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Objective: We have previously shown that Akkermansia muciniphila ingestion induces beneficial changes in behavioral tests, immune functions, and on oxidative and inflammatory status in old mice, increasing their lifespan. The aim of the present study was to determine if A. muciniphila orally supplementation for 1 month in old female mice promoted changes in the gut microbiota composition and metabolic activity. Methods: Twenty old female ICR-CD1 mice (72 ± 4 weeks) were divided into two groups: one that received A. muciniphila CIP107961 strain (108 cfu/100 µl PBS) for 1 month (OA) and another group that received only PBS (OC). In addition, another group of ten adult mice (40 ± 4 weeks) was included to compare with the two previous groups (AC). In all experimental groups, the gut microbiota composition was analyzed by 16S rRNA gene sequencing and metabolic activity by quantifying fecal short-chain fatty acids (SCFA) and branched short chain fatty acids (BSCFA) using gas chromatography. Results: Akkermansia administration promoted changes in the microbial profile of OA group in comparison with OC and AC groups, highlighting the modulation of Actinomycetota phylum and Bifidobacterium genus. Major SCFA did not show significant changes between the three groups analyzed but BSCFA were significantly lower in the OA group compared to the OC group, showing similar levels to the AC group. Conclusions: Our results indicate that A. muciniphila CIP107961 strain supplementation for one month could be considered a good nutritional strategy to promote a healthy aging through gut microbiota modulation.

Aging is interrelated with the development of immunosenescence. This article focuses on one of the cell sets of the adaptive immune system, T cells, and provides a review of the known changes in T-cells associated with aging. Such fundamental changes affect both cell molecular content and internal ordering. However, acquiring a complete description of the changes at these levels would require extensive measurements of parameters and, furthermore, important fine details of the internal ordering that may be difficult to detect. Therefore, an alternative approach for the characterization of cells consists in the performance of physical measurements of the whole cell, such as deformability measurements or migration measurements: the physical parameters, complementing the commonly used chemical biomarkers, may contribute to a better understanding of the evolution of T-cell states during aging. Mechanical measurements, among other biophysical measurements, have the advantage of their relative simplicity: one single parameter agglutinates the complex effects of the variety of changes that gradually appear in cells during aging.

Mechanical deformability of cells is an important property for their function and in development, and a useful marker of cell state. Moreover measuring mechanical properties of cells has been proven useful in preclinical studies and in clinical practice. We provide here a method to measure the two parameters, elastic modulus and Poisson coefficient, of the cellular material under the approximation of homogeneous isotropic linear elasticity. The proposed method is based on the analysis of micropipetteaspiration experiments. We show the successful application of this procedure to measure the elastic parameters of lymphocytes, for which the mechanical properties depend on the activation state, and their measurement would be useful in clinical studies and clinical practice. The method will be valuable to be implemented in future technologies, based on the micropipette aspiration technique, for the automated measurement of mechanical properties of cells.

Mechanical deformability of cells is an important property for their function and in development, and a useful marker of cell state. Moreover measuring mechanical properties of cells has been proven useful in preclinical studies and in clinical practice. We provide here a method to measure the two parameters, elastic modulus and Poisson coefficient, of the cellular material under the approximation of homogeneous isotropic linear elasticity. The proposed method is based on the analysis of micropipetteaspiration experiments. We show the successful application of this procedure to measure the elastic parameters of lymphocytes, for which the mechanical properties depend on the activation state, and their measurement would be useful in clinical studies and clinical practice. The method will be valuable to be implemented in future technologies, based on the micropipette aspiration technique, for the automated measurement of mechanical properties of cells.

[ES]: [Introducción]: En la enfermedad del Alzheimer (EA) se ha comprobado que existe un deterioro en la comunicación neuroinmunoendocrina. Sin embargo, apenas hay estudios a un nivel periférico en esta enfermedad neurodegenerativa, en concreto en lo que respecta a la función inmunitaria. Dado que recientemente se ha establecido que ciertos parámetros de función inmunitaria son marcadores de la velocidad de envejecimiento y pueden predecir la longevidad, el propósito del presente trabajo fue valorar algunas de esas funciones en leucocitos esplénicos de ratones transgénicos para la EA de diversas edades. [Material y métodos]: Se emplearon ratones triple-transgénicos para la EA (3 xTgAD) hembras, así como sus controles no transgénicos (NTg) jóvenes (4 ± 1 meses), adultos (9 ± 1 meses) y maduros (12 ± 1 meses). Se valoraron la quimiotaxis, la actividad citotóxica de las «natural killer» (NK) y la respuesta linfoproliferativa en presencia de los mitógenos concanavalina A y lipopolisacárido en leucocitos esplénicos, funciones que disminuyen al envejecer. Además, se realizó una curva de supervivencia en otro grupo de animales 3 xTgAD y NTg. [Resultados]: En los 3 xTgAD, con respecto a los NTg, la quimiotaxis se encuentra disminuida en todas las edades, mientras que dicha disminución se observa a los 4 y 9 meses en la linfoproliferación y solo en los jóvenes en el caso de la actividad NK. Los 3 xTgAD mostraron una menor supervivencia que los NTg. [Conclusiones]: Los ratones 3 xTgAD presentan una inmunosenescencia prematura, lo que podría explicar su temprana mortalidad. La valoración a nivel periférico de las funciones inmunológicas estudiadas podría ser un indicador del desarrollo de la enfermedad de Alzheimer., [EN]: [Introduction]: A deterioration of the neuroimmunoendocrine network has been observed in Alzheimer's disease (AD). However, the peripheral immune response has hardly been investigated in this pathology. Since some immune function parameters have been established as good markers of the rate of ageing, and can predict longevity, the aim of the present work was to study some of these functions in splenic leucocytes in transgenic mice for AD of different ages. [Material and methods]: Young female (4 ± 1 months), adult (9 ± 1 months), and mature (12 ± 1 months) triple-transgenic mice for AD (3 xTgAD) and non-transgenic (NTg) control mice of the same ages were used. The chemotaxis, the anti-tumour activity of «natural killer» (NK) cells and the lymphoproliferative response in the presence of the mitogens concanavalin A and lipopolysaccharide, functions that decrease with age, were determined in splenic leucocytes. In addition, the differences in lifespan between 3 xTgAD and NTg were studied in parallel using other animals, until their death through natural causes. [Results]: In 3 xTgAD, with respect to NTg, chemotaxis decreased at all ages studied, whereas in lymphoproliferative response this reduction was shown at 4 months and 9 months. NK activity was diminished only in young 3 xTgAD with respect to NTg. The 3 xTgAD showed a shorter lifespan than the NTg control group. [Conclusions]: The 3 xTgAD mice show a premature immunosenescence, which could explain their early mortality. The determination of these immune functions at peripheral level could serve as a marker of the progression of the Alzheimer's disease.

We review here our latest results regarding short- and long-term effects of a neonatal maternal deprivation (MD) stress [24 h at postnatal day (PND) 9] on diverse psychoneuroimmunoendocrine parameters, pointing out the existence of numerous sexual dimorphisms. Behavioral changes observed in MD animals might be at least in part attributable to neurodevelopmental effects of MD-induced elevated corticosterone levels. Our findings of short-term effects of MD on hippocampal and cerebellar neurons and glial cells appear to support this hypothesis. However, it is important to note that these cellular effects were more marked in males than in females. Moreover, in analyzing the effects of this neonatal stress on the endocannabinoid system (hippocampal endocannabinoid levels and CB1 receptors) we have also found that males were more affected by MD. Since all these sexual dimorphisms were found at an early neonatal age (PND 13), they are attributable to organizational effects of gonadal steroids. We discuss the potential implications of the elevated corticosterone and decreased leptin levels shown by MD animals in their diverse functional alterations, including the above mentioned neural effects as well as the intriguing persistent deficit in their immunological system. We also emphasize the necessity of analyzing the important influence of sex as regards the specific consequences of early life stress. © 2009 Elsevier Ltd. All rights reserved.

Maternal deprivation [24 h on postnatal day 9] might represent an animal model of schizophrenia and behavioural and neurochemical alterations observed in adulthood may be mediated by hippocampal impairments induced by abnormally increased glucocorticoids due to neonatal stress. We aimed to provide new data for psychoimmunoendocrine characterization of this animal model by evaluating its effects in adolescent rats of both genders. In previous studies we found that cannabinoid compounds counteracted the enhanced impulsivity of maternally deprived animals and that the cannabinoid receptor agonist WIN 55,212-2 showed neuroprotective properties in neonatal rats. So, we hypothesised that this compound could counteract at least some of the detrimental effects that we expected to find in maternally deprived animals. Accordingly, the drug was administered immediately after the maternal deprivation period. Maternally deprived males showed significantly decreased motor activity in the holeboard and the plus-maze. The cannabinoid agonist induced, exclusively in males, a significant anxiogenic-like effect, which was reversed by maternal deprivation. In the forced swimming test, both treatments independently induced depressive-like responses. Maternal deprivation reduced immunological function whereas the drug exerted tissue-dependent effects on the immune parameters analysed. Maternally deprived females showed reduced corticosterone levels whereas the cannabinoid agonist increased hormone concentration in all groups. In general, the results show detrimental effects of both treatments as well as intriguing interactions, notably in relation to emotional behaviour and certain immunological responses. © 2007 Elsevier Ltd. All rights reserved.

We have previously shown that differences in life span among members of Swiss mouse populations appear to be related to their exploration of a T-maze, with a slow exploration ('slow mice') being linked to alteration of spontaneous behavior and monoaminergic systems, impaired immune function and shorter life span. In general these traits resemble some of the characteristics of chronologically old animals. Thus, we proposed the 'slow mice' as a model of prematurely aging mice (PAM). Now, we have compared female PAM with non-prematurely aging mice (NPAM) as regards a number of behavioral, endocrine and immunological parameters which were studied under both basal and stress conditions. In the present study the animals were chronologically younger than those used in our previous work. When compared to NPAM, the PAM showed increased anxiogenic-like responses in the plus-maze, increased basal corticosterone levels and decreased corticosterone responses to stress. The PAM also showed a decreased natural killer activity as well as decreased lymphoproliferative responses to mitogens. Moreover, the mitogen-induced lymphoproliferative responses of the PAM appeared to be more susceptible to stress. The data indicate that certain characteristics of the PAM are already present in animals of very young chronological age and provide new information for a more complete characterization of the PAM from a neuroimmunoendocrine viewpoint. © 2005 Elsevier Ltd. All rights reserved.

Several neuropeptides, including gastrin-releasing peptide (GRP), modulate the immune response, specifically lymphocyte chemotaxis. In the present work the effect of GRP on the chemotaxis of murine lymphocytes from different immune locations in both, total leukocyte populations and populations depleted of adherent cells have been studied. Specificity of the GRP effect on chemotaxis using an antagonist of the GRP receptor, as well as the implication of nitric oxide (NO), using inhibitors of NO synthase and donors of NO, were investigated. The effects of GRP stimulating the chemotaxis of lymphocytes from peritoneum, axillary nodes and spleen and decreasing the chemotaxis from thymus were receptor-specific and disappeared in lymphocytes from populations depleted of adherent cells. NO synthase inhibitors blocked the GRP effect on lymphocyte chemotaxis, and this action was reversed in the presence of l-arginine. Thus, the effect of GRP on murine lymphocyte chemotaxis appears to be mediated by NO secreted by adherent cells.

Since increasing evidence suggests that upregulation of the cAMP-second messenger system may be implicated in Alzheimer's disease neurodegeneration, we have compared the cAMP and cGMP levels in cerebrospinal fluid (CSF) from patients with dementia of the Alzheimer type (DAT, n=10) with those from nondemented age-matched controls (n=10). Our results show that cAMP levels, but not cGMP, are significantly (p<0.01) elevated in CSF from patients with DAT compared to those from nondemented controls. Moreover, a linear regression analysis demonstrated a significant correlation (r=0.62; p<0.01) between cAMP and tau protein levels in CSF when controls and patients with DAT were studied together. These results suggest that upregulation of cAMP-signaling pathway is implicated in Alzheimer's disease physiopathology. Copyright (C) 1999 Elsevier Science B.V.