Immunosenescence: the role of age in multiple sclerosis.

INTRODUCTION: The number of elderly people with multiple sclerosis (MS) has increased in line with population ageing. As the immune system presents profound changes over an individual's lifetime, it is important to understand the differences between these patients and younger patients. DEVELOPMENT: Immunosenescence, defined as age-related alterations naturally occurring in the immune system, particularly influences tolerance, response, and adverse effects of disease-modifying treatments for MS. Thymic involution is the most noteworthy characteristic of this phenomenon. This process leads to a reduction in the number of virgin T cells. Other effects include an inverted CD4+/CD8+ cell ratio, severe alterations in NK cell functioning, and reduced tissue repair capacity in the brain. CONCLUSIONS: The number of older people with MS is increasing due to population ageing, advances in disease-modifying treatments, and improved health and social care of these patients. Ageing of the immune system increases the risk of infections, tumours, and autoimmune diseases in elderly individuals. Furthermore, neurodegeneration is accelerated in patients with MS due to the nervous system's loss of remyelination capacity. Understanding of the changes affecting the immune system in the elderly population is essential to improving the care provided to this ever-growing patient group.

[Improved immunity and mean lifespan in mature mice genetically deficient in catecholamine synthesis after living with wild type for two months]. / Mejoría de la inmunidad y la esperanza de vida en ratones maduros, genéticamente deficientes en la síntesis de catecolaminas, tras convivir con controles durante dos meses.

INTRODUCTION: Mice hemizygous in tyrosine hydroxylase (TH-HZ), the limiting enzyme in catecholamine synthesis, show premature immunosenescence, which in females is associated with a shorter lifespan than the corresponding controls (WT). The coexistence of TH-Hz with WT improves the immune function in both males and females in adulthood. OBJECTIVE: To test whether cohabitation for two months of mature male TH-HZ with WT improves the immune function of the former and whether this impacts the lifespan. MATERIAL AND METHODS: Mature male ICR-CD1 mice (13 ± 1 months) TH-HZ coexisted with WT (2:4 ratio in each cage) for two months. Peritoneal leukocytes were extracted from all animals at baseline, one month, and two months after cohabitation, and macrophage phagocytic capacity, macrophage and lymphocyte chemotaxis, natural killer (NK) antitumor activity, and lymphoproliferative capacity in response to the mitogens concanavalin A and lipopolysaccharide (LPS) were assessed. The animals were maintained under these conditions until their natural death. RESULTS: The TH-HZ, which start, in general, with lower values than the WT in the immune functions studied, improved them after two months of cohabitation, becoming similar to those of the controls. This improvement was already observed in NK activity after one month of cohabitation. The TH-HZ presented lower mean longevity than WT, but when they cohabited with WT, it was similar to the latter. CONCLUSION: The coexistence of TH-HZ male mice with WT mice for two months at mature age improves these genetically modified animals' immune response and longevity.

Expert consensus recommendations for the management of asthma in older adults. / Documento de consenso de expertos para el control del asma en personas mayores.

Asthma is a public health problem in patients of any age, although there is still a tendency to erroneously assume that it is almost always confined to children and young people. Epidemiological studies indicate that, from the sixth decade of life, the prevalence of this disease in countries such as Spain reaches 6-10%, with a higher prevalence among women aged 64 to 75 years. In addition, two-thirds of asthma deaths occur at this stage of life, resulting in a substantial number of hospital admissions, longer hospital stays and, from a finance point of view, significant direct economic costs. Asthma in older adults (65 years or older) is now a matter of great concern, the reality of which is underestimated and undertreated. It is therefore essential to establish appropriate recommendations for the diagnosis and treatment of asthma in the aging population. This consensus, which brings together the latest evidence available, was conceived with this objective. The proposed recommendations/conclusions are the result of a nominal consensus developed throughout 2019 and validated by panellists in successive rounds of voting.

Immunosenescence: the role of age in multiple sclerosis. / Inmunosenescencia: el rol de la edad en la esclerosis múltiple.

INTRODUCTION: The number of elderly people with multiple sclerosis (MS) has increased in line with population ageing. As the immune system presents profound changes over an individual's lifetime, it is important to understand the differences between these patients and younger patients. DEVELOPMENT: Immunosenescence, defined as age-related alterations naturally occurring in the immune system, particularly influences tolerance, response, and adverse effects of disease-modifying treatments for MS. Thymic involution is the most noteworthy characteristic of this phenomenon. This process leads to a reduction in the number of virgin T cells. Other effects include an inverted CD4 + /CD8 + cell ratio, severe alterations in NK cell functioning, and reduced tissue repair capacity in the brain. CONCLUSIONS: The number of older people with MS is increasing due to population ageing, advances in disease-modifying treatments, and improved health and social care of these patients. Ageing of the immune system increases the risk of infections, tumours, and autoimmune diseases in elderly individuals. Furthermore, neurodegeneration is accelerated in patients with MS due to the nervous system's loss of remyelination capacity. Understanding of the changes affecting the immune system in the elderly population is essential to improving the care provided to this ever-growing patient group.

The elderly traveller. / El viajero mayor.

Improved living conditions and advances in medicine have extended life expectancy and quality of life, resulting in an increasing number of elderly travellers. Pathophysiological changes and treatments can reduce the efficacy of vaccines and facilitate drug interactions. Elderly travellers have various characteristics that should be considered when offering pre-trip counselling, which should include proper management of chronic diseases that are susceptible to worsening during the trip, as well as an appropriate study and follow-up after the trip. We performed a narrative review of the main problems of elderly travellers.

[Seasonal flu vaccination for older people: Evaluation of the quadrivalent vaccine. Positioning report]. / Vacunación frente a la gripe estacional en las personas mayores. Evaluación de la vacuna tetravalente. Informe de posicionamiento.

Influenza is a significant health problem, particularly in those persons susceptible to having associated complications, older people, children less than 2 years, patients with chronic diseases, immunocompromised patients, and pregnant women. But influenza also has a large impact on the health system, with an increase in the healthcare demand and a spectacular increase in outpatient visits, overloading the emergency and hospital services. During epidemic outbreaks, the hospital admission rates of people over 65 years are at a maximum, and the mortality notified for the 2017/2018 influenza season was 960 deaths. The seasonal anti-influenza vaccine is the method with a better cost-effective ratio of primary prevention of influenza, reducing associated respiratory diseases, the number of hospital admissions, and deaths in high risk individuals, as well as work absenteeism in adults. In the last few years, influenza B has received little attention in the scientific literature, although in the periods between epidemics influenza B can be one of the main causes of seasonal epidemics, causing considerable morbidity and mortality and an increase in costs. The quadrivalent vaccine has a second-line immunological protection against influenza B, and according to a critical review of the scientific literature, it provides wider protection without affecting immunogenicity of the other three vaccine strains common to the trivalent and tetravalent vaccine. The quadrivalent vaccine is cost-effective in reducing the number of influenza cases, and is always a worthwhile intervention, with a significant cost saving for the health system and for society, by reducing the hospital admission rates and mortality associated with the complications of influenza. Supplement information: This article is part of a supplement entitled 'Seasonal flu vaccination for older people: Evaluation of the quadrivalent vaccine' which is sponsored by Sanofi-Aventis, S.A.

[Seasonal flu vaccination for older people: Evaluation of the adjuvanted vaccine. Positioning report]. / Vacunación frente a la gripe estacional en las personas mayores. Evaluación de la vacuna adyuvada: Informe de posicionamiento.

Flu is a major public health problem, particularly for older people, and creates an important clinical and economic burden. A high mortality rate was reported in Spain during the period 2015 to 2016; 3,101 serious cases were hospitalised with a confirmed diagnosis of flu, of which 11% died (352 cases). Furthermore, financial and health costs are greatly increased by the complications of flu; people aged over 65 years represent approximately 64% of the total costs. Seasonal flu vaccination is the fundamental strategy, as demonstrated by cost-benefit and cost-effectiveness studies. A priority objective is to improve the vaccine's immune response and the search for and inclusion of adjuvants and immunostimulants in vaccines is a major line of research. This positioning report evaluates vaccination for older people and the importance of the adjuvanted vaccine in the elderly in strengthening immunogenicity, by means of a critical review of the literature based on the best evidence available on its immunogenicity and effectiveness, and an economic assessment.

[Premature immunosenescence in catecholamines syntesis deficient mice. Effect of social environment]. / Inmunosenescencia prematura en ratones con una deficiencia en la síntesis de catecolaminas. Efecto del ambiente social.

INTRODUCTION: Healthy state depends on the appropriate function of the homeostatic systems (nervous, endocrine and immune systems) and the correct communication between them. The functional and redox state of the immune system is an excellent marker of health, and animals with premature immunosenescence show a shorter lifespan. Since catecholamines modulate the function of immune cells, the alteration in their synthesis could provoke immunosenescence. The social environment could be a strategy for modulating this immunosenescence. AIM: To determine if an haploinsufficiency of tyrosine hydroxylase (TH), the limiting enzyme of synthesis of catecholamines, may produce a premature immunosenescence and if this immunosenescence could be modulated by the social environment. MATERIALS AND METHODS: Adult (9±1 months) male ICR-CD1 mice with deletion of a single allele (hemi-zygotic: HZ) of the tyrosine hydroxylase enzyme (TH-HZ) and wild-type (WT) mice were used. Animals were housed in four subgroups: WT>50% (in the cage, the proportion of WT mice was higher than 50% in relation to TH-HZ), WT<50%, TH-HZ<50% and TH-HZ>50%. Peritoneal leukocytes were collected and phagocytosis, chemotaxis and proliferation of lymphocytes in the presence of lipopolysaccharide were analyzed. Glutathione reductase and glutathione peroxidase activities as well as oxidized/reduced glutathione ratio were studied. RESULTS: TH-HZ>50% mice showed a deteriorated function and redox state in leukocytes respect to WT>50% and similar to old mice. However, TH-HZ<50% animals had similar values to those found in WT<50% mice. CONCLUSION: The haploinsufficiency of TH generates premature immunosenescence, which appears to be compensated by living together with an appropriate number of WT animals.

Reduced naïve T cell numbers correlate with increased low-grade systemic inflammation during ageing and can be modulated by physical activity / Un número reducido de células T vírgenes se correlaciona con un aumento de la inflamación sistémica de bajo grado durante el envejecimiento y puede ser modulado por la actividad física

SUMMARY: Age-associated decline of immune system, termed immunosenescence, is characterized by low-grade systemic inflammation, known as inflammaging, together with T-cell functional dysregulation. Although affecting all individuals, different environmental as well genetic factors impinge on the individual´s susceptibility or resilience to immunosenescence. Physical activity has been shown to improve autonomy and functionality in older adults. However, if physical activity affects immunosenescence or inflammaging remains unknown. The purpose of this study was to analyze immunosenescence and inflammaging in elderly individuals by measuring peripheral naïve T cells and interleukin (IL) -6 from peripheral blood and evaluate the impact of physical activity on T cell dysregulation and inflammaging. Thirty (30) elderly volunteers (10 males and 20 females), and 7 young controls (2 males ad 7 females), were recruited for this study. A methodology questionnaire was used to evaluate different parameters such as physical activity, and peripheral naïve CD4+ and CD8+ T cells and serum IL-6 were measured by FACS and ELISA respectively. Our results shown that naïve T cells decline, and IL-6 levels increase as older people age. Interestingly, we observed strong negative correlation between naïve T cells numbers and IL-6 levels in older adults, suggesting a direct link between reduced naïve T cell pool and increased inflammaging. Continuous physical activity during youth did not affect immunosenescence and inflammaging in elderly, but physical activity during elderly increase naïve T cell numbers and reduce inflammaging in older subjects. Our results showed reduced number of naïve T cells and increased levels of IL-6 as elder people get older. Moreover, the strong negative correlation between these parameters suggest that naïve T cells can have a direct suppressive activity over innate immune components. Furthermore, physical activity during elderly can reduce immunosenescence and inflammaging in older subjects.

RESUMEN: El deterioro del sistema inmunológico asociado con la edad, denominado inmunosenescencia, se caracteriza por una inflamación sistémica de bajo grado, conocida como inflamaging, junto con una desregulación funcional de las células T. Aunque afectan a todos los individuos, diferentes factores ambientales y genéticos inciden en la susceptibilidad o resiliencia del individuo a la inmunosenescencia. Estudios anteriores han demostrado que la actividad física mejora la autonomía y la funcionalidad en los adultos mayores, aunque como la actividad física impacta a la inmunosenescencia e inflammaging es aún desconocido. El propósito de este estudio fue analizar la inmunosenescencia e inflammaging en personas de edad avanzada, midiendo las células T vírgenes y la interleucina (IL)-6 de sangre periférica, junto con evaluar el impacto de la actividad física sobre la inflamación basal y la inmunosenescencia. Treinta voluntarios ancianos (10 hombres y 20 mujeres) y 7 controles jóvenes (2 hombres y 5 mujeres) fueron incluidos en este estudio. Para medir actividad física, autonomía y dependencia se utilizó un cuestionario de metodología, junto con evaluar el número de células T CD4+ y CD8+ periféricas vírgenes e IL-6 sérica mediante FACS y ELISA, respectivamente. Nuestros resultados muestran que las células T vírgenes disminuyen y los niveles de IL-6 aumentan a medida que las personas mayores envejecen. Curiosamente, observamos una fuerte correlación negativa entre el número de células T vírgenes y los niveles de IL-6 en adultos mayores, lo que sugiere un vínculo directo entre la reducción de la reserva de células T vírgenes y el aumento de la inflamación. La actividad física durante la juventud no afectó la inmunosenescencia ni la inflamación en los ancianos, pero la actividad física durante la vejez aumenta el número de células T vírgenes y reduce la inflamación en los adultos mayores. Estos resultados sugieren que inmunosenescencia e inflammaging parecen estar directamente conectados, además de concluir que el desarrollo de actividad física durante la vejez reduce la inmunosenescencia y la inflamación basal en adultos mayores.

Envejecimiento inflamatorio e inmunosenescencia, la posible respuesta a la severidad de la COVID-19 en los adultos mayores. Revisión Narrativa / Inflammaging and immunosenescence, the possible response to the severity of COVID-19 in older people. Narrative Review

La infección por SARS-CoV-2 varía ampliamente con la edad, siendo generalmente más severa en los adultos mayores. En muchos de estos pacientes, puede desencadenarse un síndrome de tormenta de citocinas, caracterizado por una elevación sistémica de varias citocinas proinflamatorias, lo que podría inducir un síndrome de dificultad respiratoria aguda (SDRA), neumonía, insuficiencia orgánica múltiple y finalmente la muerte. Durante el envejecimiento, el sistema inmunitario puede experimentar una disminución gradual de su función llamada "inmunosenescencia", lo cual dificulta el reconocimiento, la señalización y la eliminación de amenazas. También se ha descrito un leve aumento crónico de la inflamación sistémica denominada "envejecimiento inflamatorio", fenómeno implicado en trastornos como diabetes mellitus, Alzheimer y aterosclerosis. Una gran cantidad de datos recientes que describen la patología y los cambios moleculares en pacientes con COVID-19 apuntan a la inmunosenescencia y al envejecimiento inflamatorio como los principales impulsores de las altas tasas de mortalidad en los pacientes mayores. El objetivo de esta revisión es analizar los datos experimentales y las observaciones clínicas que vinculan el envejecimiento inflamatorio y la inmunosenescencia con la fisiopatología de la COVID-19 en adultos mayores con infección grave

SARS-CoV-2 infection varies widely with age, generally being more severe in older adults. In many of these patients, a cytokine storm syndrome can be triggered, characterized by a systemic elevation of several pro-inflammatory cytokines, which could induce acute respiratory distress syndrome (ARDS), pneumonia, as well as multiple organ failure and ultimately death. During aging, the immune system can experience a gradual decline in immune function called immunosenescence, which makes it difficult to recognize, signal, and eliminate threats. A slight chronic increase in systemic inflammation called inflammatory aging, a phenomenon implicated in disorders such as diabetes mellitus, Alzheimer's and atherosclerosis, has also been described. A large body of recent data describing pathology and molecular changes in COVID- 19 patients points to immunosenescence and inflammatory aging as the main drivers of high death rates in older patients. The objective of this review is to summarize the experimental data and clinical observations that link inflammaging and immunosenescence with the pathophysiology of COVID-19 in severely infected older people

[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.

Manipulación de la inmunosenescencia / Immunosenescence manipulation

En la actualidad existe un aumento del envejecimiento poblacional en Cuba y a nivel mundial, consecuencia del éxito de las políticas de salud pública y del desarrollo socioeconómico. Con el incremento progresivo de la edad se evidencian cambios en el sistema inmunológico que contribuyen a una susceptibilidad incrementada a las enfermedades infecciosas, condiciones patológicas relacionadas con la inflamación, enfermedades autoinmunes, el cáncer y se manifiesta una respuesta reducida ante la vacunación. La manipulación de la inmunosenescencia a través de diferentes terapéuticas se espera que contribuya al rejuvenecimiento del sistema inmune y por consiguiente a la restauración de la inmunidad en individuos inmunocomprometidos, al control del cáncer y al incremento de la eficacia de la vacunación en ancianos(AU)

There is an increase of population aging in Cuba and globally, as a result of the success of public health policies and socio-economic development. With the progressive increase in age, there are changes in the immune system that contribute to an increased susceptibility to infectious diseases, pathological conditions related to inflammation, autoimmune diseases, cancer and a reduced response to vaccination. The manipulation of immunosenescence through different therapies has been studied. It is expected to possibly contribute to the 'rejuvenation' of the immune system and consequently, to the restoration of immunity in immunocompromised individuals, the improvement of the effectiveness of vaccination in the elderly and the control of cancer(AU)

[Impact of thymic function in age-related immune deterioration]. / Impacto de la función tímica en el deterioro inmunológico asociado a la edad.

Age-related biological deterioration also includes immune system deterioration and, in consequence, a rise in the incidence and prevalence of infections and cancers, as well as low responses to vaccination strategies. Out of all immune cell subsets, T-lymphocytes seem to be involved in most of the age-related defects. Since T-lymphocytes mature during their passage through the thymus, and the thymus shows an age-related process of atrophy, thymic regression has been proposed as the triggering event of this immune deterioration in elderly people. Historically, it has been accepted that the young thymus sets the T-lymphocyte repertoire during the childhood, whereupon atrophy begins until the elderly thymus is a non-functional evolutionary trace. However, a rising body of knowledge points toward the thymus functioning during adulthood. In the elderly, higher thymic function is associated with a younger immune system, while thymic function failure is associated with all-cause mortality. Therefore, any new strategy focused on the improvement of the elderly quality of life, especially those trying to influence the immune system, should take into account, together with peripheral homeostasis, thymus function as a key element in slowing down age-related decline.

Inmunosenescencia / Immunosenescence

Resumen La inmunosenescencia se refiere a los cambios que se producen en el sistema inmunitario a causa del envejecimiento y que afectan la inmunidad innata y adaptativa. Estos cambios predisponen a padecer enfermedades infecciosas, cáncer, autoinmunidad y a respuestas escasas tras la administración de vacunas.

Abstract Immunosenescence refers to age-related changes in the immune system affecting both innate and adaptive immune response. These changes increase the susceptibility to infectious diseases, cancer and decreased vaccine efficacy.

Inmunosenescencia: efectos de la edad sobre el sistema inmune / Immunosenescence: effects of aging process on immune system

El proceso de envejecimiento provoca cambios en el sistema inmune que afectan su funcionamiento y desarrollo. Estos cambios pueden manifestarse desde la linfopoyesis hasta la respuesta que orquesta el sistema inmune frente a determinada enfermedad o agente infeccioso. Ambas ramas de la inmunidad, innata y adaptativa, se afectan en este proceso, lo que genera un impacto negativo en la respuesta inmune de los ancianos y los predispone a padecer enfermedades infecciosas, cáncer, autoinmunidad y a desarrollar respuestas pobres tras la administración de vacunas...

The aging process produces functional and developmental changes in the immune system. Those changes may appear from lymphopoiesis up to the final response of the immune system facing a certain disease. Both branches of immunity, innate and adaptive, are affected by the aging process; hence these changes can have a negative impact on the immune response of elderly patients and increase their susceptibility to infectious diseases, cancer and decreased vaccine efficacy...

Aspectos inmunlóógicos del envejecimiento

La inmunosenescencia es un proceso complejo que involucra múltiples cambios en las poblaciones linfocitarias. Estos cambios en el adulto mayor incrementan la incidencia y severidad de las enfermedades infecciosas y algunos cánceres. En este artículo revisamos algunos de los cambios inmunológicos más relevantes que han sido descritos durante el envejecimiento y su asociación con algunas patologías.

Immunosenescence is a complex process involving multiple changes in lymphocyte subsets. In the elderly, these changes contribute to an increased incidence and severity of infectious diseases and some types of cancer. This paper reviews some of the immunological changes in the elderly and their association with certain diseases.