细胞衰老与衰老细胞

细胞衰老(cellular senescence)是一个应激导致细胞生长停滞的生理过程．一部分发生衰老的细胞会被机体自身清除,但另一些衰老的细胞会随着时间的推移在体内积累增多,并分泌一些免疫刺激因子,导致低水平炎症发生,引起周围组织衰老或癌变,这类具有特殊生物学特征和功能的细胞就是衰老细胞(senescent cell)．实验揭示,衰老细胞不仅是衰老过程的产物,也可能是组织器官进一步衰退的重要原因．近日,Baker等的一项研究成果(Nature,2011,479(7372)：232-236)表明,清除衰老细胞可延缓小鼠的衰老进程,该成果有望开辟出一条对抗衰老的新途径．     

干细胞衰老与衰老微环境调控的研究进展

干细胞衰老会损害机体组织的稳态,衰老的干细胞丧失修复能力从而引发衰老相关疾病。衰老微环境是促进机体衰老的重要因素之一。衰老相关分泌表型(SASP)是构成衰老微环境的主要成分,影响干细胞的组织修复能力,进而推动机体衰老进程。细胞外囊泡(EVs)被认为在衰老微环境中发挥重要作用,衰老细胞分泌的EVs通过运载mi RNAs等非编码RNA及SASP在内的多种活性分子参与调控衰老微环境,本文就干细胞衰老的诱发因素以及衰老微环境的研究进展进行综述,以期为干细胞的临床应用提供实验基础和理论基础。     

细胞外基质的增龄性变化及分子机制的研究进展

人口老龄化及其伴随的各种疾病已成为全球性健康问题,细胞外基质在老化过程中发生的变化及对机体产生的影响逐渐成为研究衰老的热点。在机体发育和衰老过程中,细胞外基质不仅可以为细胞提供结构支架、组织连接,调节实质细胞的形态、增殖、分化、代谢、迁移等生理活动,并且其本身组成成分、合成、代谢、重构等变化也会对机体各系统的功能产生深刻影响,具体表现为骨骼肌僵硬、左心室功能受损、神经突触传导抑制等。本文通过介绍机体在衰老过程中,运动、循环、神经等系统细胞外基质的变化及相关机制的最新研究进展,从非细胞角度探讨老化的机制,了解衰老的过程。     

磁疗与延缓衰老(二)

衰老的免疫学说衰老的免疫学说,是衰老机制学说的重要组成部分。免疫功能衰退是人和大多数哺乳动物老化过程的重要机制。自体免疫在导致衰老的细胞老化中起决定性作用,因而从根本上参与了整个机体老化。随着年龄的增长免疫功能逐渐下降,使人体抵抗病原微生物感染能力降低,从而更加剧各组织器官老化。老年人的免疫系统衰退的特点随着年龄的增加,机体的免疫系统,如免疫器官、免疫细胞及免疫分子都会发生一系列衰退性改变。免疫器官及免疫细胞老化的特点：根据目前研究得知,就防御功能的作用而言,较低等脊椎动物（鱼类和两栖类）免疫系…     

肝脏衰老中凋亡的调控机制

肝脏是机体重要的代谢器官,在机体全身衰老中尤为重要。脂肪肝、肝硬化和肝癌等老年常见病都与肝脏衰老密切相关。细胞凋亡作为一种细胞自我清除的保护机制,在生物机体衰老过程中不可或缺。越来越多的研究证据表明,凋亡在肝脏衰老中起着重要作用。适度的凋亡对于肝脏衰老是必要的;过度凋亡会造成功能细胞的大量丧失、疾病恶化,甚至最后导致肝功能衰竭;凋亡不足则会使损伤的细胞积蓄,导致细胞坏死或癌变。因此,维持细胞凋亡在衰老肝脏中的适度平衡可延缓或减轻肝脏衰老对机体的影响。该文针对肝脏衰老过程中凋亡的调控机制包括氧化应激、基因不稳定性、脂肪毒性、内质网应激、营养感应失调等的研究进展进行了分析总结。     

靶向脑衰老胶质细胞的运动防治PD研究进展

细胞衰老是一个体内平衡的生物过程,在推动机体衰老过程中起着关键作用。衰老细胞在神经系统中随着衰老和神经退行性疾病而积累,并且可能使人易患神经退行性疾病或加重其病程。帕金森病(Parkinson's disease,PD)是一种与年龄相关的神经退行性疾病。运动可通过提高衰老过程中脑细胞自噬水平,增强神经免疫信号分子以及脑内脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)的表达有效预防或延缓脑细胞衰老甚至清除脑衰老细胞,维持脑健康。大量流行病学调查结果以及临床和基础研究证实,不同形式的运动锻炼/身体活动均可改善PD患者或者PD模型动物的症状或改善症状的发展。本文以脑衰老胶质细胞为切入点,充分阐明脑衰老胶质细胞在PD中的作用以及运动干预对PD脑衰老胶质细胞的影响,以便有效和安全地利用脑衰老胶质细胞作为潜在的治疗靶点,以期为运动干预减缓(和)或改善PD运动功能障碍的神经生物学机制研究提供新的思路,为探寻PD的非药物防治或辅助疗法提供理论基础。     

免疫衰老与T、B细胞改变的相关研究

胸腺、适应性免疫系统的T、B细胞及固有免疫系统中中性粒细胞、巨噬细胞、NK/NKT细胞、树突状细胞等免疫细胞与免疫衰老（immunosenescence）均存在一定相关性。免疫衰老主要涉及适应性免疫系统的改变,本文将从T、B细胞的数目、功能、表面分子、分泌的细胞因子及其信号转导等方面的改变进行总结。     

免疫衰老及免疫细胞在衰老中的作用

人类的衰老是一个复杂的生理过程,是机体随着年龄增长出现生理结构的退行性改变以及机能衰退,表现出机体适应性和抵抗力减退的过程。免疫系统是衰老过程的主要调节系统,免疫衰老会导致机体对病原体和癌细胞的抵抗能力降低,同时伴随相关疾病的发生,如心血管疾病、神经系统疾病及癌症等。本文主要综述了免疫衰老以及免疫细胞在衰老中作用的研究进展,旨在阐明免疫衰老与衰老相关疾病的关系及免疫细胞的抗衰老机制,为精准免疫细胞抗衰老模式提供临床应用的新策略。     

细胞自噬在病毒感染与免疫调节中的作用机制

细胞自噬(autophagy)是一种主要由溶酶体介导的降解通路,作为细胞维持内环境稳态的一种保护性机制,不仅通过将长寿命蛋白和衰老细胞器降解为小肽或氨基酸为细胞提供再生资源,而且也可作为防御机制抵抗病原微生物感染和寄生. 自噬缺失与许多疾病如癌症、心血管疾病等的发生关系密切,在机体生理、病理过程中发挥重要作用. 本文拟就细胞自噬与病毒感染、机体免疫的关系加以综述,以期为研究细胞自噬的发生、参与机体免疫、发挥抗病毒感染作用及其分子机制提供参考,也为进一步研究抗病毒治疗的靶标提供新思路.     

病原微生物与巨噬细胞凋亡

病原微生物与机体细胞间的相互关系一直是一热点问题,病原微生物之所以成为病原,一定有其成为病原的理由。不论是细菌、真菌、病毒,还是其代谢产物大都能诱导宿主细胞,特别是免疫系统中某些细胞(如巨噬细胞)凋亡,这也许为其抵抗机体免疫系统的免疫防御及免疫监视,以便在宿主体内生存,进而为大量繁殖开辟了一条道路。     

The aging common marmoset's immune system: From junior to senior

The social, health, and economic challenges of a steadily increasing aging population demand the use of appropriate translational animal models to address questions like healthy aging, vaccination strategies, or potential interventions during the aging process. Due to their genetic proximity to humans, especially nonhuman primates (NHPs) with a relatively short generation period compared to humans, qualify as excellent animal models for these purposes. The use of common marmosets (Callithrix jacchus) in gerontology research steadily increased over the last decades, yet important information about their aging parameters are still missing. We therefore aimed to characterize their aging immune system by comprehensive flow cytometric phenotyping of blood immune cells from juvenile, adult, aging, and geriatric animals. Aged and geriatric animals displayed clear signs of immunosenescence. A decline in CD4/CD8 ratio, increased expression of HLA-DR and PD-1, higher frequencies of CD95⁺ memory cells, alterations in cytokine secretion, and a decline in the proliferative capacity proved T cell senescence in aging marmosets. Also, the B cell compartment was affected by age-related changes: while overall B cell numbers remained stable with advancing age, expression of the activation marker CD80 increased and immunoglobulin M expression decreased. Interestingly, marmoset B cell memory subset distribution rather mirrored the human situation than that of other NHP. CD21⁺ CD27⁻ naïve B cell frequencies decreased while those of CD21⁻ CD27⁻ tissue memory B cells increased with age. Furthermore, frequencies and numbers of NK cells as part of the innate immune system declined with advancing age. Thus, the observed immunological changes in common marmosets over their life span revealed several similarities to age-related changes in humans and encourages further studies to strengthen the common marmoset as a potential aging model.     

Hallmarks of aging and immunosenescence: Connecting the dots

Aging is a natural physiological process that features various and variable challenges, associated with loss of homeostasis within the organism, often leading to negative consequences for health. Cellular senescence occurs when cells exhaust the capacity to renew themselves and their tissue environment as the cell cycle comes to a halt. This process is influenced by genetics, metabolism and extrinsic factors. Immunosenescence, the aging of the immune system, is a result of the aging process, but can also in turn act as a secondary inducer of senescence within other tissues. This review aims to summarize the current state of knowledge regarding hallmarks of aging in relation to immunosenescence, with a focus on aging-related imbalances in the medullary environment, as well as the components of the innate and adaptive immune responses. Aging within the immune system alters its functionality, and has consequences for the person's ability to fight infections, as well as for susceptibility to chronic diseases such as cancer and cardiovascular disease. The senescence-associated secretory phenotype is described, as well as the involvement of this phenomenon in the paracrine induction of senescence in otherwise healthy cells. Inflammaging is discussed in detail, along with the comorbidities associated with this process. A knowledge of these processes is required in order to consider possible targets for the application of senotherapeutic agents - interventions with the potential to modulate the senescence process, thus prolonging the healthy lifespan of the immune system and minimizing the secondary effects of immunosenescence.     

Cellular senescence impact on immune cell fate and function

Cellular senescence occurs not only in cultured fibroblasts, but also in undifferentiated and specialized cells from various tissues of all ages, in vitro and in vivo. Here, we review recent findings on the role of cellular senescence in immune cell fate decisions in macrophage polarization, natural killer cell phenotype, and following T‐lymphocyte activation. We also introduce the involvement of the onset of cellular senescence in some immune responses including T‐helper lymphocyte‐dependent tissue homeostatic functions and T‐regulatory cell‐dependent suppressive mechanisms. Altogether, these data propose that cellular senescence plays a wide‐reaching role as a homeostatic orchestrator.     

Differential maintenance and de novo methylating activity by three DNA methyltransferases in aging and immortalized fibroblasts.

Genomic methylation, which influences many cellular processes such as gene expression and chromatin organization, generally declines with cellular senescence although some genes undergo paradoxical hypermethylation during cellular aging and immortalization. To explore potential mechanisms for this process, we analyzed the methylating activity of three DNA methyltransferases (Dnmts) in aging and immortalized WI-38 fibroblasts. Overall maintenance methylating activity by the Dnmts greatly decreased during cellular senescence. In immortalized WI-38 cells, maintenance methylating activity was similar to that of normal young cells. Combined de novo methylation activity of the Dnmts initially decreased but later increased as WI-38 cells aged and was strikingly elevated in immortalized cells. To further elucidate the mechanisms for changes in DNA methylation in aging and immortalized cells, the individual Dnmts were separated and individually assessed for maintenance and de novo methylating activity. We resolved three Dnmt fractions, one of which was the major maintenance methyltransferase, Dnmt1, which declined steadily in activity with cellular senescence and immortalization. However, a more basic Dnmt, which has significant de novo methylating activity, increased markedly in activity in aging and immortalized cells. We have identified this methyltransferase as Dnmt3b which has an important role in neoplastic transformation but its role in cellular senescence and immortalization has not previously been reported. An acidic Dnmt we isolated also had increased de novo methylating activity in senescent and immortalized WI-38 cells. These studies indicate that reduced genome-wide methylation in aging cells may be attributed to attenuated Dnmt1 activity but that regional or gene-localized hypermethylation in aging and immortalized cells may be linked to increased de novo methylation by Dnmts other than the maintenance methyltransferase.     

Functional analysis of the Drosophila immune response during aging

One of the most dramatic changes associated with aging involves immunity. In aging mammals, immune function declines and chronic inflammation develops. The biological significance of this phenomenon and its relationship with aging is a priority for aging research. Drosophila is an invaluable tool in understanding the effects of aging on the immune response. Similar to the state of chronic inflammation in mammals, Drosophila exhibits a drastic up-regulation of immunity-related genes with age. However, it remains unclear whether immune function declines with age as seen in mammals. We evaluated the impact of aging on Drosophila immune function by examining across age the ability to eliminate and survive different doses of bacterial invaders. Our findings show that aging reduces the capacity to survive a bacterial infection. In contrast, we found no evidence that aging affects the ability to eliminate bacteria indicating that the mechanisms underlying immune senescence are not involved in eliminating bacteria or preventing their proliferation.     

Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is caused by the accumulation of mutant prelamin A (progerin) in the nuclear lamina, resulting in increased nuclear stiffness and abnormal nuclear architecture. Nuclear mechanics are tightly coupled to cytoskeletal mechanics via lamin A/C. However, the role of cytoskeletal/nuclear mechanical properties in mediating cellular senescence and the relationship between cytoskeletal stiffness, nuclear abnormalities, and senescent phenotypes remain largely unknown. Here, using muscle‐derived mesenchymal stromal/stem cells (MSCs) from the Zmpste24^?/? (Z24^?/?) mouse (a model for HGPS) and human HGPS fibroblasts, we investigated the mechanical mechanism of progerin‐induced cellular senescence, involving the role and interaction of mechanical sensors RhoA and Sun1/2 in regulating F‐actin cytoskeleton stiffness, nuclear blebbing, micronuclei formation, and the innate immune response. We observed that increased cytoskeletal stiffness and RhoA activation in progeria cells were directly coupled with increased nuclear blebbing, Sun2 expression, and micronuclei‐induced cGAS‐Sting activation, part of the innate immune response. Expression of constitutively active RhoA promoted, while the inhibition of RhoA/ROCK reduced cytoskeletal stiffness, Sun2 expression, the innate immune response, and cellular senescence. Silencing of Sun2 expression by siRNA also repressed RhoA activation, cytoskeletal stiffness and cellular senescence. Treatment of Zmpste24^?/? mice with a RhoA inhibitor repressed cellular senescence and improved muscle regeneration. These results reveal novel mechanical roles and correlation of cytoskeletal/nuclear stiffness, RhoA, Sun2, and the innate immune response in promoting aging and cellular senescence in HGPS progeria.     

Epigenomic drivers of immune dysfunction in aging

Aging inevitably leads to reduced immune function, leaving the elderly more susceptible to infections, less able to respond to pathogen challenges, and less responsive to preventative vaccinations. No cell type is exempt from the ravages of age, and extensive studies have found age‐related alterations in the frequencies and functions of both stem and progenitor cells, as well as effector cells of both the innate and adaptive immune systems. The intrinsic functional reduction in immune competence is also associated with low‐grade chronic inflammation, termed “inflamm‐aging,” which further perpetuates immune dysfunction. While many of these age‐related cellular changes are well characterized, understanding the molecular changes that underpin the functional decline has proven more difficult. Changes in chromatin are increasingly appreciated as a causative mechanism of cellular and organismal aging across species. These changes include increased genomic instability through loss of heterochromatin and increased DNA damage, telomere attrition, and epigenetic alterations. In this review, we discuss the connections between chromatin, immunocompetence, and the loss of function associated with mammalian immune aging. Through understanding the molecular events which underpin the phenotypic changes observed in the aged immune system, it is hoped that the aged immune system can be restored to provide youthful immunity once more.     

The p53 network: cellular and systemic DNA damage responses in aging and cancer

Genome instability contributes to cancer development and accelerates age-related pathologies as evidenced by a variety of congenital cancer susceptibility and progeroid syndromes that are caused by defects in genome maintenance mechanisms. DNA damage response (DDR) pathways that are mediated through the tumor suppressor p53 play an important role in the cell-intrinsic responses to genome instability, including a transient cell cycle arrest, senescence and apoptosis. Both senescence and apoptosis are powerful tumor-suppressive pathways preventing the uncontrolled proliferation of transformed cells. However, both pathways can potentially deplete stem and progenitor cell pools, thus promoting tissue degeneration and organ failure, which are both hallmarks of aging. p53 signaling is also involved in mediating non-cell-autonomous interactions with the innate immune system and in the systemic adjustments during the aging process. The network of p53 target genes thus functions as an important regulator of cancer prevention and aging.     

Replicative senescence of CD8 T cells: potential effects on cancer immune surveillance and immunotherapy

The process of replicative senescence, which stringently limits the proliferative potential of normal T cells, constitutes a potential problem for cancer immunotherapy. The ability of CD8 T cells to recognize and destroy tumor cells has been well-established, but the requirement for massive, prolonged proliferative T-cell expansion and maintenance of functional integrity poses a significant obstacle to the success of cancer immunotherapy. Cancer immune surveillance may also be compromised by the long-term exposure of T cells to tumor antigens, particularly those of latent viruses, which could drive certain T cells to replicative senescence. This review summarizes the major characteristics of T-cell replicative senescence and raises the possibility that this process has the potential to affect both cancer development and treatment. Experimental strategies aimed at preventing T-cell replicative senescence are discussed in the context of cancer immunotherapy and vaccines.This article forms part of the Symposium in Writing Tumor escape from the immune response, published in Vol. 53.     

On the evolution of cellular senescence

The idea that senescent cells are causally involved in aging has gained strong support from findings that the removal of such cells alleviates many age‐related diseases and extends the life span of mice. While efforts proceed to make therapeutic use of such discoveries, it is important to ask what evolutionary forces might have been behind the emergence of cellular senescence, in order better to understand the biology that we might seek to alter. Cellular senescence is often regarded as an anti‐cancer mechanism, since it limits the division potential of cells. However, many studies have shown that senescent cells often also have carcinogenic properties. This is difficult to reconcile with the simple idea of an anti‐cancer mechanism. Furthermore, other studies have shown that cellular senescence is involved in wound healing and tissue repair. Here, we bring these findings and ideas together and discuss the possibility that these functions might be the main reason for the evolution of cellular senescence. Furthermore, we discuss the idea that senescent cells might accumulate with age because the immune system had to strike a balance between false negatives (overlooking some senescent cells) and false positives (destroying healthy body cells).