酵母细胞自然衰老分子作用机理的研究进展

衰老是任何生物都无法避免的生理现象,它由多种因素引起,其过程极其复杂.酵母细胞是目前衰老研究领域公认的模式生物,一系列影响衰老的分子作用机理及调控因素的发现均源自于对酵母细胞的研究.自然衰老是酵母细胞的衰老模式之一,由于该衰老过程与其他高等真核细胞(特别是哺乳动物细胞)极为相似,近年来受到广泛关注.全面比较酵母细胞衰老的两种模式,详细介绍自然衰老过程中分子作用机理的研究进展,重点阐述其复杂的自然寿命调控通路,包括卡路里限制以及药物添加对Ras/PKA、Sch9、Tor等营养依赖型调控通路的影响,并展望未来该领域需要解决的重要科学问题,为全面深入了解高等生物,特别是人类自身的衰老机理提供参考.     

The Age of Decline? Anxieties about Ageing in Japan

In the context of unprecedented life expectancy, the social position of the Japanese elderly is changing. Anxieties related to ageing are widely experienced by people of all ages and on a number of levels, including nationwide concerns over the ‘ageing population’ and its economic consequences; the ageing of local communities; on an interpersonal level, as older relatives may require care and support; and, finally, in relation to one's own ageing. These anxieties are examined based on ethnographic research in the city of Osaka. The concept of ikigai, often equated with purpose in life but closely associated with the elderly in public discourse, is used to illustrate how ageing implicates a number of apparently unconnected issues. It is argued that anxieties about ageing may ultimately achieve such prominence because they give focus to a range of fundamental human concerns with meaning, death, freedom, and isolation.     

The role of reaper-dependent apoptosis in radiation-induced life-span alterations in Drosophila melanogaster

This is the result of studying on a problem of radio-induced ageing. From the point of view of radiation genetics it is perspective to investigate influence of low doze irradiation on individuals with the mutant phenotypes that allows to assume a role of separate genes and mechanisms controllable by them in determination of life span and ageing. The role of a reaper-dependent way of apoptosis regulation in the induced change of life span is shown. The assumption is put forward that apoptosis has the important role during ageing an animal organism.     

Extending healthy ageing: nutrient sensitive pathway and centenarian population

Ageing is a challenge for any living organism and human longevity is a complex phenotype. With increasing life expectancy, maintaining long-term health, functionality and well-being during ageing has become an essential goal. To increase our understanding of how ageing works, it may be advantageous to analyze the phenotype of centenarians, perhaps one of the best examples of successful ageing. Healthy ageing involves the interaction between genes, the environment, and lifestyle factors, particularly diet. Besides evaluating specific gene-environment interactions in relation to exceptional longevity, it is important to focus attention on modifiable lifestyle factors such as diet and nutrition to achieve extension of health span. Furthermore, a better understanding of human longevity may assist in the design of strategies to extend the duration of optimal human health. In this article we briefly discuss relevant topics on ageing and longevity with particular focus on dietary patterns of centenarians and nutrient-sensing pathways that have a pivotal role in the regulation of life span. Finally, we also discuss the potential role of Nrf2 system in the pro-ageing signaling emphasizing its phytohormetic activation.     

mTOR与S6K在衰老进程中的作用

衰老进程受到多个基因以及信号通路的调节.哺乳动物雷帕霉素靶蛋白mTOR与核糖体S6K蛋白激酶不仅调节细胞的多种生理功能,在衰老进程中也发挥着重要作用.最近的实验表明,抑制mTORC1或S6K的活性可以延长小鼠的寿限.mTOR通路通过多种方式在衰老进程中发挥作用,包括细胞自噬、代谢副产物的积累以及影响组织干细胞的数量等等.而S6K在衰老进程中的作用并不十分清晰.目前mTOR和S6K已成为研究热点,通过对这两个分子在衰老进程中作用的研究,有望找到延长寿限的方法并揭示其中的机理,本文对此作一综述.     

Evolution of male age‐specific reproduction under differential risks and causes of death: males pay the cost of high female fitness

Classic theories of ageing evolution predict that increased extrinsic mortality due to an environmental hazard selects for increased early reproduction, rapid ageing and short intrinsic lifespan. Conversely, emerging theory maintains that when ageing increases susceptibility to an environmental hazard, increased mortality due to this hazard can select against ageing in physiological condition and prolong intrinsic lifespan. However, evolution of slow ageing under high‐condition‐dependent mortality is expected to result from reallocation of resources to different traits and such reallocation may be hampered by sex‐specific trade‐offs. Because same life‐history trait values often have different fitness consequences in males and females, sexually antagonistic selection can preserve genetic variance for lifespan and ageing. We previously showed that increased condition‐dependent mortality caused by heat shock leads to evolution of long‐life, decelerated late‐life mortality in both sexes and increased female fecundity in the nematode, Caenorhabditis remanei. Here, we used these cryopreserved lines to show that males evolving under heat shock suffered from reduced early‐life and net reproduction, while mortality rate had no effect. Our results suggest that heat‐shock resistance and associated long‐life trade‐off with male, but not female, reproduction and therefore sexually antagonistic selection contributes to maintenance of genetic variation for lifespan and fitness in this population.     

Testing for genetic trade-offs between early- and late-life reproduction in a wild red deer population

The antagonistic pleiotropy (AP) theory of ageing predicts genetically based trade-offs between investment in reproduction in early life and survival and performance in later life. Laboratory-based research has shown that such genetic trade-offs exist, but little is currently known about their prevalence in natural populations. We used random regression 'animal model' techniques to test the genetic basis of trade-offs between early-life fecundity (ELF) and maternal performance in late life in a wild population of red deer (Cervus elaphus) on the Isle of Rum, Scotland. Significant genetic variation for both ageing rates in a key maternal performance measure (offspring birth weight) and ELF was present in this population. We found some evidence for a negative genetic covariance between the rate of ageing in offspring birth weight and ELF, and also for a negative environmental covariance. Our results suggest rare support for the AP theory of ageing from a wild population.     

Embryo development and ageing in birds and mammals

The rate of ageing is a genetically influenced feature of an individual's life history that responds to selection on lifespan. Various costs presumably constrain the evolution of prolonged life, but these have not been well characterized and their general nature is unclear. The analyses presented here demonstrate a correlation among birds and mammals between rates of embryonic growth and ageing-related mortality, which are quantified by the exponents of fitted power functions. This relationship suggests that rapid early development leads to accelerated ageing, presumably by influencing some aspect of the quality of the adult individual. Although the mechanisms linking embryo growth rate and ageing are not known, a simple model of life-history optimization shows that the benefits of longer life can be balanced by connected costs of extended development.     

Ontogenetic timing as a condition‐dependent life history trait: High‐condition males develop quickly,peak early,and age fast

Within‐population variation in ageing remains poorly understood. In males, condition‐dependent investment in secondary sexual traits may incur costs that limit ability to invest in somatic maintenance. Moreover, males often express morphological and behavioral secondary sexual traits simultaneously, but the relative effects on ageing of investment in these traits remain unclear. We investigated the condition dependence of male life history in the neriid fly Telostylinus angusticollis. Using a fully factorial design, we manipulated male early‐life condition by varying nutrient content of the larval diet and, subsequently, manipulated opportunity for adult males to interact with rival males. We found that high‐condition males developed more quickly and reached their reproductive peak earlier in life, but also experienced faster reproductive ageing and died sooner than low‐condition males. By contrast, interactions with rival males reduced male lifespan but did not affect male reproductive ageing. High‐condition in early life is therefore associated with rapid ageing in T. angusticollis males, even in the absence of damaging male–male interactions. Our results show that abundant resources during the juvenile phase are used to expedite growth and development and enhance early‐life reproductive performance at the expense of late‐life performance and survival, demonstrating a clear link between male condition and ageing.     

Ageing in a eusocial insect: molecular and physiological characteristics of life span plasticity in the honey bee

Commonly held views assume that ageing, or senescence, represents an inevitable, passive, and random decline in function that is strongly linked to chronological age. In recent years, genetic intervention of life span regulating pathways, for example, in Drosophila as well as case studies in non-classical animal models, have provided compelling evidence to challenge these views.Rather than comprehensively revisiting studies on the established genetic model systems of ageing, we here focus on an alternative model organism with a wild type (unselected genotype) characterized by a unique diversity in longevity - the honey bee.Honey bee (Apis mellifera) life span varies from a few weeks to more than 2 years. This plasticity is largely controlled by environmental factors. Thereby, although individuals are closely related genetically, distinct life histories can emerge as a function of social environmental change.Another remarkable feature of the honey bee is the occurrence of reverted behavioural ontogeny in the worker (female helper) caste. This behavioural peculiarity is associated with alterations in somatic maintenance functions that are indicative of reverted senescence. Thus, although intraspecific variation in organismal life span is not uncommon, the honey bee holds great promise for gaining insights into regulatory pathways that can shape the time-course of ageing by delaying, halting or even reversing processes of senescence. These aspects provide the setting of our review.We will highlight comparative findings from Drosophila melanogaster and Caenorhabditis elegans in particular, and focus on knowledge spanning from molecular- to behavioural-senescence to elucidate how the honey bee can contribute to novel insights into regulatory mechanisms that underlie plasticity and robustness or irreversibility in ageing.     

<Emphasis Type="Italic">Arctica islandica:</Emphasis> the longest lived non colonial animal known to science

The ocean quahog, Arctica islandica is not just the longest living bivalve, it is also the longest lived, non-colonial animal known to science. With the maximum life span potential ever increasing and currently standing in excess of 400 years the clam has recently gained interest as a potential model organism for ageing research. This review details what is known about the biology of A. islandica, it discusses observed age-associated changes and reviews previous ageing research undertaken on the species and other long-lived bivalves which may be applicable to future ageing research and discusses future directions for ageing research with A. islandica. Historically much of the research on bivalves has been targeted at their utilization as a food source, environmental sentinels and more recently the use of their shells as archives of environmental change. The result of this has been an abundance of knowledge on bivalve life strategies, and a limited amount of information on the physiological changes in the cells and tissues of bivalves during the ageing process. However, research into the mechanisms of senescence of long-lived bivalves from a biogerontological perspective has advanced only recently. The research undertaken thus far has documented age-related differences in anti-oxidant defences and accumulation of oxidative products but despite the recent attention into ageing of A. islandica it is still to be ascertained if the species experiences senescence. Future directions for ageing research using A. islandica are discussed.     

Ontogenetic model of ageing and disease formation and mechanisms of natural selection

It is known that increased mortality due to environmental hazards results, in the course of natural selection, in the shortening of maximum life span and acceleration of sexual maturation in a population subjected to an intensified pressure from external environment. As a consequence, the prereproductive period/maximum life span ratio appears to be approximately the same in each species. Mechanisms responsible for this are not clear yet. Since maximum life span is limited by both ageing and formation of certain diseases (in humans, the so-called main noninfectious diseases), the paper discusses four possible models of development of ageing and age-linked disease--ecological, genetic, degenerative (metabolic) and ontogenetic. It was found that it is the ontogenetic model only that can adequately account for the development of moderate shifts in the duration of both sexual maturation and maximum life span. It also provides the rationale for the pleotropic activity of genes during the development of the organism, its ageing and formation of age-connected diseases.     

On the programmed/non-programmed nature of ageing within the life history

Understanding why and how senescence evolved is of great importance in investigating the multiple, complex mechanisms that influence the course of ageing in humans and other organisms. Compelling arguments eliminate the idea that death is generally programmed by genes for ageing, but there is still a widespread tendency to interpret data in terms of loosely defined 'age regulation', which does not usually make either evolutionary or mechanistic sense. This review critically addresses the role of natural selection in shaping ageing within the life history and examines the implications for research on genetic pathways that influence the life span. It is recognised that in exceptional circumstances the possibility exists for selection to favour limiting survival. In acknowledging that, at least in theory, ageing might occasionally be adaptive, however, the high barriers to validating actual instances of adaptive ageing are made clear.     

The effect of reproductive activity on the longevity of male Drosophila melanogaster is not caused by an acceleration of ageing

Male D. melanogaster kept supplied with virgin females had lower longevity than males kept without access to females. Cessation of reproductive activity by males previously kept with females resulted after a short lag in the same life expectancy as that of flies of the same age which had never had females. Commencement of reproductive activity resulted in life expectancy indistinguishable from that of males of the same age kept with females throughout life. The effect of reproductive activity on longevity is therefore short-term and reversible and not due to an acceleration of ageing. This finding has implications for the way that different theories of the evolution of ageing should be tested.     

Healthy aging: the Swiss experience

The quantitative importance of ageing both in developed or in developing countries raised the subtle question of the quality of life of the ageing person. Precise definitions of life expectancy, healthy life expectancy and quality of life are presented. Then, presentation of the results of two cross-sectional studies performed with the same methodology at a 15-year time interval in French-speaking Switzerland illustrates compression of morbidity theory, with increased longevity, increased good perception of health and increased quality of life. Moreover, quantitative data concerning the longevity impact of hospital geriatric care are presented from Geneva. The 4-year survival rate of over 85 year old women, discharged from the hospital for acute care, reached 48%. Explanations of these outstanding medical progresses on longevity and socio-economical challenges of extreme ageing are discussed in the world context.     

Sex‐specific mitonuclear epistasis and the evolution of mitochondrial bioenergetics,ageing, and life history in seed beetles

The role of mitochondrial DNA for the evolution of life‐history traits remains debated. We examined mitonuclear effects on the activity of the multisubunit complex of the electron transport chain (ETC) involved in oxidative phosphorylation (OXPHOS) across lines of the seed beetle Acanthoscelides obtectus selected for a short (E) or a long (L) life for more than >160 generations. We constructed and phenotyped mitonuclear introgression lines, which allowed us to assess the independent effects of the evolutionary history of the nuclear and the mitochondrial genome. The nuclear genome was responsible for the largest share of divergence seen in ageing. However, the mitochondrial genome also had sizeable effects, which were sex‐specific and expressed primarily as epistatic interactions with the nuclear genome. The effects of mitonuclear disruption were largely consistent with mitonuclear coadaptation. Variation in ETC activity explained a large proportion of variance in ageing and life‐history traits and this multivariate relationship differed somewhat between the sexes. In conclusion, mitonuclear epistasis has played an important role in the laboratory evolution of ETC complex activity, ageing, and life histories and these are closely associated. The mitonuclear architecture of evolved differences in life‐history traits and mitochondrial bioenergetics was sex‐specific.     

Divergent evolution of life span associated with mitochondrial DNA evolution

Mitochondria play a key role in ageing. The pursuit of genes that regulate variation in life span and ageing have shown that several nuclear‐encoded mitochondrial genes are important. However, the role of mitochondrial encoded genes (mtDNA) is more controversial and our appreciation of the role of mtDNA for the evolution of life span is limited. We use replicated lines of seed beetles that have been artificially selected for long or short life for >190 generations, now showing dramatic phenotypic differences, to test for a possible role of mtDNA in the divergent evolution of ageing and life span. We show that these divergent selection regimes led to the evolution of significantly different mtDNA haplotype frequencies. Selection for a long life and late reproduction generated positive selection for one specific haplotype, which was fixed in most such lines. In contrast, selection for reproduction early in life led to both positive selection as well as negative frequency‐dependent selection on two different haplotypes, which were both present in all such lines. Our findings suggest that the evolution of life span was in part mediated by mtDNA, providing support for the emerging general tenet that adaptive evolution of life‐history syndromes may involve mtDNA.     

The origins of human ageing.

The origins of human ageing are to be found in the origins and evolution of senescence as a general feature in the life histories of higher animals. Ageing is an intriguing problem in evolutionary biology because a trait that limits the duration of life, including the fertile period, has a negative impact on Darwinian fitness. Current theory suggests that senescence occurs because the force of natural selection declines with age and because longevity is only acquired at some metabolic cost. In effect, organisms may trade late survival for enhanced reproductive investments in earlier life. The comparative study of ageing supports the general evolutionary theory and reveals that human senescence, while broadly similar to senescence in other mammalian species, has distinct features, such as menopause, that may derive from the interplay of biological and social evolution.     

<Emphasis Type="Italic">Podospora anserina</Emphasis>: a model organism to study mechanisms of healthy ageing

The filamentous ascomycete Podospora anserina has been extensively studied as an experimental ageing model for more than 50 years. As a result, a huge body of data has been accumulated and various molecular pathways have been identified as part of a molecular network involved in the control of ageing and life span. The aim of this review is to summarize data on P. anserina ageing, including aspects like respiration, cellular copper homeostasis, mitochondrial DNA (mtDNA) stability/instability, mitochondrial dynamics, apoptosis, translation efficiency and pathways directed against oxidative stress. It becomes clear that manipulation of several of these pathways bears the potential to extend the healthy period of time, the health span, within the life time of the fungus. Here we put special attention on recent work aimed to identify and characterize this type of long-lived P. anserina mutants. The study of the molecular pathways which are modified in these mutants can be expected to provide important clues for the elucidation of the mechanistic basis of this type of 'healthy ageing' at the organism level.