长寿和衰老基因及相关基因研究进展

简要介绍了长寿和衰老基因及相关基因在酵母、线虫、果蝇和哺乳动物中的最新遗传学研究进展；概述了“生物钟”、端粒和端粒酶在人类长寿和衰老进程中的重要作用。相信随着人类遗传学和分子生物学研究的深入，将有更多的长寿和衰老基因及相关基因被发现，为揭示衰老机制和延年益寿提供依据。     

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。     

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。     

“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...     

HLA与长寿及寿限关系的初步观察—附超氧化物歧化酶(SOD）检查结果

目前一般认为,衰老与长寿的机理是受综 合性而非单一因素的影响,其中遗传是一个公 认的重要或主要因素〔7,9,12,15,161。研究各种族或各 地区人体白细胞抗原（HLA）与长寿老人（>90 岁）的关系,有可能对衰老与遗传的关系提供 有价值的资料及进一步研究的线索。国外对 HLA与衰老及寿限的关系尚无一致的意见[5,810 鉴于遗传可能仅在极端长寿对象中方可显示其 对寿限的效应‘,,, 选择长寿老人作为观察对象 可能较为适当[141。国外应用长寿老人作HLA 与寿限相关性的探讨,只在近年有少数资 料17,8,10,141,国内尚未见到这方面的报道。我们 于1983年检查了50例长寿老人,8例高龄老 人（80-89岁）的HLA 分型,并与210例2 0- 知岁组对照比较,同时用化学比色法测定红细 胞超氧化物歧化酶(Superoxide Dismutase, SOD) 含量及其他有关检查。兹将结果分析讨论如 下。     

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。     

饮食限制延长寿命的遗传机制

饮食限制(Dietary restriction,DR)有效延长了哺乳动物的寿命,也使许多年龄依赖性疾病的发病率降低且延缓其进展。理解饮食限制引起长寿的遗传机制,会对将来处理衰老相关的医疗问题产生深远影响。然而直到最近人们对后生动物的这些机制几乎仍一无所知。通过理解能量感知和寿命控制遗传基础的最新进展,在酵母、无脊椎动物和哺乳动物中,已开始解决这个难题。越来越多的证据表明,后生动物大脑在感应饮食限制和促进寿命延长中起关键作用,因此文章综述了近来后生动物DR长寿的调解因子与DR长寿的基因和神经调节机制及有关理论的进展。     

人类身高的遗传学研究进展

人类身高是由环境和遗传因素共同决定的,遗传学研究发现遗传因素对身高差异的影响更大。身高是典型的多基因遗传性状,科研人员试图运用传统的连锁分析和关联分析寻找和发现对人类身高具有显著影响的常见DNA序列变异,但进展缓慢。近年来,随着基因分型和DNA测序技术的发展,人类身高的遗传学研究取得了很多突破性进展。全基因组关联分析(GWAS)的应用,发现和证实了上百个与人类身高相关的单核苷酸多态性位点(SNPs),拓展了人们对人类生长和发育的相关遗传学认识,同时也为研究人类其他复杂性状提供了理论依据和借鉴。本文综述了人类身高的遗传学研究进展,探讨了目前该研究领域所存在的问题和未来发展方向,以期为今后人类身高相关的遗传学研究提供参考和借鉴。     

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...     

水稻叶片衰老相关基因的研究进展

水稻叶片的衰老是制约杂交稻产量提高的主要因素之一,有数据表明水稻籽粒灌浆所需营养物质的60%～80%来自叶片的光合作用,实践证明叶片每推迟1天衰老,产量可提高产1%左右.因此,对叶片衰老的形态、生理生化及其相关分子机理等进行研究具有重要的现实意义.近年来水稻叶片衰老的相关研究表明,叶片的衰老是一个受众多因素影响的复杂过程,在这个过程中叶片发生了巨大的形态与生理生化变化,而这些变化均离不开基因的调控作用.大量实验结果表明:在衰老过程中,叶片细胞有选择地启动或增强某些基因(叶片衰老相关基因)的表达,而关闭或减弱另一些基因(衰老下调基因)的表达,由此来调控叶片衰老的进程.目前研究者已在研究衰老突变体等相关的材料中发现了许多与水稻叶片衰老有关的基因.本文重点概述了近年来水稻叶片衰老相关基因的研究状况,并对未来研究方向等问题做了思考与探讨,以期能为开展进一步的研究工作提供参考.     

植物种子寿命的生理及分子机制研究进展

种子寿命是衡量种子质量高低的关键指标之一,直接关系到种子萌发、萌发后幼苗的生长发育以及作物产量高低。种子寿命的调控是一个复杂的生物学过程,影响种子寿命的因素包括环境因素、种子自身的结构、营养成分组成及含量以及调控种子寿命相关的关键基因。研究储藏过程中种子生理生化指标的变化,以及相应关键基因的生物学功能,掌握调控种子寿命的生理及分子机制,对于减少种子内部能量消耗,进一步延长种子寿命具有重要意义。该文综述了近年来国内外有关调控种子寿命的生理及分子机制,重点阐述了调控种子寿命的相关关键基因的研究进展,并讨论了各种外部因素对种子寿命的调控机理。     

A high recombination rate in eusocial Hymenoptera: evidence from the common wasp Vespula vulgaris

Background

Longevity expressed as the number of days between birth and death is a trait of great importance for both human and animal populations. In our analysis we use dairy cattle to demonstrate how the association of Single Nucleotide Polymorphisms (SNPs) located within selected genes with longevity can be modeled. Such an approach can be extended to any genotyped population with time to endpoint information available. Our study is focused on selected genes in order to answer the question whether genes, known to be involved into the physiological determination of milk production, also influence individual's survival.

Results

Generally, the highest risk differences among animals with different genotypes are observed for polymorphisms located within the leptin gene. The polymorphism with a highest effect on functional longevity is LEP-R25C, for which the relative risk of culling for cows with genotype CC is 3.14 times higher than for the heterozygous animals. Apart from LEP-R25C, also FF homozygotes at the LEP-Y7F substitution attribute 3.64 times higher risk of culling than the YY homozygotes and VV homozygotes at LEP-A80V have 1.83 times higher risk of culling than AA homozygotes. Differences in risks between genotypes of polymorphisms within the other genes (the butyrophilin subfamily 1 member A1 gene, BTN1A1; the acyl-CoA:diacylglycerol acyltransferase 1 gene, DGAT1; the leptin receptor gene, LEPR; the ATP-binding cassette sub-family G member 2, ABCG2) are much smaller.

Conclusions

Our results indicate association between LEP and longevity and are very well supported by results of other studies related to dairy cattle. In view of the growing importance of functional traits in dairy cattle, LEP polymorphisms should be considered as markers supporting selection decisions. Furthermore, since the relationship between both LEP polymorphism and its protein product with longevity in humans is well documented, with our result we were able to demonstrate that livestock with its detailed records of family structure, genetic, and environmental factors as well as extensive trait recording can be a good model organism for research aspects related to humans.     

Shuttling between species for pathways of lifespan regulation: A central role for the vitellogenin gene family?

Studies to find genes that affect maximum lifespan aim at identifying important determinants of ageing that may be universal across species. Model organisms show insulin signalling can play an important role in ageing. In view of insulin resistance, such loci can also be important in human ageing and health. The study of long-lived humans and their children points to the relevance of lipoprotein profiles and particle size for longevity. If ageing pathways are conserved, then the genes mediating such pathways may also be conserved. Cross-species sequence comparisons of potential longevity loci may reveal whether the pathways that they represent are central themes in lifespan regulation. Using bioinformatic tools, we performed a sequence comparison of the genes involved in lipid metabolism identified in humans as potential longevity loci. This analysis revealed that lipid storage and transport may be a common theme related to longevity in humans, honeybees and nematodes. Here, the vitellogenin family emerges as a potential key connection between lipid metabolism and the insulin/IGF-1 signalling pathway.     

Genetics of healthy aging and longevity

Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may ‘buffer’ the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.     

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.     

Genomics of human longevity

In animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent. The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex. Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction. Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small. Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology. Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death. By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress.