前景可观的senolytics延缓衰老的研究进展

细胞衰老呈现不可逆的永久性细胞周期停滞的状态,它可以促进组织在发育过程中和损伤后的重塑,但也会导致老年生物体组织再生潜力和功能的下降,以及炎症和肿瘤的发生。研究发现,清除衰老细胞可以延缓衰老相关疾病的发生。因此,探究衰老细胞的分子特征与探索清除衰老细胞的新药成为衰老研究领域的热点。近年来,人们发现一类称为senolytics的小分子化合物能特异性靶向衰老细胞并帮助清除衰老细胞,从而延长哺乳动物的寿命及健康寿命。该文对衰老细胞的分子特征、作为衰老相关疾病的治疗靶点及具有senolytics活性的化合物作用机制和潜在应用进行了综述。

细胞衰老与抗衰老药物senolytics的研究进展

细胞衰老是一种稳定的增殖抑制并伴有衰老相关的分泌表型(SASP)。其发生主要是由于细胞在复制过程中端粒酶的消耗以及外界衰老相关刺激如癌基因激活、活性氧积聚、DNA损伤等。短期内衰老细胞的产生有助于机体胚胎发育、损伤修复和肿瘤抑制等;而机体内长期积聚衰老的细胞会导致肿瘤的发生、机体老化和老化相关的疾病。近年来研究发现,特异性清除体内衰老细胞有助于延缓机体老化、重塑身体机能等;这再次将衰老相关的研究推向了一个新的高度。该文将从细胞衰老的主要特征、生理学功能、发生机制及抗衰老药物senolytics的发展等方面进行讨论,并结合相关研究的最新进展,为衰老及相关疾病的防治提供理论依据。

细胞衰老的过去、现在和未来:从科学解析到主动干预

高等生物体内的细胞衰老是机体衰老的原始驱动力,通过终止细胞周期循环来应对内外源胁迫性刺激。衰老细胞在整个生命周期中均可出现,但若长期或持续性出现,组织器官的正常功能会因其分泌的大量促炎性蛋白而受到病理性损害。在临床前模型中,针对那些持续存在并导致组织紊乱和器官损伤的衰老细胞进行干预已被证明可以有效延缓衰老、预防或缓解多种增龄相关疾病。尤其重要的,衰老医学界针对选择性清除衰老细胞的小分子药物senolytics的研发为积极预防或干预人类多种增龄相关疾病提供了强大的动力和灿烂的远景。在这篇综述中,笔者将介绍将衰老细胞作为老年疾病治疗靶点的基本原理,讨论近年正在兴起并迅速推广的人类临床试验的技术策略和发展前景,包括那些将小分子化合物senolytics及其相关衰老干预措施转化为临床应用的国际前沿探索。

Recent developments of neuroprotective agents for degenerative retinal disorders

Retinal degeneration is a debilitating ocular complication characterized by the progressive loss of photoreceptors and other retinal neurons,which are caused by a group of retinal diseases affecting various age groups,and increasingly prevalent in the elderly.Age-related macular degeneration,diabetic retinopathy and glaucoma are among the most common complex degenerative retinal disorders,posing significant public health problems worldwide largely due to the aging society and the lack of effective therapeutics.Whilst pathoetiologies vary,if left untreated,loss of retinal neurons can result in an acquired degeneration and ultimately severe visual impairment.Irrespective of underlined etiology,loss of neurons and supporting cells including retinal pigment epithelium,microvascular endothelium,and glia,converges as the common endpoint of retinal degeneration and therefore discovery or repurposing of therapies to protect retinal neurons directly or indirectly are under intensive investigation.This review overviews recent developments of potential neuroprotectants including neuropeptides,exosomes,mitochondrial-derived peptides,complement inhibitors,senolytics,autophagy enhancers and antioxidants either still experimentally or in clinical trials.Effective treatments that possess direct or indirect neuroprotective properties would significantly lift the burden of visual handicap.

Emerging role of cellular senescence in normal lung development and perinatal lung injury

Cellular senescence is a status of irreversible growth arrest,which can be triggered by the p53/p21cip1 and p16INK4/Rb pathways via intrinsic and external factors.Senescent cells are typically enlarged and flattened,and characterized by numerous molecular features.The latter consists of increased surfaceome,increased resid-ual lysosomal activity at pH 6.0(manifested by increased activity of senescence-associated beta-galactosidase[SA-𝛽-gal]),senescence-associated mitochondrial dysfunction,cytoplasmic chromatin fragment,nuclear lamin b1 exclusion,telomere-associated foci,and the senescence-associated secretory phenotype.These features vary depending on the stressor leading to senescence and the type of senescence.Cellular senescence plays pivotal roles in organismal aging and in the pathogenesis of aging-related diseases.Interestingly,senescence can also both promote and inhibit wound healing processes.We recently report that senescence as a programmed pro-cess contributes to normal lung development.Lung senescence is also observed in Down Syndrome,as well as in premature infants with bronchopulmonary dysplasia and in a hyperoxia-induced rodent model of this disease.Furthermore,this senescence results in neonatal lung injury.In this review,we briefly discuss the molecular features of senescence.We then focus on the emerging role of senescence in normal lung development and in the pathogenesis of bronchopulmonary dysplasia as well as putative signaling pathways driving senescence.Finally,we discuss potential therapeutic approaches targeting senescent cells to prevent perinatal lung diseases.

Multiple characteristic alterations and available therapeutic strategies of cellular senescence

Given its state of stable proliferative inhibition,cellular senescence is primarily depicted as a critical mechanism by which organisms delay the progression of carcinogenesis.Cells undergoing senescence are often associated with the alteration of a series of specific features and functions,such as metabolic shifts,stemness induction,and microenvironment remodeling.However,recent research has revealed more complexity associated with senescence,including adverse effects on both physiological and pathological processes.How organisms evade these harmful consequences and survive has become an urgent research issue.Several therapeutic strategies targeting senescence,including senolytics,senomorphics,immunotherapy,and function restoration,have achieved initial success in certain scenarios.In this review,we describe in detail the characteristic changes associated with cellular senescence and summarize currently available countermeasures.

NLRP3炎性小体影响血管衰老的机制及其相关药物的研发

NOD (nucleotide binding oligomerization domain)样受体家族3 (NOD-like receptor protein 3, NLRP3)炎症小体调控天冬氨酸特异蛋白酶-1 (caspase-1)、白细胞介素-18 (interleukin-18, IL-18)和IL-1β等细胞因子的分泌并参与衰老过程。研究发现, NLRP3炎性小体在衰老心脏和血管中被异常激活,抑制NLRP3炎性小体可缓解心脏与血管衰老。本文对NLRP3炎性小体在心脏血管衰老中的研究和相关药物进行综述,以促进NLRP3炎性小体在心血管衰老中作用机制的发现和相关药物的研发。

主要抗衰老药物的研究进展

衰老是导致有效生理功能下降的生物学过程。人体的衰老会导致重要器官系统的功能障碍,从而引起年龄相关疾病如神经退行性疾病、心血管疾病和免疫调节疾病的发作,严重影响人们的生活质量。随着社会的发展和科学水平的提高,旨在延长寿命、改善健康状态的抗衰老研究逐渐受到重视。这篇综述总结了目前发现的一些具有抗衰老潜力的药物,如雷帕霉素、白藜芦醇、姜黄素等。本文通过总结探讨了抗衰老药物的作用机制,旨在为抗衰老机制的探索以及发现新的具有抗衰老功效的药物提供参考。

Senescence in chronic wounds and potential targeted therapies

Chronic wounds(e.g.diabetic wounds,pressure wounds,vascular ulcers,etc.)do not usually heal in a timely and orderly manner but rather last for years and may lead to irreversible adverse events,resulting in a substantial financial burden for patients and society.Recently,a large amount of evidence has proven that cellular senescence has a crucial influence on chronic nonhealing wounds.As a defensive mechanism,cell senescence is a manner of cell-cycle arrest with increased secretory phenotype to resist death,preventing cells from stress-induced damage in cancer and noncancer diseases.A growing amount of research has advanced the perception of cell senescence in various chronic wounds and focuses on pathological and physiological processes and therapies targeting senescent cells.However,previous reviews have failed to sum up novel understandings of senescence in chronic wounds and emerging strategies targeting senescence.Herein,we discuss the characteristics and mechanisms of cellular senescence and the link between senescence and chronic wounds as well as some novel antisenescence strategies targeting other diseases that may be applied for chronic wounds.

基于肿瘤细胞衰老的癌症治疗策略

细胞衰老是一种生理现象。肿瘤细胞衰老后,生长受到抑制,表达不同以往的表型,并在一定程度上激活体内免疫监视,限制肿瘤的发生发展。近期研究表明,应激刺激、化疗放疗均可诱导肿瘤细胞衰老。衰老因此成为凋亡之外抑制肿瘤生长的另一途径,同时也成为临床控制癌症的新思路。但衰老细胞分泌的炎性因子、基质重塑蛋白酶等长期存在于肿瘤微环境,会诱导肿瘤复发及转移。随着诱导肿瘤细胞衰老逐渐成为一种治疗概念,如何发挥其优势,减少副作用是目前研究的重点。该文讨论了增强免疫监视、抑制促癌衰老相关分泌表型及应用Senolytic药物等几种方法,以期与诱导肿瘤细胞衰老相结合,为癌症治疗提供有效新策略。

Cellular senescence:from anti-cancer weapon to anti-aging target

Cellular senescence(CS)is a state of stable cell cycle arrest characterized by the production and secretion of inflammatory molecules.Early studies described oncogene-induced senescence(OIS)as a barrier to tumorigenesis,such that the therapeutic induction of CS might represent a rational anti-cancer strategy.Indeed,the validity of this approach has been borne out by the development and approval of the cyclin-dependent kinase(CDK)inhibitor palbociclib for the treatment of breast cancer.Apart from tumors,senescent cells have also been shown to accumulate during natural mammalian aging,where they produce detrimental effects on the physiology of surrounding tissues.Thus,pharmacological senescent cell depletion has been proposed as an approach to delay age-related functional decline;this has been formally demonstrated in animal models.In this review article,we describe the current mechanistic understanding of cellular senescence at the molecular level and how it informs the development of new therapeutic strategies to combat cancer and aging.

Engineering osteoarthritic cartilage model through differentiating senescent human mesenchymal stem cells for testing disease-modifying drugs

Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.

肺衰老在慢性呼吸系统疾病中的研究进展

细胞衰老是一个极其复杂的过程,其特征表现为线粒体结构功能障碍、端粒缩短、炎症微环境、蛋白稳态失衡、表观遗传改变、DNA损伤修复异常等,进而导致组织和器官的结构、功能损伤并诱发衰老相关疾病的发生和发展。衰老既包括增龄引起的生理性衰老,还包括多种因素所诱发的病理性衰老。值得注意的是,肺作为与外界空气直接接触的靶器官更易于遭受多种刺激而出现病理性早衰,即肺衰老。研究发现在大多数慢性呼吸系统疾病的肺内都存在一定比例的衰老细胞,但是这些衰老细胞诱导肺衰老及其在慢性呼吸系统疾病中作用的内在机制仍很不清楚。本文重点描述了肺衰老的诱因和分类、肺衰老参与慢性呼吸系统疾病的内在机制及抗衰老治疗在慢性呼吸系统疾病中的应用,有望为临床上慢性呼吸系统疾病的防治提供新的研究思路和理论依据。