Abstract
Oxidative stress has been reported to increase with aging, and although several age-related changes in redox parameters have been described, none of them have been verified as markers of the ...rate of aging and life span. Therefore, antioxidant (catalase, glutathione peroxidase, 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, older adult, 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. The results reveal that the age-related alterations of these markers are similar in humans and mice, with decreased antioxidants and increased oxidants in old participants, whereas long-lived individuals show similar values to those in adults. In addition, adult prematurely aging mice showed similar values to those in chronologically old mice and had a shorter life span than nonprematurely aging mice. Thus, these parameters could be proposed as markers of the rate of aging and used to ascertain biological age in humans.
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 Martínez de Toda, Irene; Vida, Carmen; Díaz-Del Cerro, Estefanía ...
The journals of gerontology. Series A, Biological sciences and medical sciences,
11/2021, Volume:
76, Issue:
11
Journal Article
Peer reviewed
Abstract
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.
In Parkinson's Disease (PD), the peripheral changes in the functional capacity and redox state of immune cells has been scarcely investigated, especially in the early PD stages. Aging is a risk ...factor for PD, and the age-related impairment of the immune system, based on a chronic-oxidative stress situation, is involved in the rate of aging. We analyzed several functions in isolated peripheral blood neutrophils and mononuclear cells from PD stage 2 patients, and compared the results to those in healthy elderly and adult controls. Several oxidative stress and damage parameters were studied in whole blood cells. The results showed an impairment of the lymphoproliferative response in stimulated conditions in the PD patients compared with age-matched controls, who also showed typical immunosenescence in comparison with adult individuals. Higher oxidative stress and damage were observed in whole blood cells from PD patients (lower glutathione peroxidase activity, and higher oxidized glutathione and malondialdehyde contents). Our results suggest an accelerated immunosenescence in PD stage 2, and that several of the parameters studied could be appropriate peripheral biomarkers in the early stages of PD.
Carbamylation is a post-translational modification of proteins that may partake in the oxidative stress-associated cell damage, and its increment has been recently proposed as a "hallmark of aging". ...The molecular mechanisms associated with aging are related to an increased release of free radicals. We have studied whether carbamylated proteins from the peripheral blood of healthy subjects are related to oxidative damage and aging, taking into account the gender and the immune profile of the subjects. The study was performed in healthy human volunteers. The detection of protein carbamylation and malondialdehyde (MDA) levels was evaluated using commercial kits. The immune profile was calculated using parameters of immune cell function. The results show that the individuals from the elderly group (60⁻79 years old) have increased carbamylated protein and MDA levels. When considered by gender, only men between 60 and 79 years old showed significantly increased carbamylated proteins and MDA levels. When those subjects were classified by their immune profile, the carbamylated protein levels were higher in those with an older immune profile. In conclusion, the carbamylation of proteins in peripheral blood is related to age-associated oxidative damage and to an aging functional immunological signature. Our results suggest that carbamylated proteins may play an important role at the cellular level in the aging process.
Abstract
Several parameters of immune function, oxidative, and inflammatory stresses have been proposed as markers of health and predictors of longevity and mortality. However, it is unknown if any ...of these parameters can be used as predictors of survival in centenarians. Therefore, in a group of 27 centenarians, at the time of admission to the Clinical Hospital of Madrid, a series of immune function, antioxidant, oxidant, and inflammatory parameters were studied. Some centenarians survived and others did not, thus establishing two groups, “survivors” (n = 9) and “nonsurvivors” (n = 18). The results show that surviving centenarians display higher neutrophil chemotaxis and microbicidal capacity, natural killer activity, lymphoproliferation, glutathione reductase activity, and basal interleukin-10 release. Moreover, lower neutrophil and lymphocyte adherence, superoxide anion and malondialdehyde concentrations, and basal release of tumor necrosis factor α are also reported. The odds ratios for survival for these parameters were also calculated, with the highest odds ratios being the lymphoproliferative capacity and the ex vivo basal and stimulated release of interleukin-6 from mononuclear cells (odds ratio = 136.00). Therefore, these parameters have the potential to be used in the clinical setting as predictors of survival in centenarians. In the survivors group, the same parameters were also analyzed after 3 months. Because survivors showed an increase in neutrophil and lymphocyte chemotaxis capacity during the recovery period, reaching similar values to those observed in healthy centenarians, these parameters could be proposed as indicators of recovery.
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 R
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.
The decrease in the proliferative response of lymphocytes is one of the most evident among the age-related changes of the immune system. This has been linked to a higher risk of mortality in both ...humans and experimental animals. However, long-lived individuals, in spite of optimally maintaining most of the functions of the immune system, also seem to show an impaired proliferative response. Thus, it was hypothesized that these individuals may have distinct evolution times in this proliferation and a different modulatory capacity through their cytokine release profiles. An individualized longitudinal study was performed on female ICR-CD1 mice, starting at the adult age (40 weeks old), analyzing the proliferation of peritoneal leukocytes at different ages in both basal conditions and in the presence of the mitogen Concanavalin A, for 4, 24 and 48 h of culture. The cytokine secretions (IL-2, IL-17, IL-1β, IL-6, TNF-α and IL-10) in the same cultures were also studied. Long-lived mice show a high proliferative capacity after short incubation times and, despite experiencing a functional decline when they are old, are able to compensate this decrease with an appropriate modulation of the lymphoproliferative response and cytokine release. This could explain their elevated resistance to infections and high longevity.
According to the oxidative-inflammatory theory of aging, there is a link between the function, the oxidative-inflammatory stress state of immune cells, and longevity. However, it is unknown which ...immune cell parameters can predict lifespan and if there would be any changes in this prediction, depending on the age of the subject. Therefore, a longitudinal study in mice was performed analysing immune function (chemotaxis of macrophages and lymphocytes, phagocytosis of macrophages, natural killer (NK) activity, and lymphoproliferation capacity), antioxidant (catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) activities as well as reduced glutathione (GSH) concentrations), oxidant (oxidized glutathione (GSSG), superoxide anion, and malondialdehyde (MDA) concentrations), and inflammation-related markers (basal release of IL-1β, IL-6, TNF-α, and IL-10) in peritoneal leukocytes from mice at the adult, mature, old, very old, and long-lived ages (40, 56, 72, 96, and 120±4 weeks of age, respectively). The results reveal that some of the investigated parameters are determinants of longevity at the adult age (lymphoproliferative capacity, lymphocyte chemotaxis, macrophage chemotaxis and phagocytosis, GPx activity, and GSH, MDA, IL-6, TNF-α, and IL-10 concentrations), and therefore, they could be proposed as markers of the rate of aging. However, other parameters are predictive of extreme longevity only at the very old age (NK activity, CAT and GR activities, and IL-6 and IL-1β concentrations), and as such, they could reflect some of the adaptive mechanisms underlying the achievement of high longevity. Nevertheless, although preliminary, the results of the present study provide a new perspective on the use of function, redox, and inflammatory parameters in immune cells as prognostic tools in aging research and represent a novel benchmark for future work aimed at prediction of lifespan.
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.
•Males and females differ in oxidative and inflammatory stress mechanisms.•Males display a higher production of ROS and less efficient antioxidant mechanisms.•Males exhibit higher basal inflammation and a weaker response against a stimulus.•The higher oxidation and inflammation of males could explain their shorter lifespan.
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