Activation-induced cytidine deaminase (AID) involved in the regulation of B cell immune senescence / 细胞与分子免疫学杂志

The humoral immune response of B cells is the key to the protection of specific immunity, and immune aging reshapes its production and function. The decreased B cell immune function is an indicator of immune senescence. The impaired humoral immune function mediated by antibody secreted by B cells leads to a decline in the response of elderly individuals to the vaccine. These people are therefore more susceptible to infection and deterioration, and have a higher incidence of tumors and metabolic diseases. Activation-induced cytidine deaminase (AID) is an enzyme that triggers immunoglobulin class conversion recombination (CSR) and somatic high frequency mutation (SHM). It decreases during immune senescence and is considered to be a biomarker of decreased B cell function in aging mice and humans. Understanding the inherent defects of B-cell immune senescence and the regulation mechanism of AID in the aging process can provide new research ideas for the susceptibility, prevention and treatment of diseases in the elderly.

Single-nucleus profiling unveils a geroprotective role of the FOXO3 in primate skeletal muscle aging

Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia, and increases the risk of many aging-related metabolic diseases. Here, we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging. A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types, indicating a higher susceptibility of skeletal muscle fiber to aging. We found a downregulation of FOXO3 in aged primate skeletal muscle, and identified FOXO3 as a hub transcription factor maintaining skeletal muscle homeostasis. Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model, we revealed that silence of FOXO3 accelerates human myotube senescence, whereas genetic activation of endogenous FOXO3 alleviates human myotube aging. Altogether, based on a combination of monkey skeletal muscle and human myotube aging research models, we unraveled the pivotal role of the FOXO3 in safeguarding primate skeletal muscle from aging, providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-related disorders.

Single-cell transcriptomic atlas of mouse cochlear aging

Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.

Avaliação dos efeitos modulatórios da hematopoese no envelhecimento: Papel das células tronco mesenquimais medulares / Evaluation of the modulatory effects of hematopoiesis during aging: Role of bone marrow mesenchymal stem cells

O envelhecimento é um processo fisiológico que traz consigo uma série de alterações no organismo que se estendem até o nível molecular. Diante disto, este é um processo complexo que afeta diversos tecidos, sendo um deles o hematopoético, local onde, através de interações da Célula Tronco Hematopoética (CTH) com o ambiente ao seu redor, incluindo a Célula Tronco Mesenquimal (CTM), ocorre a hematopoese. Embora já sejam descritas na literatura algumas alterações na medula óssea consequentes do envelhecimento, os mecanismos por trás de tais mudanças permanecem elusivas, principalmente no âmbito das interações celulares ocorrentes na medula óssea. Portanto, este trabalho buscou investigar como o envelhecimento afeta a regulação hematopoética no contexto de sua relação com as CTM medulares. Para esta pesquisa, foram utilizados camundongos machos isogênicos da linhagem C57BL/6, dividindoos em grupos conforme sua idade: jovens (3 ­ 5 meses) e idosos (18 ­ 19 meses). Foi realizada a caracterização do modelo através de aspectos físicos como consumo proteico, variação de peso, entre outros, seguido de avaliação bioquímica e hematológica. Adicionalmente, foram coletadas células medulares e, posteriormente, realizado o isolamento das CTMs. Para estudar a relação destas células com a hematopoese, foram realizados ensaios in vitro utilizando a linhagem celular leucêmica C1498 (TIB-49™, ATCC®) mantidas em contato com o sobrenadante das CTMs isoladas. Quanto aos parâmetros bioquímicos, os animais idosos apresentaram menores níveis de albumina, aspartato alanina transferase (ALT) e de triglicerídeos quando comparados aos animais jovens. Contrariamente, os animais idosos apresentaram um maior nível de colesterol. Na avaliação hematológica, foi constatado pelo hemograma que os animais idosos apresentaram valores comparáveis aos animais jovens, todavia, o mielograma mostrou menor celularidade geral, seguido de menor número de células da linhagem eritroide e maior número de precursores granulocíticos. Através da imunofenotipagem, foi revelado um maior número de CTHs e de precursores grânulosmonocíticos na medula de animais idosos quando comparado aos jovens, e uma menor frequência de progenitores linfoides. Na imunofenotipagem de sangue periférico de animais idosos houve uma redução no número de linfócitos B e de eritrócitos, e aumento na população de células natural killers. Na imunofenotipagem de CTMs, o marcador CD73 apresentou menor expressão nos animais idosos. Avaliando o secretoma destas células estromais, foram encontrados no sobrenadante de CTMs de animais idosos aumentos significativos nas concentrações de CXCL12 e SCF e redução de IL-11. No âmbito molecular, as CTMs de animais idosos apresentaram aumento na expressão de Akt1, Nos e Ppar-γ, e redução na expressão de Csf3 e Cdh2. Adicionalmente, quando comparado a ação das CTMs de animais idosos em relação as CTMs de animais jovens, observou-se que CTMs de animais idosos foram capazes de aumentar a expressão de Sox2, Pou5f1 e Nanog e diminuir a expressão de Cdkn1a de células da linhagem C1498. O sobrenadante de CTMs de animais idosos também resultou na maior proliferação e migração de células da linhagem C1498. Portanto, levando em consideração a importância das CTMs sobre a regulação do sistema hematopoético, pode-se concluir que, no envelhecimento, as CTMs criam um ambiente propício para a proliferação celular no qual a manutenção da pluripotência é estimulada, o que pode acarretar em uma desregulação do sítio hematopoético quando habitado por células malignas

Aging is a physiological process in which occurs a series of alterations in an organism that extend to a molecular level. It is a complex process that affects various tissues, one of them being the bone marrow, wherethrough the interactions of the hematopoietic stem cell (CTH) with its surrounding environment, including with the mesenchymal stem cell (CTM), hematopoiesis takes place. Although some aging-associated alterations in the bone marrow can be found described in the literature, the mechanisms behind said changes remain elusive, especially when regarding the cellular interactions present inside the bone marrow. Therefore, this research aimed to investigate how aging affects the regulation of hematopoiesis in the context of its interactions with bone marrow-derived CTMs. For this investigation, male isogenic C57BL/6 mice were used as animal models. These were separated in two groups according to their age: young (3 ­ 5 months) and aged (18 ­ 19 months). The animal models were characterized by their physical properties such as protein intake and weight variation, followed by biochemical and hematological evaluation. Bone marrow cells were obtained and identified through immunophenotyping, thus isolating different cell populations, including the CTMs. To study the relationship between these cells and hematopoiesis, in vitro assays were conducted utilizing the leukemic cell lineage C1498 (TIB-49™, ATCC®) maintained in contact with the supernatant of isolated CTMs. By their biochemical profile, aged mice showed lower levels of albumin, alanine-aspartate transferase (ALT) and triglycerides compared to the young group. In contrast, aged mice had a higher cholesterol level. Hematological evaluation by total blood count showed similar results between the two groups, however, the myelogram revealed that the aged animals had lower cellularity, with less frequent cells from the erythroid lineage, with an increase in granulocytic precursors. Through immunophenotyping, it was also revealed that aged mice have higher numbers of hematopoietic stem cells, while also being noted a reduced population of lymphoid progenitors. An increase in the granulomonocytic progenitors was also found. Immunophenotyping peripheral blood cells of aged mice revealed reduced numbers of B lymphocytes and erythrocytes, and an increased natural killer cell population. Additionally, the cell surface marker CD73 was found to be less expressed in aged mice CTMs. The secretome of these stromal cells obtained from aged mice showed higher levels of CXCL12 and SCF, and lower levels of IL-11when compared to the young counterparts. At a molecular level, CTMs obtained from aged mice expressed more Akt1, Nos and Ppar-γ, while the expression of Csf3 and Cdh2 was reduced. Additionally, when comparing the effects of aged mice CTMs with young mice CTMs, it was observed that the first expressed were capable of increasing the expression of Sox2, Pou5f1 and Nanog, while decreasing Cdkn1a expression in the C1498 cell lineage. The supernatant obtained from aged mice also favored the proliferation and cell migration of the C1498 cell line. Thus, considering the importance that CTMs have over the hematopoietic system, we can conclude that, in aging, CTMs create a special environment which favors cell proliferation and maintenance of pluripotency, which can result in a dysregulation of the hematopoietic tissue when malignant cells are present

Estudo do composto STX140, um análogo do estradiol, em linhagens de melanoma humano / STX140 compound study in human melanoma

O câncer de pele pode ser classificado como não melanoma e melanoma. O melanoma apresenta baixa incidência entre os cânceres de pele, porém é a forma mais letal e é considerado um dos tipos mais resistentes ao tratamento. Devido à infiltração de células malignas nos tecidos, vasos linfáticos e vasos sanguíneos, o melanoma invade e se espalha rapidamente. Suas metástases são frequentemente localizadas em linfonodos, cérebro, fígado e outros órgãos. Melanomas metastáticos abrigam múltiplas mutações gênicas e muitos tumores apresentam resistência aos tratamentos, como por exemplo com inibidores BRAF, devido à mutações e ativação de vias paralelas. Ou seja, existe uma necessidade clara da busca de novas opções de tratamento. Em trabalho realizado por nosso grupo, Massaro et al mostraram que o derivado de estradiol 2- Metoxiestradiol induz apoptose em células de melanoma e senescência. Neste sentido, o composto STX140, (um análogo do estradiol com biodisponibilidade superior), que já se mostrou eficaz no combate ao câncer de mama em diversos estudos in vitro e in vivo, será então avaliado para sua ação no melanoma de forma inédita. Este trabalho teve como principal objetivo explorar a ação antitumoral em células de melanoma do composto STX140, especialmente a indução de senescência. Utilizando a cultura de células de melanoma foram realizados os ensaios de: viabilidade celular - IC50, formação de colônias, análise do ciclo celular e caracterização de morte celular por citometria de fluxo, ensaio In vitro scratch, coloração para ß-galactosidase, PCR quantitativo e ELISA. Os resultados mostraram que o composto STX140: diminui a viabilidade celular, inibe a proliferação, formação de colônias e migração em linhagens de melanoma (não resistentes e resistentes ao vemurafenibe, inibidor de BRAF). Além do mais, o composto atuou diminuindo a secreção da interleucina pró-tumoral IL-8 em células resistentes. O STX140 induziu senescência nas células de melanoma que foram positivas para ß-galactosidase, também havendo aumento da expressão de genes chave de vias de senescência (CDKN1A e GADD45A) nas células de melanoma resistentes tratadas com o composto. Em conclusão, o STX140 mostrou ter um potencial antitumoral contra o melanoma, diminuindo sua viabilidade celular, inibindo sua proliferação e migração, induzindo senescência, diminuindo a secreção de interleucina pró- tumoral, com efeito mais acentuado nas linhagens de melanoma resistente

Skin cancer can be classified as non-melanoma and melanoma. Melanoma has a low incidence among skin cancers, but it is the most lethal form and is considered one of the most resistant to treatment. Due to the infiltration of malignant cells into tissues, lymphatic vessels and blood vessels, melanoma invades and spreads rapidly. Its metastases are often located in lymph nodes, brain, liver and other organs. Metastatic melanomas presents multiple gene mutations and many tumors are resistant to treatments, such as with BRAF inhibitors, due to mutations and activation of parallel pathways. In other words, there is a clear need to search for new treatment options. In work carried out by our group, Massaro et al showed that the estradiol derivative 2- Methoxyestradiol induces apoptosis in melanoma cells and senescence. In this sense, the compound STX140, (an estradiol analogue with superior bioavailability), which has already been shown to be effective against breast cancer in vitro and in vivo studies will be then evaluated for its action on melanoma. The main objective of this work is to explore the antitumor action of the compound STX140 in melanoma cells, especially the induction of senescence. Using the melanoma cell culture the following assays were performed: cell viability - IC50, clonogenic, cell cycle analysis and cell death characterization by flow cytometry, wound assay, staining for ß-galactosidase, quantitative PCR and ELISA. Preliminary data from this work showed that the compound STX140: decreases cell viability, inhibits proliferation, colony formation and migration in melanoma cell lines (non-resistant and resistant to vemurafenib, BRAF inhibitor). It also decreased the secretion of pro-tumor interleukin IL-8 in resistant cells. STX140 induced senescence in melanoma cells, that were positive for ß-galactosidase, and there was also increased expression of key genes of senescence pathways (CDKN1A and GADD45A) in resistant melanoma cells treated with the compound. In conclusion, STX140 has been shown to have antitumor potential against melanoma, decreasing its cell viability, inhibiting its proliferation and migration, inducing senescence, decreasing pro-tumor interleukin secretion, with a more pronounced effect on resistant melanoma cell lines

Envejecimiento y caídas. Su impacto social / Ageing and falls. Its social impact

RESUMEN El creciente envejecimiento demográfico observado en los diferentes países constituye un fenómeno complejo de relevancia mundial, que repercute en los diversos sectores de la sociedad, entre ellos, el de la salud. Entre los grandes problemas geriátricos que afectan la calidad de vida de los ancianos y constituyen un marcador de fragilidad se encuentran las caídas; las mismas constituyen un evento frecuente entre los adultos mayores de 60 años. Aproximadamente 1 de cada 3 adultos que viven en la comunidad tiene riesgo de presentar una caída en un año. Ese riesgo aumenta con la edad, la presencia de comorbilidades, el antecedente de caídas previas y los trastornos en la marcha, entre otros. Sus consecuencias son graves y pueden llevar a la institucionalización e incluso a la muerte. Tienen implicaciones sociales y de salud pública; por este motivo se considera de fundamental relevancia que el personal de salud y la sociedad en general puedan adquirir conocimientos básicos acerca de las caídas en los adultos mayores, para detectarlas e intervenir de manera adecuada, lo que garantiza el logro de una longevidad con bienestar (AU).

ABSTRACT The growing demographic ageing observed in different countries constitutes a complex phenomenon of global relevance, which has an impact on the various sectors of society, public health among them. Falls are found among the great geriatric problems affecting elder people´s life quality, constituting a fragility marker and a frequent event in people aged 60 years and more. Almost one of each three adults living in the community have the risk of falling once a year. The risk increases with age, the presence of co morbidities, antecedents of previous falls and gait disorders, among others. Its consequences are serious and could lead to the admittance in institutions and even death. They have social and public health implications; for that reason it is considered very relevant that health care staff and the society in general could acquire basic knowledge on falls in elder people, to detect them and properly intervene; it warranties the achievement of longevity with wellbeing (AU).

Aging and low-intensity exercise change oxidative biomarkers in brain regions and radiographic measures of femur of Wistar rats

We investigated changes in oxidative biomarkers in brain regions such as brainstem, cerebellum, and cerebral cortex of 3-, 6-, 18-, 24-, and 30-month-old rats. We also assessed the effects of low-intensity exercise on these biomarkers in these regions of 6-, 18-, and 24-month-old rats that started exercise on a treadmill at 3, 15, and 21 months of age, respectively. Radiographic images of the femur were taken for all rats. A total of 25 rats (age: twelve 6-, ten 18-, ten 24-, and three 30-month-old rats) were used. Lipid hydroperoxide levels increased in cerebellum at 18 months. Total antioxidant activity exhibited lowest values in brainstem at 3 months. Superoxide dismutase activity did not exhibit significant changes during aging. Total thiol content exhibited lowest values in brain regions of 24- and 30-month-old rats. Exercise reduced total thiol content in brainstem at 6 months, but no change occurred in other regions and other ages. Femur increased its length and width and cortical thickness with advancing age. No change occurred in medullary width. Radiolucency increased and sclerosis was found in cortical and medullary bone with advancing age. Exercise reduced radiolucency and medullary sclerosis. Therefore, aging differentially changed oxidative biomarkers in different brain regions and radiographic measures of the femur. Low-intensity exercise only ameliorated some radiographic measurements of femur. Since the present study possessed limitations (small number of rats per group), a beneficial effect of regular low-intensity exercise on oxidative markers in brain cannot be ruled out.

Contribuições da prática de pilates na aptidão física e na força de preensão manual de idosos / Elderly physical fitness and manual grip strength improvement as a result of pilates

O objetivo deste estudo foi verificar a influência do Pilates de solo na aptidão física e na força de preensão manual de idosos. Participaram do estudo 11 idosos, nove mulheres e dois homens, com média de idade de 68,73 anos (DP= 6,06). Estes realizaram 34 sessões de exercícios do Pilates de Solo, em 17 semanas, duas vezes por semana, com duração de 60 minutos cada sessão. No início da intervenção foi aplicada a ficha diagnóstica em forma de entrevista individual. Antes e após a intervenção foram aplicados os seguintes instrumentos: medidas antropométricas, preensão manual e a bateria de testes físicos para idosos (Senior Fitness Test ­ SFT). Quanto às aptidões físicas verificou-se diferença significativa após o programa de Pilates de solo na força dos membros superiores e inferiores, flexibilidade de membros inferiores, agilidade/equilíbrio dinâmico e resistência aeróbia. Não houve diferença na flexibilidade de membros superiores e na força de preensão manual. Concluiu-se neste estudo que o Método Pilates de solo influenciou na melhora da força, flexibilidade de membros inferiores, agilidade/equilíbrio dinâmico e resistência aeróbia, demonstrando ser um método que proporciona benefícios na aptidão física dos idosos.

The purpose of this study was to verify the influence of Mat Pilates in physical fitness and manual grip strength of the elderly. Eleven elderly individuals - 9 women and two men - with mean age of 68.73 years (SD = 6.06) participated in the study. They were submitted to 34 sessions of Mat Pilates exercises twice a week for 17 weeks, with 60-minute sessions. At the beginning of the intervention, a diagnostic form was applied in the form of an individual interview. Before and after the intervention, the following instruments were applied: anthropometric measures, manual gripping and a set of physical tests for the elderly (Senior Fitness Test - SFT). Regarding physical fitness, there was a significant difference after the Pilates program on the upper and lower limb strength, lower limb flexibility, dynamic agility/balance, and aerobic resistance. No differences were found in upper limb flexibility and manual grip strength. It can be concluded that the Mat Pilates Method influenced the improvement of the strength, flexibility of lower limbs, dynamic agility/balance and aerobic resistance, proving to be a method that provides benefits in the physical fitness of the elderly.

Mientras haya vida, hay todo: una mirada en la sexualidad del adulto mayor / While there is life, there is everything: a look at the elderly sexuality

Introducción.Desde un punto de vista integral, la sexualidad comprende aspectos de orden biopsicosocial. Los prejuiciosy el desconocimiento llevan a evitar hablar sobre este tema en la consulta con el adulto mayor (AM).Objetivo.Profundizar en la vivencia de la sexualidad del AM.Metodología.Estudio cualitativo, fenomenológico, realizado en dos centros de actividades recreativas para AM en SanMiguel de Tucumán, que incluyó 13 entrevistas semiestructuradas en profundidad a pacientes mayores de 60 años, 11 desexo femenino, seleccionados en forma intencional y por conveniencia en Agosto de 2018.Resultados.Existe una dicotomía entre quienes hablan del tema y quienes no; sin embargo, todos expresan el deseode naturalizarlo tanto en su círculo social como en la consulta médica. Los AM aceptan el proceso de envejecimiento,tienen una autopercepción positiva de su imagen y pese a los prejuicios, experiencias, comorbilidades y adversidades, seadaptan buscando formas para sentirse bien y disfrutar de una sexualidad plena.Conclusión.El envejecimiento y la sexualidad son conceptos dinámicos que confluyen con las experiencias de vida.Creemos que como médicos de familia es importante brindar una atención integral, abordando las diferentes dimensionesdel ser humano, incluyendo su sexualidad. (AU)

Introduction.Sexuality from an integral point of view includes aspects of biopsychosocial order. Prejudice and ignorancelead to avoid talking about this topic in the medical consultation with the Eldery.Objective.To deepen the experience of the sexuality of the Eldery.Methodology.Qualitative, phenomenological study, conducted in two centres of recreational activities for Senior Citizensin San Miguel de Tucumán, which included 13 in-depth semi-structured interviews to patients over 60 years of age, 11female, selected intentionally and for convenience in August 2018.Results.There is a dichotomy between those who talk about the subject and those who do not; however, all of themexpress the desire to naturalize it in both, their social circle and the medical consultation. The eldery patients acceptthe ageing process, have a positive self-perception of their image and despite prejudices, experiences, comorbidities andadversities, they adapt looking for ways to feel good and enjoy a full sexuality.Conclusion.Aging and sexuality are dynamic concepts that converge with life experiences. We believe that, as familydoctors, it is important to provide comprehensive care, addressing the different dimensions of the human being, wheresexuality is included. (AU)

Genes related to maintenance of autophagy and successful aging / Genes relacionados à manutenção da autofagia e envelhecimento bem-sucedido

ABSTRACT Considering aging as a phenomenon in which there is a decline in essential processes for cell survival, we investigated the autophagic and proteasome pathways in three different groups: young, older and oldest old male adults. The expression profile of autophagic pathway-related genes was carried out in peripheral blood, and the proteasome quantification was performed in plasma. No significant changes were found in plasma proteasome concentrations or in correlations between proteasome concentrations and ages. However, some autophagy- and/or apoptosis-related genes were differentially expressed. In addition, the network and enrichment analysis showed an interaction between four of the five differentially expressed genes and an association of these genes with the transcriptional process. Considering that the oldest old individuals maintained both the expression of genes linked to the autophagic machinery, and the proteasome levels, when compared with the older group, we concluded that these factors could be considered crucial for successful aging.

RESUMO Considerando o envelhecimento como um fenômeno em que há um declínio nos processos essenciais a sobrevivência celular, investigamos as vias autofágica e proteassômica em três grupos: jovens, idosos e longevos. O perfil de expressão dos genes relacionados à via autofágica foi analisado em sangue periférico, e a quantificação do proteassoma realizada em plasma. Não foram encontradas alterações significativas nas concentrações plasmáticas de proteassoma ou na correlação entre as concentrações de proteassoma e as idades. No entanto, alguns genes relacionados a autofagia e / ou apoptose foram expressos diferencialmente. Além disso, as análises de rede e de enriquecimento mostraram uma interação entre quatro dos cinco genes diferencialmente expressos e a associação desses ao processo transcricional. Considerando que os indivíduos longevos mantiveram tanto a expressão de genes ligados à maquinaria autofágica, quanto os níveis de proteassoma quando comparados aos idosos, concluímos que esses fatores poderiam ser considerados cruciais para o envelhecimento bem-sucedido.