前言——免疫衰老与老年疾病

免疫衰老(immunosenescence),即免疫系统随年龄的增长而发生的进行性退变,这种改变的逐渐积累则导致机体对感染和接种疫苗应答能力的降低.免疫衰老十分复杂,其机制尚不十分清楚,涉及固有和适应性免疫应答.随着年龄的增加,免疫器官老化、吞噬细胞的吞噬功能降低、细胞迁移特性改变、细胞类群和数量以及抗体产生的能力等也发生相应变化,从而增加感染、细胞恶变和自身免疫性疾病的机会,致使老年人的死亡率增加.若通过适当的免疫调理,如细胞因子的应用、体液免疫的替代、辅以抗氧化和热卡限制等策略,可减缓或逆转免疫衰老.     

免疫系统的衰老及其机制

人体的衰老是生命过程中的自然规律,是机体中多细胞、多组织和多系统的进行性功能衰退状态.免疫系统的主要功能是维持机体的正常免疫功能,防御病原微生物的侵袭,增加人体对传染性疾病的抵抗力;同时能识别和清除体内衰老及癌变的细胞,发挥免疫监视及保持机体内环境稳定的重要功能.目前大量的研究发现人体衰老过程中免疫功能也明显衰退,导致许多与衰老有关疾病的发生,如肿瘤、自身免疫性疾病、中枢神经系统退行性疾病以及感染等.近年的研究揭示了免疫系统衰老导致一些老年性疾病发病的机制.本文着重阐述免疫系统的衰老及分子机制的近期研究进展.     

重视老年疾病的免疫指标

机体的免疫状态随年龄的增长而变化,免疫防御、免疫监视和自身稳定功能总体趋于降低,可表现为对抗感染的能力减弱、肿瘤和自身免疫性疾病的多发等.这归咎于免疫应答的物质基础--免疫系统的衰老,以及因此导致的免疫应答调节异常.延年益寿的主观愿望需要与增强体质、提高免疫功能的自觉行动相伴.有理由相信,寿命是可塑的,可以借助有益于机体免疫力提高的健康行为和对相关免疫指标的关注,达到增强防病抗病能力之效果,实现延年益寿之目的.     

胸腺衰老与免疫衰老

在机体衰老的进程中,免疫系统功能衰退,在此体系中,胸腺功能的衰退最为明显。胸腺的衰老受神经内分泌、胸腺微环境及细胞凋亡等因素的调控,涉及T细胞功能、亚群组成和信号转导通路等都发生不同程度的改变,最终导致机体免疫功能失调。因而胸腺衰老被免疫学家看作在免疫衰老过程中最重要的事件之一。     

免疫衰老影响老年人重型新型冠状病毒肺炎发病机制的研究进展

免疫衰老是免疫系统随年龄增长而发生最为显著的改变。免疫衰老与感染性疾病、自身免疫性疾病和恶性肿瘤等存在密切关系,且导致老年人在感染SARS冠状病毒（SARS-CoV-2）后,容易进展成为重型新型冠状病毒肺炎（COVID-19）。免疫衰老通过先天性免疫系统和适应性免疫系统,改变免疫细胞数量、表型及功能,造成免疫系统功能障碍和炎症反应失衡,增加老年患者的死亡风险和预后不良事件。通过分析免疫衰老与重型新型冠状病毒肺炎之间的关系,有助于发现老年重型COVID-19的有效治疗方法,改善老年患者的生存及预后。     

老年病康复和免疫

衰老是一种生命表现形式和不可避免的生物学过程。它既是生理的必然,又与疾病有着千丝万缕的联系,是机体成熟后机能活动进行性下降的过程。在机体衰老过程中,和其他系统相似,免疫系统的机能也随着年龄增长而进行性降低。衰老时免疫系统的改变具有两方面的特征:对非已抗原的反应性下降(免疫功能减退),出现自身组织抗原的免疫反     

增龄对免疫的影响

免疫系统在维持机体的统一调节中具有重要作用,但随着年龄的增长其功能逐渐减弱。本文介绍了老化与免疫细胞变化的关系,随着老化不仅机体对外来特异性抗原的免疫应答能力下降,而且免疫细胞本身也出现老化过程。本文还简要介绍了老化的预防和治疗。     

免疫系统的衰老及其机制

免疫系统随着年龄的增加而功能退化,出现免疫系统衰老.免疫系统衰老与老年人群感染的易感性、疫苗的低效性、自身免疫性疾病增加以及肿瘤多发性密切相关.免疫系统衰老的特征表现为细胞介导的免疫功能下降以及抗体介导的体液免疫应答的降低.在衰老过程中,T细胞和B细胞功能的下降与先天性免疫系统功能的降低同时存在.本文就免疫系统随年龄衰老的改变及其内在机制进行综述.     

老年重症感染患者免疫失衡的发病机制及免疫靶向治疗策略

尽管近年来重症感染相关的诊疗技术不断提高,老年重症感染患者发病率高、临床表现不典型、预后差、病死率 高,需予以重点关注。由于老年患者机体免疫系统功能下降,即免疫衰老,其对重症感染的免疫反应尤为特殊,固有 和适应性免疫系统中各免疫细胞数量改变、亚群失衡、功能障碍,免疫失衡更加明显。因此,准确检测老年重症感染 患者免疫失衡的动态变化,明确其潜在机制,在此基础上适时应用免疫联合靶向治疗进行有效干预,对于老年重症感 染患者的治疗及疾病转归具有重大临床意义。     

衰老期细胞免疫功能的下降及其免疫实验治疗

衰老现象是生命过程中出现的生理衰退变化,其中包括免疫系统功能的改变。随年龄增长某些免疫功能出现变化,并且逐渐明显加重。机体在衰老过程中发生的许多疾病均与免疫功能的改变有密切联系。例如,免     

In vitro senescence of immune cells

Immune cells are eminently suitable model systems in which to address the possible role of replicative senescence during in vivo aging. Since there are more than 10⁸ unique antigen specificities present within the total T lymphocyte population of each individual, the immune response to any single antigen requires massive clonal expansion of the small proportion of T cells whose receptors recognize that antigen. The Hayflick Limit may, therefore, constitute a barrier to effective immune function, at least for those T cells that encounter their specific antigen more than once over the life course. Application of the fibroblast replicative senescence model to the so-called cytotoxic or CD8 T cell, the class of T cells that controls viral infection and cancer, has revealed certain features in common with other cell types as well as several characteristics that are unique to T cells. One senescence-associated change that is T cell-specific is the complete loss of expression of the activation signaling surface molecule, CD28, an alteration that enabled the documentation of high proportions of senescent T cells in vivo. The T cell model has also provided the unique opportunity to analyze telomere dynamics in a cell type that has the ability to upregulate telomerase yet nevertheless undergoes senescence. The intimate involvement of the immune system in the control of pathogens and cancer as well as in modulation of bone homeostasis suggests that more extensive analysis of the full range of characteristics of senescent T cells may help elucidate a broad spectrum of age-associated physiological changes.     

Improving immunity in the elderly: current and future lessons from nonhuman primate models

The immune system must overcome daily challenges from pathogens to protect the body from infection. The success of the immune response to infection relies on the ability to sense and evaluate microbial threats and organize their elimination, while limiting damage to host tissues. This delicate balance is achieved through coordinated action of the innate and adaptive arms of the immune system. Aging results in several structural and functional changes in the immune system, often described under the umbrella term "immune senescence". Age-related changes affect both the innate and adaptive arms of the immune system and are believed to result in increased susceptibility and severity of infectious diseases, which is further exacerbated by reduced vaccine efficacy in the elderly. Therefore, multiple strategies to improve immune function in the aged are being investigated. Traditionally, studies on immune senescence are conducted using inbred specific pathogen free (SPF) rodents. This animal model has provided invaluable insight into the mechanisms of aging. However, the limited genetic heterogeneity and the SPF status of this model restrict the successful transfer of immunological discoveries between murine models and the clinical setting. More recently, nonhuman primates (NHPs) have emerged as a leading translational model to investigate immune senescence and to test interventions aimed at delaying/reversing age-related changes in immune function. In this article, we review and summarize advances in immuno-restorative approaches investigated in the NHP model system and discuss where the NHP model can support the development of novel therapeutics.     

Microbial translocation,residual viremia and immune senescence in the pathogenesis of HIV-1 infection

The pathophysiological mechanisms that underlie the progression of human immunodeficiency virus-1 (HIV-1) disease to full-blown AIDS are not well understood. Findings suggest that, during HIV-1 infection, plasma lipopolysaccharide (LPS) levels, which are used as an indicator of microbial translocation (MT), are elevated throughout the acute and chronic phases of HIV-1 disease. The translocation of bacterial products through the damaged gastrointestinal barrier into the systemic circulation has been described as a driver of immune activation. In contrast, comorbidities that are associated with HIV-1 infection have been attributed to chronic inflammation and immune system dysfunction secondary to MT or low-level HIV-1 replication in plasma and cell reservoirs. Moreover, accelerated aging is significantly associated with chronic inflammation, immune activation, and immune senescence. In this review, we aimed to investigate the role of inflammation as a pivotal marker in the pathogenesis of HIV-1 disease. We will discuss the key features of chronic inflammation and immune activation that are observed during the natural course of the disease and those features that are detected in cART-modified infection. The review will focus on the following aspects of HIV-1 infection: (1) MT; (2) the role of residual viremia; and (3) “immune senescence” or “inflammaging.” Many questions remain unanswered about the potential mechanisms that are involved in HIV-1 pathogenesis. Further studies are needed to better investigate the mechanisms that underlie immune activation and their correlation with HIV-1 disease progression.     

Immune senescence in aged nonhuman primates

Aging is accompanied by a general dysregulation in immune system function, commonly referred to as ‘immune senescence’. This progressive deterioration affects both innate and adaptive immunity, although accumulating evidence indicates that the adaptive arm of the immune system may exhibit more profound changes. Most of our current understanding of immune senescence stems from clinical and rodent studies. More recently, the use of nonhuman primates (NHPs) to investigate immune senescence and test interventions aimed at delaying/reversing age-related changes in immune function has dramatically increased. These studies have been greatly facilitated by several key advances in our understanding of the immune system of old world monkeys, specifically the rhesus macaques. In this review we describe the hallmarks of immune senescence in this species and compare them to those described in humans. We also discuss the impact of immune senescence on the response to vaccination and the efficacy of immuno-restorative interventions investigated in this model system.     

Aging of immune system: Immune signature from peripheral blood lymphocyte subsets in 1068 healthy adults

Aging is a major risk factor for several conditions including neurodegenerative, cardiovascular diseases and cancer. Functional impairments in cellular pathways controlling genomic stability, and immune control have been identified. Biomarker of immune senescence is needed to improve vaccine response and to develop therapy to improve immune control. To identify phenotypic signature of circulating immune cells with aging, we enrolled 1068 Chinese healthy volunteers ranging from 18 to 80 years old. The decreased naïve CD4+ and CD8+ T cells, increased memory CD4+ or CD8+ T cells, loss of CD28 expression on T cells and reverse trend of CD38 and HLA-DR, were significant for aging of immune system. Conversely, the absolute counts and percentage of NK cells and CD19+B cells maintained stable in aging individuals. The Chinese reference ranges of absolute counts and percentage of peripheral lymphocyte in this study might be useful for future clinical evaluation.     

Aging and immune response: a multivariate approach

This study on the immune response was chosen as the experimental milieu for the aging process. Parameters associated with the immune response were measured in rats of different ages, thus providing multivariate conditions within which multidimensional data analysis procedures could be applied. These methods, specifically designed for analyzing complex situations, allowed for the delineation of some structural characteristics of maturity and senescence.     

Circadian nature of immune function

The primary physiological role of the circadian system is to synchronize and coordinate organ systems, particularly in response to dynamics in the environment. The immune system is under direct circadian control by systemic cues and molecular clocks within immune cells. The master circadian pacemaker called the suprachiasmatic nucleus (SCN) conveys timing information to the immune system through endocrine and autonomic pathways. These signals promote phase coherence of peripheral clocks in the immune system, and also govern daily variations in immune function. The coordination of immune response may compose an anticipatory state for optimal immune response. Interactions between circadian and immune systems are bidirectional, in that immune factors can modulate phasing of circadian clocks. Circadian disruption, such as environmental desynchronization and/or anomalous molecular clock functions, may lead to lack of system coordination, and particular vulnerabilities to infection and disease may develop.     

Sarcopenia, obesity, and natural killer cell immune senescence in aging: Altered cytokine levels as a common mechanism

Human aging is characterized by both physical and physiological frailty. A key feature of frailty, sarcopenia is the age-associated decline in skeletal muscle mass, strength, and endurance that characterize even the healthy elderly. Increases in adiposity, particularly in visceral adipose tissue, are almost universal in aging individuals and can contribute to sarcopenia and insulin resistance by increasing levels of inflammatory cytokines known collectively as adipokines. Aging also is associated with declines in adaptive and innate immunity, known as immune senescence, which are risk factors for cancer and all-cause mortality. The cytokine interleukin-15 (IL-15) is highly expressed in skeletal muscle tissue and declines in aging rodent models. IL-15 inhibits fat deposition and insulin resistance, is anabolic for skeletal muscle in certain situations, and is required for the development and survival of natural killer (NK) lymphocytes. We review the effect that adipokines and myokines have on NK cells, with special emphasis on IL-15. We posit that increased adipokine and decreased IL-15 levels during aging constitute a common mechanism for sarcopenia, obesity, and immune senescence.     

Accelerated immune senescence and reduced response to vaccination in ovariectomized female rhesus macaques

Aging is associated with a general dysregulation in immune function, commonly referred to as “immune senescence”. Several studies have shown that female sex steroids can modulate the immune response. However, the impact of menopause-associated loss of estrogen and progestins on immune senescence remains poorly understood. To help answer this question, we examined the effect of ovariectomy on T-cell homeostasis and function in adult and aged female rhesus macaques. Our data show that in adult female rhesus macaques, ovariectomy increased the frequency of naïve CD4 T cells. In contrast, ovariectomized (ovx) aged female rhesus macaques had increased frequency of terminally differentiated CD4 effector memory T cells and inflammatory cytokine-secreting memory T cells. Moreover, ovariectomy reduced the immune response (T-cell cytokine and IgG production) following vaccination with modified vaccinia ankara in both adult and aged female rhesus macaques compared to ovary-intact age-matched controls. Interestingly, hormone therapy (estradiol alone or in conjunction with progesterone) partially improved the T-cell response to vaccination in aged ovariectomized female rhesus macaques. These data suggest that the loss of ovarian steroids, notably estradiol and progesterone, may contribute to reduced immune function in post-menopausal women and that hormone therapy may improve immune response to vaccination in this growing segment of the population.     

Correlation between accelerated presbycusis and decreased immune functions

The aim of the current study is to analyze the relationship between presbycusis and the immune system, which is affected by pathogenic environments, and to devise a strategy for the prevention of presbycusis using the SAMP1 mouse, an animal model for accelerated senescence that shows both immunological dysfunction and hearing loss caused by the impairment of spiral ganglion cells in the cochlea. When these mice were bred in different pathogenic environments, we found that the development of age-related diseases such as presbycusis was delayed in the mice bred under clean conditions. Prednisolone administration showed no significant prevention of the development of presbycusis in the mice, suggesting that autoimmune mechanisms are not involved in the acceleration of presbycusis. It is conceivable that pathogen-induced infections impose a severe stress on the host, impairing the host's immune functions. A reduction in the number of pathogens may therefore prevent the acceleration of the aging process. These findings suggest that not only the gene backgrounds but also immune functions affect the development of presbycusis in SAMP1 mice. Further studies into the relationship between systemic immune functions and the neuro-generation system may provide additional information about the treatment for age-related diseases.