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.

Positive effects of pulsed electromagnetic fields on behavior, immune function, and oxidative and inflammatory state in old mice.

The establishment of chronic oxidative and inflammatory stress with aging leads to the deterioration of the nervous and immune systems and, consequently, to the loss of health. The aim of this work was to study the effect of exposure to low-frequency pulsed electromagnetic fields (PEMFs) produced by the NEURALTER® system (15 min/day for 4 weeks) in the behavior, immune functions, and oxidative and inflammatory state of old mice. Female old CD1 mice were divided into three groups: control group, handling control group and Neuralter group. Then, behavioral tests were performed, and peritoneal leukocytes were extracted to analyze function, oxidative and inflammatory parameters. In peritoneal leukocytes from old mice, the effects in vitro of 15 min with NEURALTER® were studied on function and oxidative parameters. The results show that after this type of treatment, old mice had greater coordination and locomotion, better immune function, and an oxidative-inflammatory state. Similarly, the immune function and oxidative state of leukocytes showed an improvement when these cells were exposed directly to the NEURALTER® system. In conclusion, the exposure to low-frequency PEMFs produced by the NEURALTER® system has beneficial effects on health in aging. In addition, this effect is direct, at least in part, on immune cells.

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)

[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 markers of oxidation and inflammation. Implications for ageing.

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.

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.

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.

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.

The Role of Immune Cells in Oxi-Inflamm-Aging.

Aging is the result of the deterioration of the homeostatic systems (nervous, endocrine, and immune systems), which preserve the organism's health. We propose that the age-related impairment of these systems is due to the establishment of a chronic oxidative stress situation that leads to low-grade chronic inflammation throughout the immune system's activity. It is known that the immune system weakens with age, which increases morbidity and mortality. In this context, we describe how the function of immune cells can be used as an indicator of the rate of aging of an individual. In addition to this passive role as a marker, we describe how the immune system can work as a driver of aging by amplifying the oxidative-inflammatory stress associated with aging (oxi-inflamm-aging) and inducing senescence in far tissue cells. Further supporting our theory, we discuss how certain lifestyle conditions (such as social environment, nutrition, or exercise) can have an impact on longevity by affecting the oxidative and inflammatory state of immune cells, regulating immunosenescence and its contribution to oxi-inflamm-aging.

The Immunity Clock.

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.

Vitamin C and vitamin C plus E improve the immune function in the elderly.

With aging the immune response is impaired. This immunosenescence, in which an alteration of the redox state of the immune cells appears, is involved in the rate of aging. Since leukocyte function is a good marker of health and predictor of longevity, the effects of daily oral administration of the antioxidant vitamin C (500 mg), or both vitamin C (500 mg) and vitamin E (200 mg) on several blood neutrophil (adherence, chemotaxis, phagocytosis, and superoxide anion levels) and lymphocyte (adherence, chemotaxis, proliferation, interleukin-2 secretion and natural killer activity) functions were studied in healthy elderly men and women. These parameters were analysed before supplementation, after 3 months of supplementation, and 6 months after the end of supplementation. The results showed that vitamin C, in elderly participants, improved the immune functions studied which achieved values close to those of young adults. These effects were maintained in several functions after 6 months without supplementation. Similar effects were found in the elderly supplemented with both vitamin C and E. Thus, a short period of vitamin C or vitamin C and E ingestion, with the doses used, improves the immune function in elderly men and women and could contribute to a healthy longevity.