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Adult Premature Aging Mice (PAM) show premature immunosenescence, oxidative and inflammatory stress and consequently a shorter lifespan than Exceptional Non-Prematurely Aging Mice (E-NPAM) at the same age. Indeed, adult female PAM exhibit behavioral age-related declines and abnormalities in its brain neurochemistry. Nevertheless, it is not clear whether these impairments might be accompanied by previous changes related to the neuroinflammation process in their central nervous system (CNS). Therefore, the aim of the present work was to determine if adult female PAM may show brain neuroinflammation processes comparable to those observed in chronologically old female mice. Accordingly, ICR-CD1 female mice were classified in PAM, Regular NonPrematurely Aging Mice (R-NPAM) and E-NPAM and compared to a group of chronologically old female mice (OLD) (24±1 months). Through the application of immunohistochemical techniques we evaluated changes in the expression of NeuN (a neuronal marker), Iba-1 (a microglia marker) and GFAP (an astrocyte marker) in brain areas related to the behavioral alterations previously detected in both PAM and chronologically old mice. In general, PAM showed a lower NeuN expression and a higher GFAP and Iba1 expression mainly in the Anterior Frontal Cortex and in the Medial Hippocampal Formation, when compared to E-NPAM; similar changes were observed in OLD. Other brain areas, such as the Hypothalamic Nuclei and Motor Cortex were less affected. In conclusion, adult PAM and OLD female mice share some region-dependent neuronal and glial changes that may underlie, at least in part, some of the behavioral abnormalities previously reported in these animals., Instituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional (FEDER), Universidad Complutense de Madrid (UCM), Depto. de Genética, Fisiología y Microbiología, Depto. de Fisiología, Fac. de Ciencias Biológicas, Fac. de Medicina, TRUE, pub

Oxidative and inflammatory stresses are closely related processes, which contribute to age-associated impairments that affect the regulatory systems such as the immune system and its immunosenescence. Therefore, the aim of this work was to confirm whether an oxidative/inflammatory stress occurs in immune cells from adult mice with premature aging, similar to that shown in leukocytes from chronologically old animals, and if this results in immunosenescence. Several oxidants/antioxidants and inflammatory/anti-inflammatory cytokines were analyzed in peritoneal leukocytes from adult female CD1 mice in two models of premature aging—(a) prematurely aging mice (PAM) and (b) mice with the deletion of a single allele (hemi-zygotic: HZ) of the tyrosine hydroxylase (th) gene (TH-HZ), together with cells from chronologically old animals. Several immune function parameters were also studied in peritoneal phagocytes and lymphocytes. The same oxidants and antioxidants were also analyzed in spleen and thymus leukocytes. The results showed that the immune cells of PAM and TH-HZ mice presented lower values of antioxidant defenses and higher values of oxidants/pro-inflammatory cytokines than cells from corresponding controls, and similar to those in cells from old animals. Moreover, premature immunosenescence in peritoneal leukocytes from both PAM and TH-HZ mice was also observed. In conclusion, adult PAM and TH-HZ mice showed oxidative stress in their immune cells, which would explain their immunosenescence., El estrés oxidativo (mayor presencia de oxidantes que de defensas antioxidantes) e inflamatorio (predominio de compuestos inflamatorios frente a los anti-inflamatorios), están en la base del envejecimiento. Se ha comprobado que en células inmunitarias de diferentes localizaciones (peritoneo, bazo y timo) de dos modelos de ratones adultos que ya habíamos descrito presentan envejecimiento prematuro (uno natural y otro genético), aparece un estado redox e inflamatorio similar al de los respectivos ratones controles cuando son cronológicamente viejos. Este estrés oxidativo e inflamatorio prematuro podría explicar la menor esperanza de vida que muestran esos animales., Instituto de Salud Carlos III/ FEDER, Universidad Complutense de Madrid, Depto. de Genética, Fisiología y Microbiología, Sección Deptal. de Bioquímica y Biología Molecular (Biológicas), Fac. de Ciencias Biológicas, TRUE, pub

Aging is associated with a chronic oxidative stress (increase of oxidants and decrease of antioxidants), which contributes to immunosenescence and therefore shorter longevity. Nevertheless, a positive social network has been related to the adequate maintenance of health and deceleration of aging. Adult prematurely aging mice (PAM) are characterized by their inadequate stress response to a T-maze, showing premature immunosenescence and oxidative stress establishment. These impairments contribute to shorter life spans in comparison to exceptional non-PAM (ENPAM). However, it is not known whether these characteristics of PAM could be prevented by a positive cohabitation. Therefore, the aim of the present work was to determine if the premature immunosenescence and oxidative stress shown by PAM could be avoided by the cohabitation with ENPAM, increasing their life span. Female CD1 PAM and ENPAM were divided into three experimental groups: PAM controls, ENPAM controls and a social environment experimental group, containing in the same cage ENPAM and PAM (proportion 5/2, respectively). After 2 months, mice were sacrificed and spleen, thymus, liver and heart removed. Later, several immune functions as well as oxidative stress parameters were assessed in spleen and thymus leukocytes. Also, several oxidative stress parameters were analyzed in liver and heart. The results showed that PAM, after co-housing with ENPAM, had improved immune functions and redox balance in spleen and thymus leukocytes. This improvement of redox state was also observed in liver and heart. Furthermore, all these positive effects seem to be related to the increased life span of PAM., Instituto de salud Carlos III (ISCIII)/FEDER, Universidad Complutense de Madrid, 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

Introducción: La salud depende del buen funcionamiento de los sistemas homeostáticos (el nervioso, endocrino e inmunitario) y de la adecuada comunicación entre ellos. Se ha comprobado que el estado funcional y redox del sistema inmunitario es un excelente marcador de salud, y que una inmunosenescencia prematura supone una menor esperanza de vida. Dado que las catecolaminas modulan la funcionalidad de las células inmunitarias, la alteración en su síntesis podría contribuir a esa inmunosenescencia. Entre las estrategias que se pueden utilizar para controlarla está el ambiente social. Objetivo: Comprobar si una haploinsuficiencia de la tirosina hidroxilasa (TH), enzima limitante de la síntesis de catecolaminas, generaría una inmunosenescencia prematura, y si es posible la modulación de esta por el ambiente social. Material y métodos: Se usaron ratones machos ICR-CD1 adultos (9 ± 1 meses) hemizigotos (HZ) para la tirosina hidroxilasa (TH-HZ) y controles (WT), que fueron distribuidos en cuatro subgrupos: WT > 50% (en la jaula, la proporción de WT fue mayor al 50%), WT < 50%, TH-HZ < 50% y TH-HZ > 50%. En leucocitos peritoneales se valoró la fagocitosis, quimiotaxis y linfoproliferación en presencia de lipopolisacárido. También, la actividad de las enzimas antioxidantes glutatión reductasa y glutatión peroxidasa, y el cociente glutatión oxidado/glutatión reducido. Resultados: Los TH-HZ > 50% presentaron, en leucocitos, una funcionalidad y estado redox deteriorados respecto a WT > 50 y similar a ratones viejos. Sin embargo, los TH-HZ < 50% mostraron valores similares a los WT < 50%. Conclusión: Una haploinsuficiencia de la enzima TH provoca una inmunosenescencia prematura, la cual puede ser compensada por la convivencia con un número apropiado de animales WT., Introduction: Healthy state depends on the appropriate function of the homeostatic systems (nervous, endocrine and immune systems) and the correct communication between them. The functional and redox state of the immune system is an excellent marker of health, and animals with premature immunosenescence show a shorter lifespan. Since catecholamines modulate the function of immune cells, the alteration in their synthesis could provoke immunosenescence. The social environment could be a strategy for modulating this immunosenescence. Aim: To determine if an haploinsufficiency oftyrosine hydroxylase (TH),the limiting enzyme of synthesis of catecholamines, may produce a premature immunosenescence and if this immunosenescence could be modulated by the social environment. Materials and methods: Adult (9 ± 1 months) male ICR-CD1 mice with deletion of a single allele (hemizygotic: HZ) of the tyrosine hydroxylase enzyme (TH-HZ) and wild-type (WT) mice were used. Animals were housed in four subgroups: WT > 50% (in the cage, the proportion of WT mice was higher than 50% in relation to TH-HZ), WT < 50%, TH-HZ < 50% and TH-HZ > 50%. Peritoneal leukocytes were collected and phagocytosis, chemotaxis and proliferation of lymphocytes in the presence of lipopolysaccharide were analyzed. Glutathione reductase and glutathione peroxidase activities as well as oxidized/reduced glutathione ratio were studied. Results: TH-HZ > 50% mice showed a deteriorated function and redox state in leukocytes respect to WT > 50% and similar to old mice. However, TH-HZ < 50% animals had similar values to those found in WT < 50% mice. Conclusion: The haploinsufficiency of TH generates premature immunosenescence, which appears to be compensated by living together with an appropriate number of WT animals., Ministerio de Ciencia e Innovación (MICINN), Instituto de Salud Carlos III (ISCIII), Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidaddel Instituto de Salud Carlos III-FEDER, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas deI ISCIII-FEDER de la Unión Europea, y Grupo de investigación UCM, 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