The genetics of aging in the yeastSaccharomyces cerevisiae

The yeastSaccharomyces cerevisiae possesses a finite life span similar in many attributes and implications to that of higher eukaryotes. Here, the measure of the life span is the number of generations or divisions the yeast cell has undergone. The yeast cell is the organism, simplifying many aspects of aging research. Most importantly, the genetics of yeast is highly-developed and readily applicable to the dissection of longevity. Two candidate longevity genes have already been identified and are being characterized. Others will follow through the utilization of both the primary phenotype and the secondary phenotypes associated with aging in yeast. An ontogenetic theory of longevity that follows from the evolutionary biology of aging is put forward in this article. This theory has at its foundation the asymmetric reproduction of cells and organisms, and it makes specific predictions regarding the genetics, molecular mechanisms, and phenotypic features of longevity and senescence, including these: GTP-binding proteins will frequently be involved in determining longevity, asymmetric cell division will be often encountered during embryogenesis while binary fission will be more characteristic of somatic cell division, tumor cells of somatic origin will not be totipotent, and organisms that reproduce symmetrically will not have intrinsic limits to their longevity.     

Aging and longevity genes

The genetics of aging has made substantial strides in the past decade. This progress has been confined primarily to model organisms, such as filamentous fungi, yeast, nematodes, fruit flies, and mice, in which some thirty-five genes that determine life span have been cloned. These genes encode a wide array of cellular functions, indicating that there must be multiple mechanisms of aging. Nevertheless, some generalizations are already beginning to emerge. It is now clear that there are at least four broad physiological processes that play a role in aging: metabolic control, resistance to stress, gene dysregulation, and genetic stability. The first two of these at least are common themes that connect aging in yeast, nematodes, and fruit flies, and this convergence extends to caloric restriction, which postpones senescence and increases life span in rodents. Many of the human homologs of the longevity genes found in model organisms have been identified. This will lead to their use as candidate human longevity genes in population genetic studies. The urgency for such studies is great: The population is graying, and this research holds the promise of improvement in the quality of the later years of life.     

Integrating evolutionary and molecular genetics of aging

Aging or senescence is an age-dependent decline in physiological function, demographically manifest as decreased survival and fecundity with increasing age. Since aging is disadvantageous it should not evolve by natural selection. So why do organisms age and die? In the 1940s and 1950s evolutionary geneticists resolved this paradox by positing that aging evolves because selection is inefficient at maintaining function late in life. By the 1980s and 1990s this evolutionary theory of aging had received firm empirical support, but little was known about the mechanisms of aging. Around the same time biologists began to apply the tools of molecular genetics to aging and successfully identified mutations that affect longevity. Today, the molecular genetics of aging is a burgeoning field, but progress in evolutionary genetics of aging has largely stalled. Here we argue that some of the most exciting and unresolved questions about aging require an integration of molecular and evolutionary approaches. Is aging a universal process? Why do species age at different rates? Are the mechanisms of aging conserved or lineage-specific? Are longevity genes identified in the laboratory under selection in natural populations? What is the genetic basis of plasticity in aging in response to environmental cues and is this plasticity adaptive? What are the mechanisms underlying trade-offs between early fitness traits and life span? To answer these questions evolutionary biologists must adopt the tools of molecular biology, while molecular biologists must put their experiments into an evolutionary framework. The time is ripe for a synthesis of molecular biogerontology and the evolutionary biology of aging.     

Chronological aging-induced apoptosis in yeast

Saccharomyces cerevisiae is the simplest among the major eukaryotic model organisms for aging and diseases. Longevity in the chronological life span paradigm is measured as the mean and maximum survival period of populations of non-dividing yeast. This paradigm has been used successfully to identify several life-regulatory genes and three evolutionary conserved pro-aging pathways. More recently, Schizosaccharomyces pombe has been shown to age chronologically in a manner that resembles that of S. cerevisiae and that depends on the activity of the homologues of two pro-aging proteins previously identified in the budding yeast. Both yeast show features of apoptotic death during chronological aging. Here, we review some fundamental aspects of the genetics of chronological aging and the overlap between yeast aging and apoptotic processes with particular emphasis on the identification of an aging/death program that favors the dedifferentiation and regrowth of a few better adapted mutants generated within populations of aging S. cerevisiae. We also describe the use of a genome-wide screening technique to gain further insights into the mechanisms of programmed death in populations of chronologically aging S. cerevisiae.     

Genetic determinants of human health span and life span: progress and new opportunities

We review three approaches to the genetic analysis of the biology and pathobiology of human aging. The first and so far the best-developed is the search for the biochemical genetic basis of varying susceptibilities to major geriatric disorders. These include a range of progeroid syndromes. Collectively, they tell us much about the genetics of health span. Given that the major risk factor for virtually all geriatric disorders is biological aging, they may also serve as markers for the study of intrinsic biological aging. The second approach seeks to identify allelic contributions to exceptionally long life spans. While linkage to a locus on Chromosome 4 has not been confirmed, association studies have revealed a number of significant polymorphisms that impact upon late-life diseases and life span. The third approach remains theoretical. It would require longitudinal studies of large numbers of middle-aged sib-pairs who are extremely discordant or concordant for their rates of decline in various physiological functions. We can conclude that there are great opportunities for research on the genetics of human aging, particularly given the huge fund of information on human biology and pathobiology, and the rapidly developing knowledge of the human genome.     

Resveratrol and rapamycin: are they anti‐aging drugs?

Studies of the basic biology of aging have advanced to the point where anti‐aging interventions, identified from experiments in model organisms, are beginning to be tested in people. Resveratrol and rapamycin, two compounds that target conserved longevity pathways and may mimic some aspects of dietary restriction, represent the first such interventions. Both compounds have been reported to slow aging in yeast and invertebrate species, and rapamycin has also recently been found to increase life span in rodents. In addition, both compounds also show impressive effects in rodent models of age‐associated diseases. Clinical trials are underway to assess whether resveratrol is useful as an anti‐cancer treatment, and rapamycin is already approved for use in human patients. Compounds such as these, identified from longevity studies in model organisms, hold great promise as therapies to target multiple age‐related diseases by modulating the molecular causes of aging.     

Linking the maximum reported life span to the aging rate in wild birds

Dozens of surrogates have been used to reflect the rate of aging in comparative biology. For wild organisms, the maximum reported life span is often considered a key metric. However, the connection between the maximum reported life span for a single individual and the aging rate of that species is far from clear. Our objective was to identify a pragmatic solution to calculate the aging rate from the maximum reported life span of wild birds. We explicitly linked the maximum reported life span to the aging process by employing a Weibull distribution and calculating the shape parameter in this model, which reflects the change in mortality across ages and be used as a surrogate for the aging rate. From simulated data, we demonstrated that the percentile estimator is suitable for calculating the aging rate based on the maximum reported life span. We also calculated the aging rate in 246 bird species based on published information from EURING and tested its relationship with body mass. Our study constitutes a new approach for using maximum reported life span in aging research. The aging rate calculated in the study is based on numerous assumptions/prerequisites and can be improved as more is learned about these assumptions/prerequisites.     

Ciona intestinalis notochord as a new model to investigate the cellular and molecular mechanisms of tubulogenesis

Biological tubes are a prevalent structural design across living organisms. They provide essential functions during the development and adult life of an organism. Increasing progress has been made recently in delineating the cellular and molecular mechanisms underlying tubulogenesis. This review aims to introduce ascidian notochord morphogenesis as an interesting model system to study the cell biology of tube formation, to a wider cell and developmental biology community. We present fundamental morphological and cellular events involved in notochord morphogenesis, compare and contrast them with other more established tubulogenesis model systems, and point out some unique features, including bipolarity of the notochord cells, and using cell shape changes and cell rearrangement to connect lumens. We highlight some initial findings in the molecular mechanisms of notochord morphogenesis. Based on these findings, we present intriguing problems and put forth hypotheses that can be addressed in future studies.     

综述: 秀丽线虫胰岛素类生长因子和雷帕霉素受体信号通路对衰老的调节作用

衰老表现为随着时间推移而带来的功能上的衰退和死亡率的上升.利用模式生物,研究人员已经证明,衰老受高度保守的信号通路所调控,而且遗传与环境因素的改变可以显著延长寿命并延缓功能上的衰退.作为一种模式生物,秀丽线虫由于其遗传操作的简单性以及基因组的高度保守性,已被广泛应用于现代生物学研究中.许多关于衰老的分子机理最初是在秀丽线虫中被阐明的.本文总结了秀丽线虫中高度保守的胰岛素类生长因子(IGF-1)和雷帕霉素受体(TOR)这两条信号通路调控衰老的研究进展,并对未来的研究方向展开了评述.     

Marine molecular biology: an emerging field of biological sciences

An appreciation of the potential applications of molecular biology is of growing importance in many areas of life sciences, including marine biology. During the past two decades, the development of sophisticated molecular technologies and instruments for biomedical research has resulted in significant advances in the biological sciences. However, the value of molecular techniques for addressing problems in marine biology has only recently begun to be cherished. It has been proven that the exploitation of molecular biological techniques will allow difficult research questions about marine organisms and ocean processes to be addressed. Marine molecular biology is a discipline, which strives to define and solve the problems regarding the sustainable exploration of marine life for human health and welfare, through the cooperation between scientists working in marine biology, molecular biology, microbiology and chemistry disciplines. Several success stories of the applications of molecular techniques in the field of marine biology are guiding further research in this area. In this review different molecular techniques are discussed, which have application in marine microbiology, marine invertebrate biology, marine ecology, marine natural products, material sciences, fisheries, conservation and bio-invasion etc. In summary, if marine biologists and molecular biologists continue to work towards strong partnership during the next decade and recognize intellectual and technological advantages and benefits of such partnership, an exciting new frontier of marine molecular biology will emerge in the future.     

黏菌学的发展

黏菌是一类在陆地生态系统中广泛分布的真核生物,在其生活史的不同阶段,既有体现原生动物运动性的营养体,也具有高度特异化的繁殖体,其形态结构与生理特征,兼具了“菌物”与“动物”的特性,独特的进化地位以及与环境、人类健康的密切关系,使得以黏菌为模式生物的研究在生物学、遗传学、生理学、生态学、信息科学等学科均具有广泛的科学意义和重要的应用价值。自17世纪以来,黏菌研究者们从早期的经典分类学,逐步拓展到从生物学各分支学科领域系统全面地认识黏菌类群。在近几十年中,黏菌研究在系统学、生物学、生态学等方向取得了长足的进步。本文扼要介绍了黏菌学在各领域内的代表性研究进展和前沿性科学问题,同时对相关领域未来的发展进行了展望。     

ASY1 coordinates early events in the plant meiotic recombination pathway

Meiosis is a fundamental and evolutionarily conserved process that is central to the life cycles of all sexually reproducing eukaryotes. An understanding of this process is critical to furthering research on reproduction, fertility, genetics and breeding. Plants have been used extensively in cytogenetic studies of meiosis during the last century. Until recently, our knowledge of the molecular and functional aspects of meiosis has emerged from the study of non-plant model organisms, especially budding yeast. However, the emergence of Arabidopsis thaliana as the model organism for plant molecular biology and genetics has enabled significant progress in the characterisation of key genes and proteins controlling plant meiosis. The development of molecular and cytological techniques in Arabidopsis, besides allowing investigation of the more conserved aspects of meiosis, are also providing insights into features of this complex process which may vary between organisms. This review highlights an example of this recent progress by focussing on ASY1, a meiosis-specific Arabidopsis protein which shares some similarity with the N-terminus region of the yeast axial core-associated protein, HOP1, a component of a multiprotein complex which acts as a meiosis-specific barrier to sister-chromatid repair in budding yeast. In the absence of ASY1, synapsis is interrupted and chiasma formation is dramatically reduced. ASY1 protein is initially detected during early meiotic G2 as numerous foci distributed over the chromatin. As G2 progresses the signal appears to be increasingly continuous and is closely associated with the axial elements. State-of-the-art cytogenetic techniques have revealed that initiation of recombination is synchronised with the formation of the chromosome axis. Furthermore, in the context of the developing chromosome axes, ASY1 plays a crucial role in co-ordinating the activity of a key member of the homologous recombination machinery, AtDMC1.     

The dog aging project: translational geroscience in companion animals

Studies of the basic biology of aging have identified several genetic and pharmacological interventions that appear to modulate the rate of aging in laboratory model organisms, but a barrier to further progress has been the challenge of moving beyond these laboratory discoveries to impact health and quality of life for people. The domestic dog, Canis familiaris, offers a unique opportunity for surmounting this barrier in the near future. In particular, companion dogs share our environment and play an important role in improving the quality of life for millions of people. Here, we present a rationale for increasing the role of companion dogs as an animal model for both basic and clinical geroscience and describe complementary approaches and ongoing projects aimed at achieving this goal.     

Ontogenetic variation of the human genome

The human genome demonstrates variable levels of instability during ontogeny. Achieving the highest rate during early prenatal development, it decreases significantly throughout following ontogenetic stages. A failure to decrease or a spontaneous increase of genomic instability can promote infertility, pregnancy losses, chromosomal and genomic diseases, cancer, immunodeficiency, or brain diseases depending on developmental stage at which it occurs. Paradoxically, late ontogeny is associated with increase of genomic instability that is considered a probable mechanism for human aging. The latter is even more appreciable in human diseases associated with pathological or accelerated aging (i.e. Alzheimer's disease and ataxia-telangiectasia). These observations resulted in a hypothesis suggesting that somatic genomic variations throughout ontogeny are determinants of cellular vitality in health and disease including intrauterine development, postnatal life and aging. The most devastative effect of somatic genome variations is observed when it manifests as chromosome instability or aneuploidy, which has been repeatedly noted to produce pathologic conditions and to mediate developmental regulatory and aging processes. However, no commonly accepted concepts on the role of chromosome/genome instability in determination of human health span and life span are available. Here, a review of these ontogenetic variations is given to propose a new "dynamic genome" model for pathological and natural genomic changes throughout life that mimic those of phylogenetic diversity.     

Long-lived worms and aging

Several investigators have generated long-lived nematode worms (Caenorhabditis elegans) in the past decade by mutation of genes in the organism in order to study the genetics of aging and longevity. Dozens of longevity assurance genes (LAG) that dramatically increase the longevity of this organism have been identified. All long-lived mutants of C. elegans are also resistant to environmental stress, such as high temperature, reactive oxygen species (ROS), and ultraviolet irradiation. Double mutations of some LAGs further extended life span up to 400%, providing more insight into cellular mechanisms that put limits on the life span of organisms. With the availability of the LAG mutants and the combined DNA microarray and RNAi technology, the understanding of actual biochemical processes that determine life span is within reach: the downstream signal transduction pathway may regulate life span by up-regulating pro-longevity genes such as those that encode antioxidant enzymes and/or stress-response proteins, and down-regulating specific life-shortening genes. Furthermore, longevity could be modified through chemical manipulation. Results from these studies further support the free radical theory of aging, suggest that the molecular mechanism of aging process may be shared in all organisms, and provide insight for therapeutic intervention in age-related diseases.     

Model organisms for genetics in the domain Archaea: methanogens, halophiles, Thermococcales and Sulfolobales

The tree of life is split into three main branches: eukaryotes, bacteria, and archaea. Our knowledge of eukaryotic and bacteria cell biology has been built on a foundation of studies in model organisms, using the complementary approaches of genetics and biochemistry. Archaea have led to some exciting discoveries in the field of biochemistry, but archaeal genetics has been slow to get off the ground, not least because these organisms inhabit some of the more inhospitable places on earth and are therefore believed to be difficult to culture. In fact, many species can be cultivated with relative ease and there has been tremendous progress in the development of genetic tools for both major archaeal phyla, the Euryarchaeota and the Crenarchaeota. There are several model organisms available for methanogens, halophiles, and thermophiles; in the latter group, there are genetic systems for Sulfolobales and Thermococcales. In this review, we present the advantages and disadvantages of working with each archaeal group, give an overview of their different genetic systems, and direct the neophyte archaeologist to the most appropriate model organism.     

Environmental effects on the expression of life span and aging: an extreme contrast between wild and captive cohorts of Telostylinus angusticollis (Diptera: Neriidae)

Most research on life span and aging has been based on captive populations of short-lived animals; however, we know very little about the expression of these traits in wild populations of such organisms. Because life span and aging are major components of fitness, the extent to which the results of many evolutionary studies in the laboratory can be generalized to natural settings depends on the degree to which the expression of life span and aging differ in natural environments versus laboratory environments and whether such environmental effects interact with phenotypic variation. We investigated life span and aging in Telostylinus angusticollis in the wild while simultaneously estimating these parameters under a range of conditions in a laboratory stock that was recently established from the same wild population. We found that males live less than one-fifth as long and age at least twice as rapidly in the wild as do their captive counterparts. In contrast, we found no evidence of aging in wild females. These striking sex-specific differences between captive and wild flies support the emerging view that environment exerts a profound influence on the expression of life span and aging. These findings have important implications for evolutionary gerontology and, more generally, for the interpretation of fitness estimates in captive populations.     

进化发育生物学--发育、进化和遗传的再联合

发育生物学和进化生物学,以及遗传学历史上曾一度是彼此不分的统一体,后来由于各自研究重点的不同和相应研究手段的独立发展彼此分道扬镳了。如今,由于分子遗传学研究手段的革新使得基因序列测定成为分析发育机理、区分物种和评估种间亲缘关系的常规手段,三者又在基因水平上再度统一起来了,并形成一门被称为进化发育生物学（ｅｖｏｌｕｔｉｏｎａｒｙ ｄｅｖｅｌｏｐｍｅｎｔａｌ ｂｉｏｌｏｇｙ）的新学科。     

Mitochondrial signaling, TOR, and life span

Growing evidence supports the concept that mitochondrial metabolism and reactive oxygen species (ROS) play a major role in aging and determination of an organism's life span. Cellular signaling pathways regulating mitochondrial activity, and hence the generation of ROS and retrograde signaling events originating in mitochondria, have recently moved into the spotlight in aging research. Involvement of the energy-sensing TOR pathway in both mitochondrial signaling and determination of life span has been shown in several studies. This brief review summarizes the recent progress on how mitochondrial signaling might contribute to the aging process with a particular emphasis on TOR signaling from invertebrates to humans.