Improvement of immune function and redox state in several organs of old and prematurely aging female mice after a short social interaction with adults.

Aging is associated with chronic oxidative stress, which contributes to the deterioration of the immune system, increasing morbidity and mortality. A positive social environment permits health maintenance and a slower rate of aging. Improvements in immune function and oxidative stress were shown in peritoneal leukocytes and organs of old mice and adult prematurely aging mice (PAM) after cohabitation with adults or exceptional non-prematurely aging mice (ENPAM), respectively, for 2 months, but adults and ENPAM experienced deterioration. This was solved by shortening the cohabitation time to 15 min/day for 2 months, where old mice and PAM maintained immune and redox state improvements in their peritoneal leukocytes, as well as a greater longevity, and adults and ENPAM did not show deterioration. However, it is unknown whether the positive effects of this short cohabitation are reflected in the immunity and redox state of the organs. The aim of the present study was to test whether a cohabitation of 15 min/day for 2 months maintains these positive effects in the organs of retired breeder female old mice and PAM and avoids the negative ones in adults and ENPAM. After cohabitation the animals were sacrificed, and the thymus and spleen were extracted to evaluate the immune function. The oxidative state was also analyzed in the spleen, liver, heart, lung, and kidney. The results show that after cohabitation, old mice and PAM improved their immunity and redox state, and adults and ENPAM showed no deterioration. This cohabitation can be suggested to improve health and slow down aging.

Frailty and biological age. Which best describes our aging and longevity?

Frailty and Biological Age are two closely related concepts; however, frailty is a multisystem geriatric syndrome that applies to elderly subjects, whereas biological age is a gerontologic way to describe the rate of aging of each individual, which can be used from the beginning of the aging process, in adulthood. If frailty reaches less consensus on the definition, it is a term much more widely used than this of biological age, which shows a clearer definition but is scarcely employed in social and medical fields. In this review, we suggest that this Biological Age is the best to describe how we are aging and determine our longevity, and several examples support our proposal.

Influence of consumption of the food additive carrageenan on the gut microbiota and the intestinal homeostasis of mice.

The safety of the carrageenan (CGN) consumption as a food additive is under debate, with negative effects being associated with the products of hydrolysis of CGN. Moreover, there is an increasing need to integrate gut microbiome analysis in the scientific risk assessment of food additives. The objective of this study was to test the effects of CGN consumption on the gut microbiota and the intestinal homeostasis of young male and female mice. Female and male ICR-CD1 mice (8 weeks old) orally received 540 mg kg-1 day-1 of CGN, representing the maximum-level exposure assessment scenario surveyed for children, over the course of two weeks. Fecal material and peritoneal immune cells were analyzed to determine changes in the fecal microbiota, based on the analysis of bacterial 16S rRNA gene amplicon sequences and short-chain fatty acid (SCFA) concentrations, and some immune functions and redox parameters of peritoneal leukocytes. Non-significant microbiota taxonomical changes associated with CGN intake were found in the mouse stools, resulting the housing time in an increase in bacterial groups belonging to the Bacteroidota phylum. The PICRUSt2 functional predictions showed an overall increase in functional clusters of orthologous genes (COGs) involved in carbohydrate transport and metabolism. A significant increase in the cytotoxicity of fecal supernatants was observed in CGN-fed mice, which correlated with worsening of immune functions and oxidative parameters. The altered immunity and oxidative stress observed in young mice after the consumption of CGN, along with the fecal cytotoxicity shown towards intestinal epithelial cells, may be associated with the gut microbiota's capacity to degrade CGN. The characterization of the gut microbiota's ability to hydrolyze CGN should be included in the risk assessment of this food additive.

Intracellular cytokines in peritoneal leukocytes relate to lifespan in aging and long-lived female mice.

Peritoneal immune cell function is a reliable indicator of aging and longevity in mice and inflammaging is associated with a shorter lifespan. Nevertheless, it is unknown if the content of cytokines in these immune cells is linked to individual differences in lifespan. Therefore, this work aimed to investigate different peritoneal leukocyte populations and their content in intracellular pro-inflammatory (TNF and IL-6) and anti-inflammatory (IL-10) cytokines by flow cytometry in adult (10 months-old, n = 8) and old (18 months-old, n = 20) female Swiss/ICR mice. In addition, old mice were monitored longitudinally throughout their aging process, and the same markers were analyzed at the very old (24 months-old, n = 8) and long-lived (30 months-old, n = 4) ages. The longitudinal follow-up allowed us to relate the investigated parameters to individual lifespans. The results show that long-lived female mice exhibit an adult-like profile in most parameters investigated but also display specific immune adaptations, such as increased CD4+ and CD8+ T cells containing the pro-inflammatory TNF cytokine and CD4+ T cells and macrophages containing the anti-inflammatory cytokine IL-10. These adaptations may underlie their exceptional longevity. In addition, a negative correlation was obtained between the percentage of cytotoxic T cells, KLRG-1/CD4, large peritoneal macrophages, and the percentage of CD4+ T cells containing IL-6 and macrophages containing IL-10 in old age and lifespan, whereas a positive correlation was found between the CD4/CD8 ratio and the longevity of the animals at the same age. These results highlight the crucial role of peritoneal leukocytes in inflammaging and longevity.

Predictive Models of Life Span in Old Female Mice Based on Immune, Redox, and Behavioral Parameters.

The development of mathematical models capable of predicting the lifespan of animals is growing. However, there are no studies that compare the predictive power of different sets of parameters depending on the age of the animals. The aim of the present study is to test whether mathematical models for life span prediction developed in adult female mice based on immune, redox, and behavioral parameters can predict life span in old animals and to develop new models in old mice. For this purpose, 29 variables, including parameters of immune function, redox state, and behavioral ones, were evaluated in old female Swiss mice (80 ± 4 weeks). Life span was registered when they died naturally. Firstly, we observed that the models developed in adults were not able to accurately predict the life span of old mice. Therefore, the immunity (adjusted R2 = 73.6%), redox (adjusted R2 = 46.5%), immunity-redox (adjusted R2 = 96.4%), and behavioral (adjusted R2 = 67.9%) models were developed in old age. Finally, the models were validated in another batch of mice. The developed models in old mice show certain similarities to those in adults but include different immune, redox, and behavioral markers, which highlights the importance of age in the prediction of life span.

The immunity and redox clocks in mice, markers of lifespan.

Immune function and redox markers are used for estimating the aging rate, namely biological age (BA). However, it is unknown if this BA and its changes can be reflected in longevity. Thus, we must quantify BA in experimental animals. In peritoneal immune cells of 202 female mice (ICR/CD1) in different ages, 10 immune and 6 redox parameters were evaluated to construct two mathematical models for BA quantification in mice by multiple linear regression. Immune and redox parameters were selected as independent variables and chronological age as dependent, developing two models: the Immunity and the Redox Clocks, reaching both an adjusted R2 of 80.9% and a standard error of 6.38 and 8.57 weeks, respectively. Both models were validated in a different group of healthy mice obtaining a Pearson's correlation coefficient of 0.844 and 0.800 (p < 0.001) between chronological and BA. Furthermore, they were applied to adult prematurely aging mice, which showed a higher BA than non-prematurely aging mice. Moreover, after positive and negative lifestyle interventions, mice showed a lower and higher BA, respectively, than their age-matched controls. In conclusion, the Immunity and Redox Clocks allow BA quantification in mice and both the ImmunolAge and RedoxAge in mice relate to lifespan.

Components of the Glutathione Cycle as Markers of Biological Age: An Approach to Clinical Application in Aging.

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.

El tacto, un sentido crucial en las interacciones sociales para mejorar la homeostasis en el envejecimiento y promover una longevidad saludable / Touch, a crucial sense in social interactions to improve homeostasis in aging and promote healthy longevity

El envejecimiento se asocia con el deterioro generalizado del organismo, siendo de gran relevancia el que experimentan los sistemas homeostáticos como el sistema nervioso, inmunitario y endocrino, lo que aumenta el riesgo de morbilidad y mortalidad. Entre las estrategias de estilo de vida que se han investigado para mejorar esos sistemas y conseguir una mayor longevidad saludable, esta revisión se focalizará en el ambiente social. Para poder comprobar la efectividad de este, tanto en la mejoría de la homeostasis como en la esperanza de vida, se comentarán las investigaciones llevadas a cabo con animales de experimentación que han permitido hacerlo. Además, como se ha observado que el contacto físico es crucial para que se produzcan los resultados positivos de la interacción social sobre los sistemas homeostáticos y la longevidad, nos centraremos en ese mecanismo, así como en algunas de las posibles vías moleculares subyacentes a los efectos encontrados. (AU)

Aging is associated with the generalized deterioration of the organism, being of great relevance experienced by homeostatic systems such as the nervous, immune, and endocrine systems, which increases the risk of morbidity and mortality. Among the lifestyle strategies that have been researched to improve these systems and achieve greater healthy longevity, this review will focus on the social environment. In order to verify the effectiveness of these both in the improvement of homeostasis and in life expectancy, the research carried out with experimental animals that have allowed this to be done will be discussed. In addition, as it has been observed that physical contact is crucial for the positive outcomes of social interaction on homeostatic systems and longevity to occur, we will focus on that mechanism, as well as some of the possible molecular pathways underlying the effects found. (AU)

In Response to a Punctual Stress Male and Female Tyrosine Hydroxylase Haploinsufficient Mice Show a Deteriorated Behavior, Immunity, and Redox State.

An inadequate stress response is associated with impaired neuroimmunoendocrine communication, increasing morbidity and mortality. Since catecholamines (CA) constitute one of the acute stress response pathways, female mice with an haploinsufficiency of the tyrosine hydroxylase gene (TH-HZ), the main limiting enzyme in CA synthesis, show low CA amounts, exhibiting an impairment of homeostatic systems. The aim of this study was to investigate the effect of a punctual stress in TH-HZ mice, determining the differences with wild-type (WT) mice and those due to sex by restraint with a clamp for 10 min. After restraint, a behavioral battery was performed, and several immune functions, redox state parameters, and CA amounts were evaluated in peritoneal leukocytes. Results show that this punctual stress impaired WT behavior and improved female WT immunity and oxidative stress, whereas in TH-HZ mice, all parameters were impaired. In addition, different responses to stress due to sex were observed, with males having a worse response. In conclusion, this study confirms that a correct CA synthesis is necessary to deal with stress, and that when a positive stress (eustress) occurs, individuals may improve their immune function and oxidative state. Furthermore, it shows that the response to the same stressor is different according to sex.

[Touch, a crucial sense in social interactions to improve homeostasis in aging and promote healthy longevity]. / El tacto, un sentido crucial en las interacciones sociales para mejorar la homeostasis en el envejecimiento y promover una longevidad saludable.

Aging is associated with the generalized deterioration of the organism, being of great relevance experienced by homeostatic systems such as the nervous, immune, and endocrine systems, which increases the risk of morbidity and mortality. Among the lifestyle strategies that have been researched to improve these systems and achieve greater healthy longevity, this review will focus on the social environment. In order to verify the effectiveness of these both in the improvement of homeostasis and in life expectancy, the research carried out with experimental animals that have allowed this to be done will be discussed. In addition, as it has been observed that physical contact is crucial for the positive outcomes of social interaction on homeostatic systems and longevity to occur, we will focus on that mechanism, as well as some of the possible molecular pathways underlying the effects found.

Sex differences in neuroimmunoendocrine communication. Involvement on longevity.

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.

Skin-to-Skin Contact: Crucial for Improving Behavior, Immunity, and Redox State after Short Cohabitation of Chronologically Old Mice and Prematurely Aging Mice with Adult Mice.

(1) Background: Aging is characterized by a deterioration of the homeostatic systems, namely the nervous and immune systems. The rate of aging can be modified by lifestyle factors such as social interactions. Recently, improvements in behavior, immune function, and oxidative state were observed in adult prematurely aging mice (PAM) and chronologically old mice after cohabitation with exceptional non-PAM (E-NPAM) and adult mice, respectively, for 2 months. However, the cause of this positive effect is not known. The objective of the present work was to study whether skin-to-skin contact promotes these improvements both in chronologically old mice and in adult PAM. (2) Methods: Old and adult CD1 female mice were used as well as adult PAM and E-NPAM. After cohabitation for 15 min/day for 2 months (two old mice or PAM with five adult mice or E-NPAM, respectively, with both non- and skin-to-skin contact), several behavioral tests were performed and functions and oxidative stress parameters in peritoneal leukocytes were analyzed. (3) Results: This social interaction improved behavioral responses, immune functions, redox state, and longevity, but only if the animals had skin-to-skin contact. (4) Conclusions: Physical contact seems to be crucial to experiencing the positive effects of social interaction.

Daily ingestion of Akkermansia mucciniphila for one month promotes healthy aging and increases lifespan in old female mice.

The ingestion of certain probiotics has been suggested as a promising nutritional strategy to improve aging. The objective of this work was to evaluate the effects of the daily intake, for a month, of a new probiotic Akkermansia muciniphila (AKK) (2 × 108 cfu/100µL PBS) on behavior, as well as function and redox state of immune cells of old female ICR-CD1 mice (OA group). For this, several behavioral tests were performed, and function and oxidative-inflammatory stress parameters of peritoneal leukocytes were analyzed in OA group, in a group of the same age that did not take AKK (old control, OC group) and in another adult control (AC) group. The results showed, in OA group, a significant improvement of several behavioral responses (coordination, balance, neuromuscular vigor, exploratory ability and anxiety like-behaviors), as well as in immune functions (chemotaxis, phagocytosis, NK activity and lymphoproliferation) and in oxidative stress parameters (glutathione peroxidase and reductase activities, oxidized glutathione and lipid oxidation concentrations) of the peritoneal leukocytes in comparison to those observed in OC group. In addition, peritoneal immune cells from the OA group released lower basal concentrations of pro-inflammatory cytokines (IL-2, IL-6 and TNF-α) compared to those from the OC group. The values of parameters in OA were similar to those in AC group. These improvements in the old mice receiving the probiotic were reflected in an increase in their lifespan. In conclusion, our data indicate that AKK supplementation for a short period could be a good nutritional strategy to promote healthy longevity.

A short social interaction between adult and old mice improves the homeostatic systems and increases healthy longevity.

The aging process can be influenced by environmental factors, such as the social environment. The continuous cohabitation of the chronologically old mice with adult animals improves them at the behavioral level, immune function, oxidative stress and longevity, but causes a deterioration of these parameters in adults. Therefore, the objective of the study was to study whether the coexistence for only 15 min a day of old mice with adult mice, can produce that improvement and greater longevity in old animals without causing deterioration in adults. For that, old and adult CD1 female mice, after two months of that social interaction, were submitted to a behavioral battery and then peritoneal leukocytes were collected to assess several immune functions, oxidative and inflammatory stress parameters as well as catecholamine concentrations. When the adult mice reached old age, the same parameters were again analyzed. The life span of each animal was also recorded. Plasmatic concentration of oxytocin was also studied. The results showed that old mice presented better behavioral capacity, immunity and oxi-inflammatory state after this social interaction with adult animals, and consequently an extended life span. Adult mice, in general, did not show any changes after social interaction with old animals, but when they achieved old age, improvements of some parameters and of longevity were observed in comparison with animals that never had a that social interaction. In conclusion, a short social interaction between old and adult individuals can be an excellent strategy for improving in both the health state and longevity.