“衰老基因”与“长寿基因”

“衰老基因”与“长寿基因”童坦君,张宗玉（北京医科大学生物化学与分子生物学系,北京１０００８３）关键词衰老基因,长寿基因衰老过程存在着遗传程序控制,这一看法确有证据。至于生物体内是否存在专门引起衰老的“衰老基因”或专使寿命延长的“长寿基因”,近年来也...     

人类长寿相关基因研究进展

人类长寿是多因素、系统性生物学现象。衰老死亡是不可抗拒的自然规律,但通过科学研究可以延缓衰老达到延长寿命目的。影响长寿的因素可分为遗传和环境两种,其中遗传因素是决定长寿的内因,而环境因素则作为影响长寿的外因。本文介绍了人类长寿研究领域的研究现状和进展,概括人类长寿相关基因研究中取得的成果,并将人类染色体长寿相关基因归纳为三类,分别是控制炎症和代谢的长寿相关基因,以及控制信号通路的长寿相关基因,并进一步对三类基因中的代表性基因进行介绍。同时,对长寿研究的方向与未来提出了展望。     

寿命相关基因与衰老的生化机制

衰老和长寿基因方面的研究多以线虫 (如C .elegans)、酵母、果蝇、小鼠为模型 ,目前已鉴定了数十种衰老相关基因 ,改变某些基因的活性会延长寿命或促进衰老。最早引起人们兴趣的“老年基因”是DAF 16 ,但其机制至今未明。daf 16编码转录因子DAF 16 ,后者是一种调节其它基因活性的蛋白。DAF 16是C .elegans寿命的重要调节因子 ,它的作用可被某种激素信号途径 (例如由类似于哺乳类胰岛素和胰岛素样生长因子的蛋白激活的信号途径 )所阻断 ,减弱这一信号途径的活动能使成年C .elegans的寿命明显延长 ,对果蝇和小鼠也如此。因此要想完全阐明…     

免疫基因多态性与衰老和增龄相关疾病关系

衰老是进行性的、多细胞普遍存在的、不可逆的功能减退状态。免疫衰老主要表现为造血干细胞再生和淋巴系分化能力下降、机体对感染和疫苗的反应减弱、对炎症反应的放大和自身的免疫反应增加, 与衰老和增龄相关疾病密切相关。免疫基因变异, 影响机体免疫反应, 可加速或延缓衰老和增龄相关疾病。获得性免疫基因, 如对自身免疫性疾病起保护性作用的HLA II 抗原基因DRB1*11和DRB*16相关的单倍型在长寿老人频率增加。抗炎因子IL-10-1082G等位基因频率和TGFβ1单倍型cnd10T/C、cnd25G/G、-988C/C、-800G/A频率的下降, 促炎因子TNFα低表达相关的扩展的TNF-A基因型-1031C/C、-863C/A、-857C/C、IL-6-174 CC基因型, 和IFN-γ+874 T等位基因频率减少与免疫炎症反应易感性, 衰老相关疾病的发病率和死亡率正相关。固有免疫基因, 如高频表达抗炎的+896 G KIR4等位基因、CCR5Δ32突变、-765 C Cox-2等位基因、-1708 G和21 C 5-Lox等位基因多见于长寿老人。KIR 单倍型 KIR2DS5、A1B10减少, MBL2表达缺乏的单倍型LYPB、LYQC 和HYPD增加的老年人常伴有较高血清CMV抗体滴度。高频出现的CRP ATG单倍型和CFH 402 His 等位基因预示老年人高死亡率风险。文章对固有和获得性免疫基因多态性、单倍体与衰老及衰老相关疾病关系进展进行综述。加强分析扩展的单倍型、表观遗传学和造血干细胞衰老的遗传学研究将有助于更好地理解衰老和长寿的免疫遗传学基础。     

daf—2和daf—16基因的结构与功能研究进展

在长寿和衰老的研究中,人们发现调控休眠态的幼虫形成的基因（daf基因）能影响线虫的长寿,其中daf-2、daf-16是作用于这一遗传调宾通路下游的两个重要基因,daf-2是胰岛素受体样基因,daf-16是编码转录调控因子中叉头家族/肝细胞核心因子3（HNF-3）的成员。     

长寿与衰老相关分子机制研究进展

长寿是一个复杂的特征,因遗传、环境等因素的差异而不同,理想情况下主要取决于衰老速率。相关分子机制多种多样,主要有生长激素(GH)和胰岛素样生长因子1(IGF-1)途径、Forkhead box O3基因(FOXO3)、AMP活化蛋白激酶(AMPK)、sirtuins家族基因、载脂蛋白E基因(APOE)、端粒酶基因、mTOR信号通路、抑癌基因p53、慢性炎症转录因子NF-κB、自噬-溶酶体信号通路、长链非编码RNA(lncRNAs)、蛋氨酸亚砜还原酶系统(Msr)。同时,环境因素也影响着人类的寿命,例如饮食限制、运动、地理条件、环境压力等。本文从遗传和环境两方面综述影响人类寿命因素的最新研究进展。     

《基因组研究》：美科学家发现25个“长寿基因”

新华网消息：美国科学家日前通过对芽殖酵母和线虫的基因分析,鉴别出两种生物共有的25个负责调控寿命长短的基因。美国华盛顿大学等机构的科学家3月13日在《基因组研究》（Genome Research）杂志上报告说,在这25个“长寿基因”中,至少15个在人的基因组内存在相似版本。这意味着,科学家有可能借此锁定人体内的基因目标,研究如何减缓人的衰老过程,治疗衰老引发的相关疾病。     

衰老的分子机制与干预研究的最新进展

随着全球老龄化时代的到来,衰老和衰老相关疾病带来的健康问题日益突出。如何最大限度地维持老龄人口健康、干预衰老相关疾病并延缓衰老的发生对于医疗系统、科研机构乃至整个社会都是巨大的挑战。目前,对于衰老的分子机制研究已经有长足的进步,对于衰老进程的生物学和遗传学机制已有突破性的认识,对于衰老相关疾病的发病机制也有了深刻的理解。但这些研究成果还远远达不到能够延缓人类衰老并遏制衰老相关疾病的发生的要求。该文将从衰老的分子机制和干预手段这两个方面入手,综述衰老的理论研究和实际应用中的主要成果和最新进展。     

基因重组技术在衰老研究中的应用

近年来应用基因重组技术在发现衰老相关基因,研究中枢神经系统衰老,构建老年病模型及老年性疾病的基因治疗等方面取得了一些进展。１．衰老相关基因的发现日本学者Ｋｕｒｏ等发现突变的ｋｌｏｔｈｏ基因缺陷小鼠产生衰老表现,且寿命缩短。他们是在研究高血压病遗传变化...     

果蝇有类似人类的衰老基因

英国科学家在果蝇身上发现一种基因,其角色类似于人类衰老基因。果蝇因而可能成为研究人类衰老的试验对象。人类有一种沃纳综合征,患者在青春期前便过早衰老,其根源在于一种叫做WRN的基因的变异。之前科学家只能研究该基因在单个细胞中的工作方式,却无法探索其在发育中和整体上     

HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging

The search for longevity‐determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were recruited and stratified according to their genetically inferred ethnic affiliation to account for population structure. Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These results were replicated in a second population. A profile of healthy aging was developed using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity.     

Why genes extending lifespan in model organisms have not been consistently associated with human longevity and what it means to translation research

A recent paper by Deelen et al. (2014) in Human Molecular Genetics reports the largest genome-wide association study of human longevity to date. While impressive, there is a remarkable lack of association of genes known to considerably extend lifespan in rodents with human longevity, both in this latest study and in genetic association studies in general. Here, I discuss several possible explanations, such as intrinsic limitations in longevity association studies and the complex genetic architecture of longevity. Yet one hypothesis is that the lack of correlation between longevity-associated genes in model organisms and genes associated with human longevity is, at least partly, due to intrinsic limitations and biases in animal studies. In particular, most studies in model organisms are conducted in strains of limited genetic diversity which are then not applicable to human populations. This has important implications and, together with other recent results demonstrating strain-specific longevity effects in rodents due to caloric restriction, it questions our capacity to translate the exciting findings from the genetics of aging to human therapies.     

Wide‐scale comparative analysis of longevity genes and interventions

Hundreds of genes, when manipulated, affect the lifespan of model organisms (yeast, worm, fruit fly, and mouse) and thus can be defined as longevity‐associated genes (LAGs). A major challenge is to determine whether these LAGs are model‐specific or may play a universal role as longevity regulators across diverse taxa. A wide‐scale comparative analysis of the 1805 known LAGs across 205 species revealed that (i) LAG orthologs are substantially overrepresented, from bacteria to mammals, compared to the entire genomes or interactomes, and this was especially noted for essential LAGs; (ii) the effects on lifespan, when manipulating orthologous LAGs in different model organisms, were mostly concordant, despite a high evolutionary distance between them; (iii) LAGs that have orthologs across a high number of phyla were enriched in translational processes, energy metabolism, and DNA repair genes; (iv) LAGs that have no orthologs out of the taxa in which they were discovered were enriched in autophagy (Ascomycota/Fungi), G proteins (Nematodes), and neuroactive ligand–receptor interactions (Chordata). The results also suggest that antagonistic pleiotropy might be a conserved principle of aging and highlight the importance of overexpression studies in the search for longevity regulators.     

衰老机制及其学说

不同物种,同一个体的不同组织和细胞,它们的衰老速度并不相同。究其原因,遗传与环境都能影响衰老的进程。个体的平均寿命和物种的最高寿限可以从不同侧面反映衰老的进程。目前认为平均寿命主要与环境相关,而物种最高寿限与遗传相关。从两者的关系看,不良环境影响是通过对遗传物质或其产物的作用而影响衰老的进程。从遗传因素看,衰老并非由单一基因或单一作用所决定,而是一连串基因激活和阻抑及其通过各自产物相互作用的结果。DNA（特别是线粒体DNA）并不像原先设想的那样稳定,目前业已证明,包括基因在内的遗传控制体系可受内、外环境,特别是氧自由基等损伤因素的影响,从而加速衰老的进程。     

Genetics and epigenetics of aging and longevity

Evolutionary theories of aging predict the existence of certain genes that provide selective advantage early in life with adverse effect on lifespan later in life (antagonistic pleiotropy theory) or longevity insurance genes (disposable soma theory). Indeed, the study of human and animal genetics is gradually identifying new genes that increase lifespan when overexpressed or mutated: gerontogenes. Furthermore, genetic and epigenetic mechanisms are being identified that have a positive effect on longevity. The gerontogenes are classified as lifespan regulators, mediators, effectors, housekeeping genes, genes involved in mitochondrial function, and genes regulating cellular senescence and apoptosis. In this review we demonstrate that the majority of the genes as well as genetic and epigenetic mechanisms that are involved in regulation of longevity are highly interconnected and related to stress response.     

The influence of metabolic rate on longevity in the nematode Caenorhabditis elegans

Much of the recent interest in aging research is due to the discovery of genes in a variety of model organisms that appear to modulate aging. A large amount of research has focused on the use of such long-lived mutants to examine the fundamental causes of aging. While model organisms do offer many advantages for studying aging, it also critical to consider the limitations of these systems. In particular, ectothermic (poikilothermic) organisms can tolerate a much larger metabolic depression than humans. Thus, considering only chronological longevity when assaying for long-lived mutants provides a limited perspective on the mechanisms by which longevity is increased. In order to provide true insight into the aging process additional physiological processes, such as metabolic rate, must also be assayed. This is especially true in the nematode Caenorhabditis elegans, which can naturally enter into a metabolically reduced state in which it survives many times longer than its usual lifetime. Currently it is seen as controversial if long-lived C. elegans mutants retain normal metabolic function. Resolving this issue requires accurately measuring the metabolic rate of C. elegans under conditions that minimize environmental stress. Additionally, the relatively small size of C. elegans requires the use of sensitive methodologies when determining metabolic rates. Several studies indicating that long-lived C. elegans mutants have normal metabolic rates may be flawed due to the use of inappropriate measurement conditions and techniques. Comparisons of metabolic rate between long-lived and wild-type C. elegans under more optimized conditions indicate that the extended longevity of at least some long-lived C. elegans mutants may be due to a reduction in metabolic rate, rather than an alteration of a metabolically independent genetic mechanism specific to aging.     

Predicting aging/longevity-related genes in the nematode Caenorhabditis elegans

We present a novel mathematical/computational strategy for predicting genes/proteins associated with aging/longevity. The novelty of our method arises from the topological analysis of an organismal longevity gene/protein network (LGPN), which extends the existing cellular networks. The LGPN nodes represent both genes and corresponding proteins. Links stand for all known interactions between the nodes. The LGPN of C. elegans incorporated 362 genes/proteins, 160 connecting and 202 age-related ones, from a list of 321 with known impact on aging/longevity. A 'longevity core' of 129 directly interacting genes or proteins was identified. This core may shed light on the large-scale mechanisms of aging. Predictions were made, based upon the finding that LGPN hubs and centrally located nodes have higher likelihoods of being associated with aging/longevity than do randomly selected nodes. Analysis singled-out 15 potential aging/longevity-related genes for further examination: mpk-1, gei-4, csp-1, pal-1, mkk-4, 4O210, sem-5, gei-16, 1O814, 5M722, ife-3, ced-10, cdc-42, 1O776Co, and 1O690.     

Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans

Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians'' offspring, and 65 age‐matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified 1312 proteins that significantly differ between centenarians and their offspring and controls (FDR < 1%), and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with 2 independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age. The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence‐associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence. Protein co‐expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity.     

Lithocholic acid extends longevity of chronologically aging yeast only if added at certain critical periods of their lifespan

Our studies revealed that LCA (lithocholic bile acid) extends yeast chronological lifespan if added to growth medium at the time of cell inoculation. We also demonstrated that longevity in chronologically aging yeast is programmed by the level of metabolic capacity and organelle organization that they developed before entering a quiescent state and, thus, that chronological aging in yeast is likely to be the final step of a developmental program progressing through at least one checkpoint prior to entry into quiescence. Here, we investigate how LCA influences longevity and several longevity-defining cellular processes in chronologically aging yeast if added to growth medium at different periods of the lifespan. We found that LCA can extend longevity of yeast under CR (caloric restriction) conditions only if added at either of two lifespan periods. One of them includes logarithmic and diauxic growth phases, whereas the other period exists in early stationary phase. Our findings suggest a mechanism linking the ability of LCA to increase the lifespan of CR yeast only if added at either of the two periods to its differential effects on various longevity-defining processes. In this mechanism, LCA controls these processes at three checkpoints that exist in logarithmic/diauxic, post-diauxic and early stationary phases. We therefore hypothesize that a biomolecular longevity network progresses through a series of checkpoints, at each of which (1) genetic, dietary and pharmacological anti-aging interventions modulate a distinct set of longevity-defining processes comprising the network; and (2) checkpoint-specific master regulators monitor and govern the functional states of these processes.