Effect of Early Intervention of Yishen Huazhuo Prescription on Learning and Memory of Accelerated Aging SAMP8 Mice and Its Mechanism / 中国实验方剂学杂志

ObjectiveTo investigate the impact of early intervention with Yishen Huazhuo prescription （YHP） on the learning and memory of accelerated aging model mice， as well as its underlying mechanism. MethodForty-eight 3-month-old male SAMP8 mice were randomly assigned into four groups， including the model group， low-dose YHP group， high-dose YHP group， and donepezil group. Additionally， 24 SAMR1 mice of the same age were divided into a control group and a YHP treatment control group， each consisting of 12 mice. The YHP groups received YHP at doses of 6.24 g·kg-1 and 12.48 g·kg-1， while the donepezil group was treated with donepezil at a dose of 0.65 mg·kg-1. The model group and control groups were given physiological saline. The mice were gavaged once daily for a duration of four weeks. Spatial learning and memory abilities of mice were assessed using the Morris water maze test. Immunofluorescence staining was employed to evaluate neuronal density as well as expression levels of M1 microglial （MG） polarization marker inducible nitric oxide synthase （iNOS） and M2 MG polarization marker arginase-1 （Arg-1） in the hippocampus region. Enzyme-linked immunosorbent assay （ELISA） was used to measure serum levels of pro-inflammatory factor interleukin 1β （IL-1β） and anti-inflammatory factor transforming growth factor-β1 （TGF-β1）. Furthermore， Western blot analysis was conducted to determine expressions of amyloid β peptide1-42 （Aβ1-42） along with triggering receptor expressed on myeloid cells 2 （TREM2）/nuclear factor kappa B （NF-κB） signaling pathway-related proteins TREM2， phospho （p）-NF-κB p65， and phospho-inhibitory kappa B kinase β （IKKβ） in the hippocampus. ResultCompared with the control group， the model group exhibited a significantly prolonged escape latency （P<0.01）， a significant reduction in neuron-specific nuclear protein （NeuN） expression in the hippocampus， a significant increase in iNOS expression in MG， and a significant decrease in Arg-1 expression. The serum IL-1β content was significantly increased， while the TGF-β1 content was significantly decreased. Additionally， there was a significant decrease in TREM2 expression in the hippocampus and significant increases in p-NF-κB p65， p-IKKβ， and Aβ1-42 expressions （P<0.05， P<0.01）. However， no significant changes were observed in escape latency， times of crossing the platform， and hippocampal NeuN expression in the YHP treatment control group. Conversely， iNOS expression in MG as well as the hippocampal p-NF-κB p65， p-IKKβ， and Aβ1-42 expressions were significantly decreased. Furthermore， TREM2 expression was significantly increased （P<0.05， P<0.01）. In comparison to the model group， the low-dose YHP group showed a significantly shortened escape latency and an increased number of crossing the platform （P<0.05， P<0.01）. In the high-dose YHP group， the escape latency was significantly shortened （P<0.05）. In the low-dose YHP group， high-dose YHP group， the expression of NeuN in the hippocampus was significantly increased， the expression of iNOS in MG was significantly decreased， and the expression of Arg-l was significantly increased. The serum IL-1β content was significantly decreased， while the TGF-β1 content was significantly increased. Furthermore， the expression of TREM2 in the hippocampus was significantly increased， and the expressions of p-NF-κB p65， p-IKKβ， and Aβ1-42 were significantly decreased （P<0.01）. ConclusionEarly YHP intervention may promote the transformation of hippocampal MG from M1 to M2 by regulating the TREM2/NF-κB signaling pathway， reduce the release of neuroinflammatory factors， protect hippocampal neurons， and reduce the deposition of Aβ1-42， and finally delay the occurrence of learning and memory decline in SAMP8 mice.

UnderstandingComplement-mediatedNervous System aginginOrder toDevelop Neurodegenerative Therapeutics

Aging is becoming one of the biggest burdens to the developed world, mainly due to it being linked to a variety of diseases from neurodegenerative disorders such as Alzheimer’s disease to cancer. It involves the dysregulation of virtually every biological process known, affecting every organ and tissue by distinct mechanisms, the nature of which is only now beginning to be truly understood. This is also true for memory loss, which is considered one of the most typical signs of old age. This is not surprising, given the still limited knowledge regarding how memories and thoughts are stored and utilised by the Central Nervous System (CNS). A potential hint, however, is the recent discovery that the complement system plays a role in synaptic pruning, which is essential for erasing unneeded memories. This is particularly intriguing given that the complement system is a branch of the innate immune system which has been documented as being overactive with aging. This review will thus cover what is currently known about the relationship between the immune system and aging and how the changes in the immune system with age affect the brain in an effort to direct further research. This topic has not been reviewed as a whole, which is why this paper aims to summarise the information on this topic whilst also elaborating on the gaps in research in order to develop potential therapies for neurodegeneration and immunosenescence.

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.

COPD as a Disease of Immunosenescence

Although chronic obstructive pulmonary disease (COPD) is regarded as a chronic inflammatory lung disease, the disease mechanism is still not known. Intriguingly, aging lungs are quite similar to COPD-affected lungs in many ways, and COPD has been viewed as a disease of accelerated premature aging of the lungs. In this paper, based on a literature review, we would like to propose immunosenescence, age-associated decline in immunity, as a critical mechanism for the development of COPD. Immunosenescence can cause a low-grade, systemic inflammation described as inflammaging. This inflammaging may be directly involved in the COPD pathogenesis. The potential contributors to the development of inflammaging in the lungs possibly leading to COPD are discussed in the review paper. A notable fact about COPD is that only 15% to 20% of smokers develop clinically significant COPD. Given that there is a substantial inter-individual variation in inflammaging susceptibility, which is genetically determined and significantly affected by the history of the individual's exposure to pathogens, immunosenescence and inflammaging may also provide the answer for this unexpectedly low susceptibility of smokers to clinically significant COPD.

Effects of natural aging and gender on pro-inflammatory markers

The term inflammaging is now widely used to designate the inflammatory process of natural aging. During this process, cytokine balance is altered, presumably due to the loss of homeostasis, thus contributing to a greater predisposition to disease and exacerbation of chronic diseases. The aim of the study was to analyze the relationship between pro-inflammatory markers and age in the natural aging process of healthy individuals. One hundred and ten subjects were divided into 5 groups according to age (22 subjects/group). Interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) were quantified using the ELISA method. High-sensitivity C-reactive protein (hsCRP) was analyzed by turbidimetry according to laboratory procedures. The main findings of this study were: a positive correlation between hsCRP and IL-6 as a function of age (110 subjects); women showed stronger correlations; the 51-60 age group had the highest values for hsCRP and IL-6; women presented higher values for hsCRP in the 51-60 age group and higher values for IL-6 in the 61-70 age group; and men showed higher values in the 51-60 age group for hsCRP and IL-6. In conclusion, the natural aging process increased IL-6 and hsCRP levels, which is consistent with the inflammaging theory; however, women presented stronger correlations compared to men (IL-6 and hsCRP) and the 51-60 age range seems to be a key point for these increases. These findings are important because they indicate that early preventive measures may minimize the increase in these inflammatory markers in natural human aging.

Desarrollo y cambios con la edad en el tubo digestivo, hígado y páncreas / Digestive tract, liver and pancreas: development and changes with age

An adequate functioning of the digestive tract, liver and pancreas is fundamental to providing the organism with the necessary conditions for its development and maintaining its digestive and systemic homeostasis. Life expectancy has increased, it is estimated that adults over 65 years old by 2050, will represent 25% of the local population. The morphological and functional changes associated with aging in the digestive system, liver and pancreas are modest except for those that occur in the microbiota. Recently it has been possible to establish the contribution of the microbiota to life expectancy and establish a link between gastrointestinal microbiota, inflammation associated with aging (inflammaging) and survival. This represents a shift in the paradigm of our understanding physiology, chronic diseases, neoplasms and for the development of new therapies.

Un adecuado funcionamiento del tubo digestivo, hígado y páncreas es fundamental para poder brindar al organismo las condiciones necesarias para su desarrollo y mantener su homeostasis digestiva y sistémica. La expectativa de vida se ha incrementado, estimándose a nivel nacional que para el año 2050 los adultos mayores de 65 años representarán el 25% de la población. Los cambios morfológicos y funcionales asociados al envejecimiento en el aparato digestivo, hígado y páncreas son modestos a excepción, de los que se producen en la microbiota. Recientemente se ha podido establecer la contribución de la microbiota a la esperanza de vida y establecer un nexo entre microbiota gastrointestinal, inflamación asociada al envejecimiento y sobrevida. Esto representa un cambio en el paradigma sobre cómo comprendemos la fisiología, las patologías crónicas, neoplásicas y en el desarrollo de nuevas terapias.

Flavonoids: Broad Spectrum Agents on Chronic Inflammation

Flavonoids are major plant constituents with numerous biological/pharmacological actions both in vitro and in vivo. Of these actions, their anti-inflammatory action is prominent. They can regulate transcription of many proinflammatory genes such as cyclooxygenase-2/inducible nitric oxide synthase and many cytokines/chemokines. Recent studies have demonstrated that certain flavonoid derivatives can affect pathways of inflammasome activation and autophagy. Certain flavonoids can also accelerate the resolution phase of inflammation, leading to avoiding chronic inflammatory stimuli. All these pharmacological actions with newly emerging activities render flavonoids to be potential therapeutics for chronic inflammatory disorders including arthritic inflammation, meta-inflammation, and inflammaging. Recent findings of flavonoids are summarized and future perspectives are presented in this review.

Effect of inflammaging on periodontitis / 华西口腔医学杂志

Inflammaging is the chronic, systematic, and controllable upregulation of a pro-inflammation state with advancing age. Chronic low-grade inflammation accompanied by sustained stimuli is correlated with various age-related diseases (ARDs). Recent studies on ARDs have prompted further research interest in the inner mechanisms underlying inflammaging to establish prevention and treatment plans for inflammatory diseases. In this article, we discuss inflammaging and its significant role in periodontitis.