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El rigor y la evidencia científica debe ser siempre una máxima a la hora de compartir contenido en los medios digitales, sin embargo, muchas noticias, avances o incluso recomendaciones terapéuticas quedan “enmascarados” por contenidos sensacionalistas que no se han contrastado correctamente. Como docentes y científicos debemos lograr que nuestros estudiantes, los profesionales del futuro, adquieran un pensamiento crítico que les permita discernir entre las noticias con rigor científico, de aquellas que son confusas, presentan una deficiente evidencia o son incluso falsas. El conocimiento científico, así como los datos generados en los últimos años han alcanzado un volumen importante que, gracias al desarrollo tecnológico y las herramientas de comunicación, permiten una divulgación eficiente entre la comunidad científica, así como la transmisión de estos resultados a los medios de comunicación y en última instancia a la sociedad a nivel mundial. Las últimas directrices de cómo debe ser el científico del futuro, no solo enmarca competencias de investigación o docentes, sino que cada día se exige que los profesionales del futuro adquieran competencias de divulgación científica, que permitan transmitir los avances de su investigación a la sociedad. Sin embargo, es evidente y plausible, que el acceso universal a la red, así como la capacidad de crear y publicar contenido de forma universal, puede suponer un hándicap; de hecho, somos conscientes de que noticias, o fuentes de información con robusta evidencia científica, coexisten muchas veces con noticias de baja evidencia, con carácter sensacionalista o incluso con intereses empresariales o económicos. Uno de los mayores peligros se encuentra en contenidos relacionados con la enfermedad del ser humano, ya que esta condición supone un momento de vulnerabilidad del individuo. Así, desgraciadamente, en los últimos años se ha experimentado una creciente proliferación de noticias confusas sobre la casi totalidad de procesos p

Objectives: oxidative stress plays a major role in the onset and progression of involutional osteoporosis. However, classical antioxidants fail to restore osteoblast function. Interestingly, the bone anabolism of parathyroid hormone (pTH) has been shown to be associated with its ability to counteract oxidative stress in osteoblasts. The pTH counterpart in bone, which is the pTHrelated protein (pTHrp), displays osteogenic actions through both its n-terminal pTH-like region and the c-terminal domain. Methods: We examined and compared the antioxidant capacity of pTHrp (1-37) with the c-terminal pTHrp domain comprising the 107-111 epitope (osteostatin) in both murine osteoblastic Mc3T3-e1 cells and primary human osteoblastic cells. Results: We showed that both n- and c-terminal pTHrp peptides at 100 nM decreased reactive oxygen species production and forkhead box protein o activation following hydrogen peroxide (H2o2)-induced oxidation, which was related to decreased lipid oxidative damage and caspase-3 activation in these cells. This was associated with their ability to restore the deleterious effects of H2o2 on cell growth and alkaline phosphatase activity, as well as on the expression of various osteoblast differentiation genes. The addition of Rp-cyclic 3′,5′-hydrogen phosphorothioate adenosine triethylammonium salt (a cyclic 3',5'-adenosine monophosphate antagonist) and calphostin c (a protein kinase c inhibitor), or a pTH type 1 receptor antagonist, abrogated the effects of n-terminal pTHrp, whereas protein phosphatase 1 (an src kinase activity inhibitor), sU1498 (a vascular endothelial growth factor receptor 2 inhibitor), or an anti osteostatin antiserum, inhibited the effects of c-terminal pTHrp. Conclusion: These findings indicate that the antioxidant properties of pTHrp act through its n- and c- terminal domains and provide novel insights into the osteogenic action of pTHrp., RETICEF [FEDER “una manera de hacer Europa”], Ministerio de Economía y Competitividad. Programa Juan de la Cierva, Instituto de Salud Carlos III /Fundación para la Investigación Ósea y Metabolismo Mineral-FEIOMM, Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

2023 Descuento MDPI, The oxidative-inflammatory theory of aging states that aging is the result of the establishment of a chronic oxidative-inflammatory stress situation in which the immune system is implicated. Among the redox parameters, those involved in the glutathione cycle have been suggested as essential in aging. Thus, the first objective of this study was to determine if several components of the glutathione cycle (glutathione reductase (GR) and glutathione peroxidase (GPx) activities, and concentrations of oxidized glutathione (GSSG) and reduced glutathione (GSH)) in leukocytes) are associated with the biological age (ImmunolAge) estimated using the Immunity Clock in 190 men and women. The second objective was to identify the best blood fraction (whole blood, blood cells, erythrocytes, or plasma) to quantify these components and correlate them with the estimated ImmunolAge. The results show that the oxidative state of peripheral leukocytes correlates with their functionality, supporting the idea that this is the basis of immunosenescence. In blood, the correlations are more significant in the fraction of blood cells with respect to ImmunolAge (positive correlations with GSSG concentration and the GSSG/GSH ratio, and negative correlations with GPx and GR activities). Therefore, blood cells are proposed as the most effective sample to estimate the biological age of individuals in clinical settings., Universidad Complutense de Madrid, Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub, Descuento UCM

Sexual dimorphism is a key factor to consider in the ageing process given the impact that it has on life expectancy. The oxidative-inflammatory theory of ageing states that the ageing process is the result of the establishment of oxidative stress which, due to the interplay of the immune system, translates into inflammatory stress, and that both processes are responsible for the damage and loss of function of an organism. We show that there are relevant gender differences in a number of oxidative and inflammatory markers and propose that they may account for the differential lifespan between sexes, given that males display, in general, higher oxidation and basal inflammation. In addition, we explain the significant role of circulating cell-free DNA as a marker of oxidative damage and an inductor of inflammation, connecting both processes and having the potential to become a useful ageing marker. Finally, we discuss how oxidative and inflammatory changes take place differentially with ageing in each sex, which could also have an impact on the sex-differential lifespan. Further research including sex as an essential variable is needed to understand the grounds of sex differences in ageing and to better comprehend ageing itself., Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

Endocrine, nervous, and immune systems work coordinately to maintain the global homeostasis of the organism. They show sex differences in their functions that, in turn, contribute to sex differences beyond reproductive function. Females display a better control of the energetic metabolism and improved neuroprotection and have more antioxidant defenses and a better inflammatory status than males, which is associated with a more robust immune response than that of males. These differences are present from the early stages of life, being more relevant in adulthood and influencing the aging trajectory in each sex and may contribute to the different life lifespan between sexes., Universidad Complutense de Madrid, Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

Un aspecto fundamental de nuestra docencia es motivar a nuestros estudiantes y promover su participación en clase, aunque esto es especialmente difícil de conseguir cuando tenemos grupos muy numerosos. En estos casos, los docentes debemos implementar medidas adicionales. Una herramienta que ha demostrado ser muy eficaz incrementando la motivación y participación de los estudiantes es el trabajo colaborativo, que fomenta la interacción directa con los profesores y con el resto de los compañeros. La asignatura de Inmunología y Análisis clínicos, se imparte en el 4º curso del Grado en Biología de la UCM, en la Mención de Biosanitaria y tiene entre 150-160 estudiantes matriculados, repartidos en tres grupos. Con un número tan numeroso, conseguir una participación elevada de los estudiantes es difícil, por lo que creemos que una buena medida para lograrla puede ser la implementación del trabajo colaborativo. Por otra parte, dado el reducido número de horas de las que disponemos durante el curso académico, no podemos abordar algo fundamental como es que los estudiantes puedan conocer los aspectos más prácticos de la inmunología. Por ello, proponemos un proyecto de Innovación educativa (PIE) donde los estudiantes puedan interaccionar directamente con profesionales sanitarios biólogos (inmunólogos), para conocer los aspectos profesionales más relevantes relacionados con esta asignatura, lo que les acercará al mundo laboral incrementando su interés y motivación, y añadiendo la experiencia de profesionales que comparten grado con ellos y que han elegido ser profesionales de la biología sanitaria. Para ello, el proyecto se ha dividido en dos tareas. En la primera, los estudiantes realizarán un trabajo colaborativo sobre un tema específico de la asignatura; en la segunda elaborarán un banco de preguntas que posteriormente serán trasladadas a profesionales, y realizarán una breve presentación en formato vídeo. Tanto el trabajo colaborativo como las grabaciones de las entrevistas

The immune system has been for long considered a marker of health. The age-related decline in its function results in a greater incidence of infections, autoimmune diseases, and cancer. Nevertheless, it is still not known if immune function can be used to accurately estimate the rate of aging of an individual. A set of 14 immune function variables were measured in 214 healthy individuals ranging from 19 to 88 years old. All immune variables were selected as independent variables for the prediction of age by multiple linear regression. The Immunity Clock was constructed including the following 5 immune variables: natural killer activity, phagocytosis and chemotaxis of neutrophils, and chemotaxis and proliferative capacity of lymphocytes, reaching an adjusted R2 of 80.3% and a standard error of the estimate of 4.74 years. The Immunity Clock was validated in a different group of healthy individuals (N = 106) obtaining a Pearson's correlation coefficient of .898 (p < .001) between chronological age and the age estimated by the Immunity Clock, the ImmunolAge. Moreover, we demonstrate that women with anxiety (N = 10) show a higher ImmunolAge than their chronological age, whereas healthy centenarians (N = 8) show a lower one. In addition, the Immunity Clock provided here proves to be useful for monitoring the effectiveness of a nutritional intervention lasting 1 month, by detecting a diminished ImmunolAge in the same individuals. Further research will be needed to ascertain if the Immunity Clock is a passive marker of the aging process or it plays an active role in it., En este trabajo se muestra el desarrollo de un modelo matemático que permite determinar la edad biológica de un individuo, esto es, la velocidad a la que está envejeciendo, en función de la capacidad funcional de sus células inmunitarias. Se sabe que el sistema inmunitario se deteriora con el envejecimiento. Esta inmunosenescencia es responsable de la mayor incidencia de infecciones, enfermedades autoinmunes y de cánceres que tiene lugar al envejecer. Se analizaron una serie de funciones en leucocitos de sangre periférica de más de 300 individuos de distintas edades. Posteriormente, se construyó un modelo matemático para la predicción de la edad biológica, mediante regresión lineal múltiple, el cual seleccionó 5 de esas funciones inmunitarias: actividad citotóxica antitumoral Natural Killer, capacidad fagocítica y quimiotáctica de neutrófilos y la quimiotáctica y respuesta proliferativa de linfocitos. A este modelo le hemos denominado “Immunity Clock” y a la edad biológica que estima “ImmunolAge”. Además, se ha validado este “Immunity Clock” en una cohorte de individuos distinta a la utilizada para su construcción. La eficacia del modelo se ha comprobado en un grupo de mujeres con ansiedad en las que detecta un envejecimiento acelerado, al presentar estas personas una edad biológica significativamente mayor que la cronológica. Por su parte, en un grupo de centenarios la aplicación del “Immunity Clock” permitió observar como en los mismos se daba un envejecimiento más enlentecido, mostrando una “ImmunolAge” significativamente más joven. También, se ha verificado que el modelo es útil para monitorizar la efectividad de una intervención nutricional llevada a cabo durante un mes, al detectar como los hombres y mujeres del estudio presentaban un rejuvenecimiento de su edad biológica tras dicha intervención. Aunque queda demostrada la validez del “Immunity Clock” para determinar con precisión la velocidad a la que está envejeciendo cada individuo, son necesarias más inves, Universidad Complutense de Madrid (UCM), Fondo de Investigaciones Sanitarias (FIS), Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

Chronic obstructive pulmonary disease (COPD) is characterised by inflammatory and oxidative alterations in the lung and extrapulmonary compartments, through involvement of the immune system. Several leukocyte functions are health markers and good predictors of longevity, and high pro-inflammatory and oxidative states are related to more aged profiles. Here, we aimed to investigate the aging rate in terms of immunosenescence in COPD men with respect to healthy age-matched controls. Several neutrophil (adherence, chemotaxis, phagocytosis, superoxide anion stimulated production) and lymphocyte (adherence, chemotaxis, lymphoproliferation, natural killer activity) functions, cytokine concentrations released in response to lipopolysaccharide (tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, IL-10) and redox parameters (intracellular glutathione content, basal superoxide anion level) were assessed in circulating leukocytes of men with moderate and severe stages of COPD, and compared to healthy age-matched volunteers. The biological age or aging rate in each participant was determined using the values of leukocyte functions. The results indicated impairment of immune functions in COPD patients, both in innate and adaptive immunity, and higher pro-inflammatory and oxidative states in peripheral leukocytes than controls. In general, these changes were more remarkable at the severe stage of airway obstruction. Importantly, COPD patients were found to be aging at a faster rate than age-matched healthy counterparts., La enfermedad pulmonar obstructiva crónica (EPOC) es una patología respiratoria grave que supone la tercera causa de muerte en el mundo, y que se caracteriza por la presencia de un elevado estrés oxidativo-inflamatorio tanto a nivel pulmonar como general del organismo, en el que se encuentra implicado el sistema inmunitario. Entre los factores de riesgo de esta enfermedad se incluye de forma importante el tabaquismo, pero también el envejecimiento. El proceso de envejecimiento se caracteriza por el establecimiento de un estrés oxidativo-inflamatorio crónico, en el que el que las células inmunitarias juegan un papel fundamental. Se ha comprobado que ciertas funciones de estas células inmunitarias son marcadores del estado de salud y, como ha propuesto nuestro grupo, resultan predictores de longevidad y permiten determinar la velocidad a la que está envejeciendo cada individuo, esto es, su edad biológica, lo que se consigue utilizando un modelo matemático, previamente publicado, que hemos denominado “The Immunity Clock”. Por lo indicado, se quiso investigar si los pacientes con EPOC severo, pero también moderado, tienen un mayor estrés oxidativo-inflamatorio y una mayor velocidad de envejecimiento, evidenciada por una mayor edad biológica. Para ello, se procedió a la valoración de una serie de funciones de neutrófilos y de linfocitos, de las concentraciones de citoquinas pro-inflamatorias y anti-inflamatorias (para comprobar el estrés inflamatorio), así como de una serie de compuestos oxidantes y antioxidantes (para determinar el estrés oxidativo), en sangre periférica de hombres con estadio moderado y severo de EPOC, y se compararon con personas sanas de la misma edad (controles). Los resultados muestran un deterioro de las funciones inmunitarias, esto es, una inmunosenescencia acelerada, y un mayor estrés oxidativo e inflamatorio en los pacientes con EPOC, en comparación con los controles, cambios que fueron más notables en los pacientes que se encontraban en el est, Instituto de Salud Carlos III (ISCIII)/FEDER, Gobierno Vasco, Zambon S.A., Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

The aim of the present study was to investigate whether the late onset of diet-induced obesity (DIO) in middle-aged mice affected behavioral, immunological and oxidative stress parameters as well as life span of male and female mice. Also, it was analyzed whether the late DIO onset aggravated immunosenescence in old female mice. Late-adult male and female ICR/CD1 mice (28 weeks old) were fed either a high-fat diet or a standard diet during 14 weeks. After that, in these middle-aged (42 weeks old) diet-induced obese (DIO) and non-DIO controls, behavior as well as functions and redox state of peritoneal leukocytes were evaluated. These same parameters (excepting behavioral tests) were repeated when female mice were old (72 weeks old). The results showed lower exploratory activity and higher anxiety-like behavior in middle-aged male and female DIO than in controls. Moreover, these DIO animals from both sexes exhibited statistically significant impaired immune cell functions, such as chemotaxis of macrophages and lymphocytes, phagocytosis of macrophages, natural killer activity and lymphoproliferation in response to ConA and LPS, as well as an oxidative stress state in comparison with controls. Male DIO mice exhibited higher impairments in a variety of the evaluated parameters and a shorter life span than their female counterparts. In addition, female DIO mice, at old age, showed aggravated immunosenescence. In conclusion, the late DIO onset leads to impairments in behavior as well as in immune system functions of middle-aged male and female mice, males being significantly more affected than females., Universidad Complutense de Madrid, Instituto de Salud Carlos III (ISCIII), Fondo Europeo de Desarrollo Regional (FEDER), Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

Oxidative stress has been reported to increase with aging and although several agerelated changes in redox parameters have been described, none of them have been verified as markers of the rate of aging and lifespan. Therefore, antioxidant (catalase, glutathione peroxidase and reductase activities and reduced glutathione) and oxidant (oxidized glutathione, basal superoxide anion and malondialdehyde concentrations)parameters were studied in whole blood cells from humans divided into different age groups (adult, mature, elderly, nonagenarian and centenarian) in a cross-sectional study. Moreover, the same parameters were investigated in peritoneal leukocytes of mice at the analogous human ages (adult, mature, old, very old and long-lived) in a longitudinal study as well as in adult prematurely aging mice (PAM). The results reveal that the agerelated alterations of these markers are similar in humans and mice, with decreased antioxidants and increased oxidants in old subjects whereas long-lived individuals show similar values to those in adults. Additionally, adult PAM showed similar values to those in chronologically old mice and had a shorter lifespan than non-prematurely aging mice. Thus, these parameters could be proposed as markers of the rate of aging and used to ascertain biological age in humans, Se sabe que el estrés oxidativo (mayores cantidades de oxidantes que de defensas antioxidantes) aumenta al envejecer. En este trabajo se han estudiado toda una serie de oxidantes y antioxidantes en células sanguíneas de hombres y mujeres adultos, maduros, mayores, nonagenarios y centenarios. Los mismos parámetros se han analizado en células inmunitarias peritoneales de ratones, en un estudio longitudinal, a las correspondientes edades (adultos, maduros, viejos, muy viejos y longevos). Se ha comprobado una evolución similar con la edad de los parámetros analizados en ratones y en humanos, dándose en ambas especies un aumento de oxidantes y disminución de antioxidantes al envejecer. No obstante, los individuos que logran superar la esperanza de vida media presentan dichos parámetros similares a los de los adultos mientras que los longevos, como los centenarios, presentan una “firma redox” muy diferenciada, con una gran actividad de defensas antioxidantes., Instituto de Salud Carlos III / FEDER, Universidad Complutense de Madrid, Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

Oxidative stress plays an essential and early role in the pathophysiology of Alzheimer’s disease (AD). Alterations in the redox state in AD and in mild cognitive impairment (MCI) patients appear in the brain and at peripheral level. Given that it is easier to study the latter, most of the research has been focused on plasma. However, the analysis of redox parameters in whole blood cells (including erythrocytes and leukocytes) has not really been investigated. Moreover, the association of these parameters with Mini-Mental State Examination (MMSE) clinical scores, has scarcely been studied. Therefore, the aim of the present work was to analyze several redox markers in whole blood cells from male and female MCI and AD patients. Antioxidant (superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), and reductase (GR) activities, and reduced glutathione (GSH) concentration) together with oxidant parameters (oxidized glutathione (GSSG) and thiobarbituric acid-reactive substances (TBARS)) were investigated using MCI and AD (10 women and 10 men in each group) and their age-matched control groups (15 women and 15 men). The results show an altered redox state in whole blood cells from AD patients (higher CAT, GSSG/GSH, TBARS and lower GPx, GR, GSH). Some of these redox parameters are already affected in MCI patients (higher TBARS and lower GPx and GR activities) in both sexes and, consequently, they could be used as markers of prodromal AD. Since GR, GSH, GSSG, and GSSG/GSH were found to be associated with MMSE scores, they seem to be useful clinically to monitor cognitive decline in AD progression., Uno de los objetivos más importantes en las investigaciones sobre la enfermedad de Alzheimer (EA), la patología neurodegenerativa más frecuentes en nuestra sociedad actual y aún sin un tratamiento efectivo, es el conseguir marcadores periféricos prodrómicos de la enfermedad. Nuestro grupo ya había propuesto en trabajos previos que los pacientes con EA presentaban varios parámetros de función y especialmente de estado redox de las células inmunitarias de sangre periférica que podían utilizarse como marcadores del desarrollo de la enfermedad. El objetivo del presente trabajo ha sido estudiar, en una muestra de fácil utilización en clínica, como es la sangre total de hombres y mujeres con deterioro cognitivo leve (DCL) y con EA, comparando con controles sanos de edades similares, una serie de parámetros de estrés oxidativo para poder detectar posibles marcadores tempranos de esta patología. Los resultados demuestran que varios de esos parámetros de estrés oxidativo que están específicamente alterados en personas con DCL, podrían servir como marcadores prodrómicos de la enfermedad. Además, otros parámetros aparecen afectados en personas con EA, y se correlacionan con las puntuaciones obtenidas en el Minimental, por lo que detectarían el deterioro cognitivo en el progreso de la enfermedad., Instituto de Salud Carlos III (ISCIII) / FEDER, Universidad Complutense de Madrid, Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

El envejecimiento puede definirse como un proceso universal en el que se produce toda una serie de cambios biológicos, y que se caracteriza por una disminución progresiva y generalizada de la función del organismo y por una menor capacidad para restaurar la homeostasis. Además, el proceso de envejecimiento presenta una gran heterogeneidad, de manera que los individuos de una población, pertenecientes a una misma especie y con idéntica edad cronológica, pueden hacer este proceso a diferente velocidad. Este hecho ha llevado a desarrollar el concepto de edad biológica, para cuyo establecimiento es necesario determinar una serie de variables que cambian con la edad y que están relacionadas con una muerte prematura. Esta edad biológica es más adecuada que la cronológica como indicador del estado de salud, el rendimiento físico y mental, así como de la velocidad a la que está envejeciendo un individuo..., Aging may be defined as a universal process in which a series of biological alterationstake place and which is characterized by the progressive and general deterioration of thefunctions of the organism that leads to a lower ability to adaptively react to changes andpreserve homeostasis. Moreover, the aging process is heterogeneous in such a way, that thediverse members of a population of the same chronological age can be aging at different rates.This phenomenon led to the concept of “biological age”. For the determination of this it isnecessary to identify a series of markers that change with age and that are associated with apremature death. This biological age is more accurate than the chronological one as an indicatorof the health status, physical and mental capacity as well as of the rate of aging experienced byeach individual...

The development of frailty scores suitable for mice and which resemble those used in the clinical scenario is of great importance to understand human frailty. The aim of the study was to determine an individual frailty score for each mouse at different ages and analyze the association between the frailty score and its lifespan. For this purpose, the “Valencia Score” for frailty was used. Thus, a longitudinal study in mice was performed analyzing weight loss, running time and speed, grip strength and motor coordination at the late-adult, mature and old ages (40, 56 and 80 weeks old, respectively). These parameters are equivalent to unintentional weight loss, poor endurance, slowness, weakness, and low activity level, respectively, in humans. A cut-off point was used to identify frail mice for each criterion. All the measurements were also performed on chronologically adult prematurely aging mice. The results show that by using the “Valencia Score” for frailty a prematurely aged phenotype can be identified even during the adulthood of animals. This opens up the possibility of carrying out preventive long-term interventions. Moreover, the individual frailty score of a given mouse at the late-adult, mature and old ages is shown to be a relevant predictor of its lifespan., Universidad Complutense de Madrid, Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), ISCIII/FEDER, Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

Oxidative damage is an important contributor to the morphological and functional changes in osteoporotic bone. Aging increases the levels of reactive oxygen species (ROS) that cause oxidative stress and induce osteoblast apoptosis. ROS modify several signaling responses, including mitogen-activated protein kinase (MAPK) activation, related to cell survival. Both parathyroid hormone (PTH) and its bone counterpart, PTH-related protein (PTHrP), can regulate MAPK activation by modulating MAPK phosphatase-1 (MKP1). Thus, we hypothesized that PTHrP might protect osteoblasts from ROS-induced apoptosis by targeting MKP1. In osteoblastic MC3T3-E1 and MG-63 cells, H2 O2 triggered p38, JNK, ERK and p66Shc phosphorylation, and cell apoptosis. Meanwhile, PTHrP (1-37) rapidly but transiently increased ERK and Akt phosphorylation without affecting p38, JNK, or p66Shc activation. H2 O2 -induced p38 and ERK phosphorylation and apoptosis were both decreased by pre-treatment with specific kinase inhibitors or PTHrP (1-37) in both osteoblastic cell types. These dephosphorylating and prosurvival actions of PTHrP (1-37) were prevented by a phosphatase inhibitor cocktail, the phosphatase MKP1 inhibitor sanguinarine or a MKP1 siRNA. PTHrP (1-37) promptly enhanced MKP1 protein and gene expression and MKP1-dependent catalase activity in osteoblastic cells. Furthermore, exposure to PTHrP (1-37) adsorbed in an implanted hydroxyapatite-based ceramic into a tibial defect in aging rats increased MKP1 and catalase gene expression in the healing bone area. Our findings demonstrate that PTHrP counteracts the pro-apoptotic actions of ROS by a mechanism dependent on MKP1-induced dephosphorylation of MAPKs in osteoblasts., Ministerio de Ciencia e Innovación (MICINN)- Juan de la Cierva (España), Instituto deSalud Carlos III, (España), Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

The age-related changes in the immune functions (immunosenescence) may be mediated by an increase of oxidative stress and damage affecting leukocytes. Although the “oxidation-inflammation” theory of aging proposes that phagocytes are the main immune cells contributing to “oxi-inflamm-aging”, this idea has not been corroborated. The aim of this work was to characterize the age-related changes in several parameters of oxidative stress and immune function, as well as in lipofuscin accumulation (“a hallmark of aging”), in both total peritoneal leukocyte population and isolated peritoneal macrophages. Adult, mature, old and long-lived mice (7, 13, 18 and 30 months of age, respectively) were used. The xanthine oxidase (XO) activity-expression, basal levels of superoxide anion and ROS, catalase activity, oxidized (GSSG) and reduced (GSH) glutathione content and lipofuscin levels, as well as both phagocytosis and digestion capacity were evaluated. The results showed an age-related increase of oxidative stress and lipofuscin accumulation in murine peritoneal leukocytes, but especially in macrophages. Macrophages from old mice showed lower antioxidant defenses (catalase activity and GSH levels), higher oxidizing compounds (XO activity/expression and superoxide, ROS and GSSG levels) and lipofuscin levels, together with an impaired macrophage functions, in comparison to adults. In contrast, long-lived mice showed in their peritoneal leukocytes, and especially in macrophages, a well-preserved redox state and maintenance of their immune functions, all which could account for their high longevity. Interestingly, macrophages showed higher XO activity and lipofuscin accumulation than lymphocytes in all the ages analyzed. Our results support that macrophages play a central role in the chronic oxidative stress associated with aging, and the fact that phagocytes are key cells contributing to immunosenescence and “oxi-inflamm-aging”. Moreover, the determination of oxidative stress and i, ISCIII-FEDER of the European Union and Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

Chronological age is not a good indicator of how each individual ages and thus how to maintain good health. Due to the long lifespan in humans and the consequent difficulty of carrying out longitudinal studies, finding valid biomarkers of the biological age has been a challenge both for research and clinical studies. The aim was to identify and validate several immune cell function parameters as markers of biological age. Adult, mature, elderly and long‐lived human volunteers were used. The chemotaxis, phagocytosis, natural killer activity and lymphoproliferation in neutrophils and lymphocytes of peripheral blood were analyzed. The same functions were measured in peritoneal immune cells from mice, at the corresponding ages (adult, mature, old and long lived) in a longitudinal study. The results showed that the evolution of these functions was similar in humans and mice, with a decrease in old subjects. However, the long‐lived individuals maintained values similar to those in adults. In addition, the values of these functions in adult prematurely aging mice were similar to those in chronologically old animals, and they died before their non‐prematurely aging mice counterparts. Thus, the parameters studied are good markers of the rate of aging, allowing the determination of biological age., Universidad Complutense de Madrid, Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), FIS, ISCIII-FEDER, Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

Under stressful conditions, the expression of the chaperone Hsp70 is induced, which acts as a cellular defense mechanism. The impairment in this induction has been related to aging, whereas an increased expression has been related to longevity. Nevertheless, it is still not known if the basal levels of Hsp70 can be indicative of the aging rate of different tissues. The aim of this study was to quantify the basal levels of Hsp70 in tissues from female mice throughout their aging process including long-lived mice, as well as from prematurely aging mice (PAM). Adult, old and long-lived (6, 18 and 30 months of age, respectively) female ICR-CD1 and Balb/C mice were used. Tissues with mainly mitotic (liver and renal medulla) or post-mitotic (heart, renal cortex, cerebral cortex, spleen) cells and peritoneal leukocytes from these animals as well as from adult PAM and non-prematurely aging mice (NPAM), were studied. Basal levels of Hsp70 were assessed using an ELISA method. The results showed that the aging-associated variation of the levels of Hsp70 followed a different pattern in post-mitotic and mitotic tissues, being lower or higher in old mice comparing to adults, respectively. In all the tissues analyzed the Hsp70 levels from long-lived mice were similar to those from adult animals. In addition, in adult PAM these Hsp70 levels were similar to those in chronologically old animals. In conclusion, Hsp70 basal levels show tissue-specific age-associated variations and are preserved in long-lived animals, demonstrating their role as markers of the rate of aging and longevity., Ministerio de Economía y Competitividad (MINECO), Universidad Complutense de Madrid, FIS (ISCIII-FEDER), Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub

Repeated exposure to mild heat shock (HS) has been shown to induce a wide range of health promoting hormetic effects in various biological systems, including human cells undergoing aging in vitro. In order to understand how cells distinguish between mild and severe stress, we have investigated the extent of early and immediate HS response by analyzing the nuclear translocation of the transcription factor heat shock factor-1 (HSF1), in serially passaged normal adult human facial skin fibroblasts exposed to mild (41 °C) or severe (43 °C) HS. Cells respond differently when exposed to mild and severe HS at different passage levels in terms of the extent of HSF1 translocation. In early passage young cells there was a 5-fold difference between mild and severe HS in the extent of HSF1 translocation. However, in near senescent late passage cells, the difference between mild and severe stress in terms of the extent of HSF1 translocation was reduced to less than 2-fold. One of the reasons for this age-related attenuation of heat shock response is due to the fact there was a higher basal level of HSF1 in the nuclei of late passage cells, which is indicative of increased intrinsic stress during cellular aging. These observations are consistent with previously reported data that whereas repeated mild stress given at younger ages can slow down aging and increase the lifespan, the same level of stress given at older ages may not provide the same benefits. Therefore, elucidating the early and immediate steps in the induction of stress response can be useful in deciding whether a particular level of stress is potentially hormetically beneficial or not., LVMH, France, Depto. de Genética, Fisiología y Microbiología, Fac. de Ciencias Biológicas, TRUE, pub