Plasma acylcarnitines and gut-derived aromatic amino acids as sex-specific hub metabolites of the human aging metabolome.

Aging biology entails a cell/tissue deregulated metabolism that affects all levels of biological organization. Therefore, the application of "omic" techniques that are closer to phenotype, such as metabolomics, to the study of the aging process should be a turning point in the definition of cellular processes involved. The main objective of the present study was to describe the changes in plasma metabolome associated with biological aging and the role of sex in the metabolic regulation during aging. A high-throughput untargeted metabolomic analysis was applied in plasma samples to detect hub metabolites and biomarkers of aging incorporating a sex/gender perspective. A cohort of 1030 healthy human adults (45.9% females, and 54.1% males) from 50 to 98 years of age was used. Results were validated using two independent cohorts (1: n = 146, 53% females, 30-100 years old; 2: n = 68, 70% females, 19-107 years old). Metabolites related to lipid and aromatic amino acid (AAA) metabolisms arose as the main metabolic pathways affected by age, with a high influence of sex. Globally, we describe changes in bioenergetic pathways that point to a decrease in mitochondrial ß-oxidation and an accumulation of unsaturated fatty acids and acylcarnitines that could be responsible for the increment of oxidative damage and inflammation characteristic of this physiological process. Furthermore, we describe for the first time the importance of gut-derived AAA catabolites in the aging process describing novel biomarkers that could contribute to better understand this physiological process but also age-related diseases.

Accelerated immunosenescence, oxidation and inflammation lead to a higher biological age in COPD patients.

Chronic obstructive pulmonary disease (COPD) is characterised by inflammatory and oxidative alterations in the lung and extrapulmonary compartments, through involvement of the immune system. Several leukocyte functions are health markers and good predictors of longevity, and high pro-inflammatory and oxidative states are related to more aged profiles. Here, we aimed to investigate the aging rate in terms of immunosenescence in COPD men with respect to healthy age-matched controls. Several neutrophil (adherence, chemotaxis, phagocytosis, superoxide anion stimulated production) and lymphocyte (adherence, chemotaxis, lymphoproliferation, natural killer activity) functions, cytokine concentrations released in response to lipopolysaccharide (tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, IL-10) and redox parameters (intracellular glutathione content, basal superoxide anion level) were assessed in circulating leukocytes of men with moderate and severe stages of COPD, and compared to healthy age-matched volunteers. The biological age or aging rate in each participant was determined using the values of leukocyte functions. The results indicated impairment of immune functions in COPD patients, both in innate and adaptive immunity, and higher pro-inflammatory and oxidative states in peripheral leukocytes than controls. In general, these changes were more remarkable at the severe stage of airway obstruction. Importantly, COPD patients were found to be aging at a faster rate than age-matched healthy counterparts.

Immune function parameters as markers of biological age and predictors of longevity.

Chronological age is not a good indicator of how each individual ages and thus how to maintain good health. Due to the long lifespan in humans and the consequent difficulty of carrying out longitudinal studies, finding valid biomarkers of the biological age has been a challenge both for research and clinical studies. The aim was to identify and validate several immune cell function parameters as markers of biological age. Adult, mature, elderly and long-lived human volunteers were used. The chemotaxis, phagocytosis, natural killer activity and lymphoproliferation in neutrophils and lymphocytes of peripheral blood were analyzed. The same functions were measured in peritoneal immune cells from mice, at the corresponding ages (adult, mature, old and long lived) in a longitudinal study. The results showed that the evolution of these functions was similar in humans and mice, with a decrease in old subjects. However, the long-lived individuals maintained values similar to those in adults. In addition, the values of these functions in adult prematurely aging mice were similar to those in chronologically old animals, and they died before their non-prematurely aging mice counterparts. Thus, the parameters studied are good markers of the rate of aging, allowing the determination of biological age.

Human Aging Is a Metabolome-related Matter of Gender.

A molecular description of the mechanisms by which aging is produced is still very limited. Here, we have determined the plasma metabolite profile by using high-throughput metabolome profiling technologies of 150 healthy humans ranging from 30 to 100 years of age. Using a nontargeted approach, we detected 2,678 metabolite species in plasma, and the multivariate analyses separated perfectly two groups indicating a specific signature for each gender. In addition, there is a set of gender-shared metabolites, which change significantly during aging with a similar tendency. Among the identified molecules, we found vitamin D2-related compound, phosphoserine (40:5), monoacylglyceride (22:1), diacylglyceride (33:2), and resolvin D6, all of them decreasing with the aging process. Finally, we found three molecules that directly correlate with age and seven that inversely correlate with age, independently of gender. Among the identified molecules (6 of 10 according to exact mass and retention time), we found a proteolytic product (l-γ-glutamyl-l-leucine), which increased with age. On the contrary, a hydroxyl fatty acid (25-hydroxy-hexacosanoic), a polyunsaturated fatty acid (eicosapentaenoic acid), two phospholipids (phosphocholine [42:9]and phosphoserine [42:3]) and a prostaglandin (15-keto-prostaglandin F2α) decreased with aging. These results suggest that lipid species and their metabolism are closely linked to the aging process.

Function and redox state of peritoneal leukocytes as preclinical and prodromic markers in a longitudinal study of triple-transgenic mice for Alzheimer's disease.

The aging process involves the impairment of the immune system (immunosenescence), based on the imbalance of the redox status, as occurs in neurodegenerative diseases such as Alzheimer's disease (AD). Since in AD there is a systemic disorder, we aimed to assess longitudinally, from before the onset until the complete establishment of AD, cell populations, several functions, and oxidative stress parameters in peritoneal leukocytes of triple transgenic mice for AD (3xTgAD). These animals mimic the human AD pathophysiology. The results indicate a premature immunosenescence in 3xTgAD at 4 months of age, when the immunoreactivity against intracellular amyloid-ß fibrils appears. Thus, decreases in functions such as chemotaxis, phagocytosis, and lymphoproliferation, as well as a lower reduced glutathione content and higher xanthine oxidase activity, appear in leukocytes. Moreover, NK percentage and cytotoxic activity, CD25+ B and naïve CD8 T cells percentage, GSSG/GSH ratio, and GSH content were already changed before the onset of AD, at the age of 2 months. Furthermore, the changes in some parameters such as CD5+ B1 cells, phagocytosis, lymphoproliferation, and xanthine oxidase activity continue at 15 months of age, when AD pathophysiology is completely established. Because the immune system parameters studied are markers of health and longevity, the premature immunosenescence could explain the shorter life span shown by 3xTgAD observed in the present work. These results suggest that peripheral immune cell functions and their oxidative stress status could be good early peripheral markers of the preclinical and prodromal stages and progression of AD.

Lifelong treatment with atenolol decreases membrane fatty acid unsaturation and oxidative stress in heart and skeletal muscle mitochondria and improves immunity and behavior, without changing mice longevity.

The membrane fatty acid unsaturation hypothesis of aging and longevity is experimentally tested for the first time in mammals. Lifelong treatment of mice with the ß1-blocker atenolol increased the amount of the extracellular-signal-regulated kinase signaling protein and successfully decreased one of the two traits appropriately correlating with animal longevity, the membrane fatty acid unsaturation degree of cardiac and skeletal muscle mitochondria, changing their lipid profile toward that present in much more longer-lived mammals. This was mainly due to decreases in 22:6n-3 and increases in 18:1n-9 fatty acids. The atenolol treatment also lowered visceral adiposity (by 24%), decreased mitochondrial protein oxidative, glycoxidative, and lipoxidative damage in both organs, and lowered oxidative damage in heart mitochondrial DNA. Atenolol also improved various immune (chemotaxis and natural killer activities) and behavioral functions (equilibrium, motor coordination, and muscular vigor). It also totally or partially prevented the aging-related detrimental changes observed in mitochondrial membrane unsaturation, protein oxidative modifications, and immune and behavioral functions, without changing longevity. The controls reached 3.93 years of age, a substantially higher maximum longevity than the best previously described for this strain (3.0 years). Side effects of the drug could have masked a likely lowering of the endogenous aging rate induced by the decrease in membrane fatty acid unsaturation. We conclude that it is atenolol that failed to increase longevity, and likely not the decrease in membrane unsaturation induced by the drug.

Chronobiology of the neuroimmunoendocrine system and aging.

The health maintenance depends on the preservation of the homeostatic systems, such as nervous, endocrine and immune system, and a proper communication between them. In this regard, the circadian system, which promotes a better physiological system functions and thus well being, could be considered part of that homeostatic complex, since the neuroimmunoendocrine system possesses circadian patterns in most variables, as well as circannual or seasonal variations. With aging, an impairment of the homeostatic systems occurs and an alteration of circadian system regulation has been demonstrated. In the immune system, several function parameters, which are good markers of health and of the rate of aging, change not only with age (immunosenescence) but also throughout the day and year. Indeed, with advancing age there is a modification of immune cell circadian function especially in lymphocytes. Moreover, immune functions at early afternoon correspond to more aged values than at morning, especially in mature subjects (60-79 years of age). In addition, these mature men and women showed a significant impaired immune cell function, which is especially remarkable in the winter. It is noteworthy the role of immunomodulatory hormones, such as melatonin, in the regulation of biological rhythms and their involvement in the aging process. Furthermore, the evidence of a neuroimmune regulation of the circadian system and its disturbance with aging, highlights the importance of proinflammatory cytokines in this complex cross-talk. The biological rhythms disruption with age and some diseases (jet lag, cancer and seasonal affective disorder), could contribute increasing the immune system impairment and consequently the loss of health.

Inmunosenescencia prematura en ratones triple-transgénicos para la enfermedad del Alzheimer / Premature immunosenescence in triple-transgenic mice for Alzheimer's disease

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 (AU)

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 (AU)

[Premature immunosenescence in triple-transgenic mice for Alzheimer's disease]. / Inmunosenescencia prematura en ratones triple-transgénicos para la enfermedad del Alzheimer.

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 ¼ (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.

Peripheral immune system and neuroimmune communication impairment in a mouse model of Alzheimer's disease.

Neurodegenerative diseases such as Alzheimer's disease (AD) can be understood in the context of the aging of neuroimmune communication. Although the contribution to AD of the immune cells present in the brain is accepted, the role of the peripheral immune system is less well known. The present review examines the behavior and the function and redox state of peripheral immune cells in a triple-transgenic mouse model (3×Tg-AD). These animals develop both beta-amyloid plaques and neurofibrillary tangles with a temporal- and regional-specific profile that closely mimics their development in the human AD brain. We have observed age and sex-related changes in several aspects of behavior and immune cell functions, which demonstrate premature aging. Lifestyle strategies such as physical exercise and environmental enrichment can improve these aspects. We propose that the analysis of the function and redox state of peripheral immune cells can be a useful tool for measuring the progression of AD.

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.

Gender-specific neuroimmunoendocrine aging in a triple-transgenic 3xTg-AD mouse model for Alzheimer's disease and its relation with longevity.

In the present work, we briefly review the evidence on the key role played by the neuroimmunoendocrine network in the etiopathogenesis of Alzheimer's disease (AD) and provide new behavioral, immune and endocrinological data obtained on old male and female triple-transgenic 3xTg-AD mice harboring PS1(M146V), APP(Swe) and tau(P301L) transgenes in contrast to wild-type animals. The results indicate that several aspects of the impairment of the neuroimmunoendocrine network that occurs with aging are more evident in the 3xTg-AD mice, especially in males. This supports the hypothesis of a premature immunosenescence as a pathogenically relevant factor in AD which was found to be enhanced in the 3xTg-AD males, suggesting that this could also be responsible for the increased morbidity and mortality of these subjects. Therefore, future research on strategies that could improve the immune system and the other regulatory systems, such as the nervous and the endocrine system, as well as their communication, could have preventive and/or therapeutical effects on that disease. The results also show the relevance of gender differences that should be taken into consideration in both basic and clinical research for assessing new strategies for the control of AD.

Neutrophils of centenarians show function levels similar to those of young adults.

OBJECTIVES: To analyze several functions and antioxidant parameters of peripheral blood neutrophils from healthy centenarians (men and women) and compare them with those of healthy young (aged 25-35) and middle-aged (aged 65-75) men and women. DESIGN: Cross-sectional study. SETTING: Community-based. PARTICIPANTS: Twenty-one healthy centenarians (8 men), 30 young adults (15 men), and 30 middle-aged adults (15 men). MEASUREMENTS: Several neutrophil functions (adherence, chemotaxis, phagocytosis, and stimulated and nonstimulated intracellular superoxide anion levels) and antioxidant parameters (glutathione levels and catalase activity) were measured in peripheral blood neutrophil suspension in the three study groups. RESULTS: Neutrophil functions of the middle-aged group were worse than those of young adults and centenarians (lower chemotaxis and phagocytosis and higher adherence and superoxide anion levels). The neutrophil functions of the centenarians were closer to those of the young adults. Age-related differences in neutrophil functions were fundamentally similar in men and women, except for intracellular superoxide anion levels, which were lower in young adult women than in young adult men. With normal aging, total glutathione levels decrease, but the centenarians in this study showed levels similar to those of young adults. Centenarians showed the highest catalase activity of the three groups. CONCLUSION: Progressive impairment of the immune system accompanies aging. The better preservation of function and antioxidant systems in the neutrophils of centenarians could play a key role in the longevity of these subjects.

[Smoking habit: physiopathology and prevention]. / Tabaquismo: fisiopatología y prevención.

Smoking has a history almost as old as the own leaf of the tobacco, although in fact the act to smoke was restored in the general society after the discovery of America, considering itself even beneficial for the health, but fundamentally like a social and conventional conduct of the high nobility. In XVI century the first detractors began to appear but it was necessary many years to arrive the XX century when it was begun to relate the habit to tobacco and cancer, some years after the commercialization at industrial level of this habit. At the present the social awareness is tried towards the sanitary prevention. The declaration of Warsaw, the Marco Agreement and other sanitary measures forehead the habit to tobacco, are clear examples of this medical-social restlessness that tries to exile the smoking as a social, conventional and good seen conduct to try a prevention and a greater quality of life of the individuals.