113839RB-I00 funded by MCIN/ AEI/10.13039/501100011033, PCIN-2017-117 of the Ministry of Economy and Competitiveness, and the EU Joint Programming Initiative ‘A Healthy Diet for a Healthy Life’ (JPI HDHL INTIMIC-085) to CB. We also acknowledge funding from the Spanish Ministry of Science, Innovation, and Universities (RTI2018099200-B-I00), the Generalitat of Catalonia, Agency for management of University and Research Grants (2017SGR696) and the Department of Health (SLT002/16/00250) to RP. Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-fnanced with ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020). M.J. is a “Serra Hunter” Fellow

Copenhagen consensus statement 2019: physical activity and ageing

From 19th to 22nd November 2018, 26 researchers representing nine countries and a variety of academic disciplines met in Snekkersten, Denmark, to reach evidence-based consensus about physical activity and older adults. It was recognised that the term ‘older adults’ represents a highly heterogeneous population. It encompasses those that remain highly active and healthy throughout the life-course with a high intrinsic capacity to the very old and frail with low intrinsic capacity. The consensus is drawn from a wide range of research methodologies within epidemiology, medicine, physiology, neuroscience, psychology and sociology, recognising the strength and limitations of each of the methods. Much of the evidence presented in the statements is based on longitudinal associations from observational and randomised controlled intervention studies, as well as quantitative and qualitative social studies in relatively healthy community-dwelling older adults. Nevertheless, we also considered research with frail older adults and those with age-associated neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, and in a few cases molecular and cellular outcome measures from animal studies. The consensus statements distinguish between physical activity and exercise. Physical activity is used as an umbrella term that includes both structured and unstructured forms of leisure, transport, domestic and work-related activities. Physical activity entails body movement that increases energy expenditure relative to rest, and is often characterised in terms of intensity from light, to moderate to vigorous. Exercise is defined as a subset of structured physical activities that are more specifically designed to improve cardiorespiratory fitness, cognitive function, flexibility balance, strength and/or power. This statement presents the consensus on the effects of physical activity on older adults’ fitness, health, cognitive functioning, functional capacity, engagement, motivation, psychological well-being and social inclusion. It also covers the consensus on physical activity implementation strategies. While it is recognised that adverse events can occur during exercise, the risk can be minimised by carefully choosing the type of activity undertaken and by consultation with the individual’s physician when warranted, for example, when the individual is frail, has a number of co-morbidities, or has exercise-related symptoms, such as chest pain, heart arrhythmia or dizziness. The consensus was obtained through an iterative process that began with the presentation of the state-of-the-science in each domain, followed by group and plenary discussions. Ultimately, the participants reached agreement on the 30-item consensus statements

Jardins per a la salut

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia. Assignatura: Botànica farmacèutica. Curs: 2014-2015. Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són el recull de les fitxes botàniques de 128 espècies presents en el Jardí Ferran Soldevila de l’Edifici Històric de la UB. Els treballs han estat realitzats manera individual per part dels estudiants dels grups M-3 i T-1 de l’assignatura Botànica Farmacèutica durant els mesos de febrer a maig del curs 2014-15 com a resultat final del Projecte d’Innovació Docent «Jardins per a la salut: aprenentatge servei a Botànica farmacèutica» (codi 2014PID-UB/054). Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pels professors de l’assignatura. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica. També s’ha pretès motivar els estudiants a través del retorn de part del seu esforç a la societat a través d’una experiència d’Aprenentatge-Servei, deixant disponible finalment el treball dels estudiants per a poder ser consultable a través d’una Web pública amb la possibilitat de poder-ho fer in-situ en el propi jardí mitjançant codis QR amb un smartphone