Premature impairment of methylation pathway and cardiac metabolic dysfunction in fa/fa obese Zucker rats.

Increasing evidence suggests that obesity is a chronic inflammatory disease, in which adipose tissue is involved in a network of endocrine signals to modulate energy homeostasis. These oxidative-inflammatory pathways, which are associated with cardiovascular complications, are also observed during the aging process. In this study, we investigated the interaction between aging and the development of obesity in a hyperphagic rat model. Metabolic profiles of the liver, white adipose tissue (WAT) and heart from young and adult Zucker lean (fa/+) and obese (fa/fa) rats were characterized using a (1)H NMR-based metabonomics approach. We observed premature metabolic modifications in all studied organs in obese animals, some of which were comparable to those observed in adult lean animals. In the cardiac tissue, young obese rats displayed lower lactate and scyllo-inositol levels associated with higher creatine, choline and phosphocholine levels, indicating an early modulation of energy and membrane metabolism. An early alteration of the hepatic methylation and transsulfuration pathways in both groups of obese rats indicated that these pathways were affected before diabetic onset. These findings therefore support the hypothesis that obesity parallels some metabolic perturbations observed in the aging process and provides new insights into the metabolic modifications occurring in prediabetic state.

Effect of environmental enrichment on the immunoendocrine aging of male and female triple-transgenic 3xTg-AD mice for Alzheimer's disease.

We have previously shown that 3xTgAD mice (triple-transgenic mice for Alzheimer's disease, harboring PS1(M146V), AßPP(Swe), tau(P301L) transgenes) suffer detrimental changes in some key lymphocyte functions, described as health and longevity markers, with males being more affected than females and showing higher mortality rates. In the present work, 3xTgAD and wild type 129/C57BL6 male and female non- and environmentally enriched mice were used. The enriched environment (EE) began in the adulthood (6 months) and lasted for 5.5 months. The animals were sacrificed at advanced stages of the disease (15 month-old), and spleen, thymus, and plasma were obtained. The results indicate that 3xTg-AD males are especially benefitted from EE exposure, as shown by the improvement in lymphocyte functional activities such as chemotaxis and natural killer cytotoxicity, as well as in plasma corticosterone levels. By contrast, wild type females seem to be highly sensitive to EE removal, as regards the proliferation capacity of lymphocytes and their intracellular glutathione content. These results support the relevance of gender differences in AD when screening for new strategies for the control of the disease, and suggest that active life, by means of EE, should be maintained until natural death in order to preserve all the positive effects that this strategy exerts on the immune system.

Ovariectomy causes immunosenescence and oxi-inflamm-ageing in peritoneal leukocytes of aged female mice similar to that in aged males.

Immunosenescence involves age-associated restructuring changes of innate and adaptative immune functions. We have suggested that these changes of the immune system participate in the rate of ageing through modulating oxi-inflamm-ageing. Thus, age-related changes in the immune system can be biological age markers and predictors of longevity. Gender differences in oxidation status and immune functions have been observed in rats, with males showing higher oxidation and immunosenescence than females of the same age. Oestrogens are sex hormones that actively participate in modulating the mammalian immune function and, therefore, the age-related impairment of the immune response is drastically accelerated in females during the menopausal transition. Ovariectomy in rodents constitutes a good model for mimicking human oestrogen loss and thus the menopausal situation. Recently, we have shown the deleterious effects of oestrogen loss on several functions of leukocytes from immune organs in rats and mice. In addition, ovariectomised rats show similar levels in these immune functions to those in males. The present work studied several functions as well as inflammatory and oxidative stress parameters in mouse peritoneal macrophages and lymphocytes from old sham and ovariectomised females, as well as in males of the same age. In general, the results show that females, which have a higher immune response and a lower oxidation and inflammation than males, appear similar to males in the parameters studied when they have lost oestrogens by ovariectomy. Thus, these data support the positive role of oestrogens in the immune function through the ageing process.

Soybean and green tea polyphenols improve immune function and redox status in very old ovariectomized mice.

In previous work we have observed that ovariectomy in rodents, a good model of mimicking human ovarian hormone loss, causes premature aging of the immune system. The prooxidative and inflammatory state that underlies the aging process is the base of that premature immunosenescence. It has been found that nutritional interventions with polyphenolic antioxidants constitute a good alternative to rejuvenate age-affected immune functions. In this study, we administered a diet supplemented with polyphenols (coming from soybean isoflavones and green tea) to sham-operated and ovariectomized mature mice for 15 weeks, until they reached a very old age. We have studied the effect of this supplementation on a broad range of parameters of immune function (in macrophages and lymphocytes) and oxidative stress (enzymatic and nonenzymatic antioxidant defences, oxidant compounds, and lipid peroxidation damage) in peritoneal leukocytes. The results showed that ovariectomy accelerates the age-related impairment of immune functions in very old mice as well as the oxidative and proinflammatory imbalance, and that the administration of soybean isoflavones and green tea improve the immune and redox state in these animals. Because the immune system is a good marker of health and a predictor of longevity, we suggest that an adequate nutritional treatment with polyphenols could be a highly recommended tool to fight against the detrimental effects of the lack of female sex hormones, through an improvement of the immune cell functions and redox state.

Environmental enrichment improves age-related immune system impairment: long-term exposure since adulthood increases life span in mice.

Age-related changes in immunity have been shown to highly influence morbidity and mortality. The aim of the present work was to study the effects of environmental enrichment (EE) (8-16 weeks) on several functions and oxidative stress parameters of peritoneal leukocytes, previously described as health and longevity markers, in mice at different ages, namely adult (44 +/- 4 weeks), old (69 +/- 4 weeks), and very old (92 +/- 4 weeks). Mortality rates were monitored in control and enriched animals, and effects on survival of long-term exposure to EE until natural death were determined. The results showed that exposure to EE was efficient in improving the function (i.e., macrophage chemotaxis and phagocytosis, lymphocyte chemotaxis and proliferation, natural killer cell activity, interleukin-2 and tumor necrosis factor-alpha levels) and decreasing the oxidative-inflammatory stress (i.e., lowered oxidized glutathione content, xanthine oxidase activity, expression of Toll-like receptors 2 and 4 on CD4 and CD8 cells, and increased reduced glutathione and glutathione peroxidase and catalase activities) of immune cells. These positive effects of EE were especially remarkable in animals at older ages. Importantly, long-term exposure to EE from adult age and until natural death stands out as a useful strategy to extend longevity. Thus, the present work confirms the importance of maintaining active mental and/or physical activity aiming to improve quality of life in terms of immunity, and demonstrates that this active life must be initiated at early stages of the aging process and preserved until death to improve life span.

Differential expression of Toll-like receptor 2 and 4 on peritoneal leukocyte populations from long-lived and non-selected old female mice.

The aim of the present study was to determine Toll-like receptor (TLR)-2 and TLR-4 membrane expression on the major peritoneal leukocyte populations throughout the aging process, including subjects that had achieved exceptional longevity. ICR (CD1) female mice of different ages: adult (44 +/- 4 weeks), old (69 +/- 4), very old (92 +/- 4) and extreme long-lived (125 +/- 4), were used. Peritoneal leukocytes were collected, and percentages of CD11b, CD11c, CD3CD4, CD3CD8 and CD19 cells present in the samples were analysed, as well as the expression of TLR-2 and TLR-4 on them, by flow cytometry. The results showed increased TLR expression on CD11b+ cells from animals at very old ages and especially in the extreme long-lived. Old subjects showed lower percentage of CD11c+ cells, but no age-related changes were found in the TLR expression on these cells. TLRs on CD3CD4+ and CD3CD8+ cells from very old animals were increased as compared to the adults, whereas long-lived subjects showed preserved levels. However, TLR expression on CD19+ cells was higher in long-lived individuals with respect to subjects at all the other younger ages. These data suggest that differential age-related changes in the expression of TLR-2 and TLR-4 on leukocyte populations from long-lived and non-selected younger old mice could contribute to a different age-related immune remodelling in long-lived subjects, which could allow better preservation of their immune responses.

[Social isolation during old age worsens cognitive, behavioral and immune impairment]. / El aislamiento social durante la vejez empeora el deterioro cognitivo, conductual e inmunitario.

INTRODUCTION: Several studies by the World Health Organization indicate that widows and widowers show lower physical and mental health indexes than the age-matched general population. In addition, widowhood and social isolation are common in the elderly, with women being more affected than men due to their longer life span. Thus, the aim of the present study was to create an animal model of solitude in old age to study the behavioral, cognitive and immunological changes induced by social isolation at this late stage of life. MATERIAL AND METHODS: Twenty female C57b/129sv mice, housed in groups of 4-5 until their old age (18 months), remained in groups (controls, n=10) or were isolated after reaching the age of 18 months and until they reached the age of 24 months (isolated, n=10). At this advanced age, the animals were submitted to a battery of tests to assess neophobia (corner test), anxiety (open-field test), and learning and memory (Morris water maze). Thereafter, the animals were sacrificed and the thymus was removed. The natural killer (NK) activity of the thymic cells against the YAC-1 murine tumor cell line was evaluated. RESULTS: Animals isolated during old age showed functional and cognitive decline, with increased neophobia and anxiety as well as learning and memory deficits. In addition, isolation reduced the NK activity of thymic cells. CONCLUSIONS: We demonstrate the importance of social isolation and solitude during old age. Both social isolation and solitude exacerbate mental and immunological involution during this period, despite normal social life during previous stages of life.

El aislamiento social durante la vejez empeora el deterioro cognitivo, conductual e inmunitario / Social isolation during old age worsens cognitive, behavioral and immune impairment

Introducción: Los estudios de la Organización Mundial de la Salud indican que las personas viudas muestran menores índices de salud física y mental que el resto de la población de la misma edad cronológica. Por otra parte, la viudez y el aislamiento social son condiciones frecuentes en los mayores; sin embargo, las mujeres son las que presentan mayor incidencia, dada su mayor esperanza de vida media. Así, el objetivo del presente trabajo fue crear un modelo animal de soledad durante la vejez para estudiar en éste los cambios en el perfil cognitivo, conductual e inmunitario a los que conduce el aislamiento social en esta etapa de la vida. Materiales y métodos: Veinte ratones hembras de la cepa C57b/129sv estabulados en grupos de 4 a 5 animales hasta su vejez (18 meses de edad) siguieron en grupo (grupo control, n=10) o se aislaron a partir de ese momento y hasta alcanzar 24 meses de edad (ratones aislados, n=10). A esta edad avanzada los animales realizaron una serie de pruebas para valorar neofobia (test de esquinas), ansiedad (campo abierto) y aprendizaje y memoria (laberinto acuático de Morris). Posteriormente, se sacrificó a los animales, se obtuvo el timo y de éste la suspensión celular en la que se analizó la capacidad citotóxica de las células natural killer (NK) frente a la línea tumoral murina YAC-1. Resultados: El estudio conductual puso de manifiesto que los animales aislados durante la vejez muestran un declive funcional y cognitivo, con aumento de la neofobia y de la ansiedad así como problemas de aprendizaje y memoria. Además, la soledad conduce a una disminución de la actividad de las células NK tímicas. Conclusiones: Se demuestra la importancia del aislamiento y de la soledad durante la vejez, lo que exacerba la involución mental e inmunitaria durante este período a pesar de haber mantenido una vida social normal durante las etapas vitales anteriores (AU)

Introduction: Several studies by the World Health Organization indicate that widows and widowers show lower physical and mental health indexes than the age-matched general population. In addition, widowhood and social isolation are common in the elderly, with women being more affected than men due to their longer life span. Thus, the aim of the present study was to create an animal model of solitude in old age to study the behavioral, cognitive and immunological changes induced by social isolation at this late stage of life. Material and methods: Twenty female C57b/129sv mice, housed in groups of 4–5 until their old age (18 months), remained in groups (controls, n=10) or were isolated after reaching the age of 18 months and until they reached the age of 24 months (isolated, n=10). At this advanced age, the animals were submitted to a battery of tests to assess neophobia (corner test), anxiety (open-field test), and learning and memory (Morris water maze). Thereafter, the animals were sacrificed and the thymus was removed. The natural killer (NK) activity of the thymic cells against the YAC-1 murine tumor cell line was evaluated. Results: Animals isolated during old age showed functional and cognitive decline, with increased neophobia and anxiety as well as learning and memory deficits. In addition, isolation reduced the NK activity of thymic cells. Conclusions: We demonstrate the importance of social isolation and solitude during old age. Both social isolation and solitude exacerbate mental and immunological involution during this period, despite normal social life during previous stages of life (AU)

Improvement of immune cell functions in aged mice treated for five weeks with soybean isoflavones.

Aging is associated with an impaired immune system as well as with a decline of several hormones, such as estrogens. Dietary phytoestrogens have been proposed as an alternative to hormone replacement therapy. The beneficial action of soybean compounds is probably due to isoflavones, whose role as immunomodulators has been investigated with increasing interest. The aim of the present work was to study whether a 5-week administration of a diet enriched in soybean isoflavones and green tea could influence the immune function of mice that were sham-operated or ovariectomized. Natural killer activity (NK) and lymphoproliferation in response to the mitogens concanavaline A (Con A) and lipopolysaccharide (LPS), were studied in peritoneal leukocytes. Both treatments with soybean or green tea plus soybean were highly effective in improving these immune parameters with respect to control groups. Since the immune system is a marker of health and a predictor of longevity, an adequate treatment with isoflavones could be useful in slowing down the effects of the aging process through an improvement in the two relevant immune functions studied.

Influence of aging and enriched environment on motor activity and emotional responses in mice.

We have evaluated different behavioral parameters in ICR (CD1) female mice of three different ages (38-39 weeks: mature; 62 weeks: late mature; 90 weeks: old), and addressed the effects of an enriched housing condition. We employed the following battery of tests: Holeboard, open field, elevated plus-maze (EPM), and forced swimming test (FST). The results suggest that aging process differentially affects diverse aspects of behavior. With respect to motor activity, late mature animals were more affected by enrichment, whereas old animals appeared to be more affected when emotional responses were considered. We propose that the diminished percentage of time in the open arms of the EPM showed by enriched mice may be indicative of decreased novelty seeking, whereas their decreased climbing behavior may indicate a reduced escape-related behavior in an inescapable situation.