Invertebrate gerontology: the age mutations of Caenorhabditis elegans.
01 Oct 1996-BioEssays (Wiley Subscription Services, Inc., A Wiley Company)-Vol. 18, Iss: 10, pp 809-815
TL;DR: Rather than invertebrate ageing being determined by a ‘clock mechanism’, a picture is emerging of ageing as a non‐adaptive process determined, in part, by resistance to intrinsic stress mediated by stress‐response genes.
Abstract: Ageing is a complex phenomenon which remains a major challenge to modern biology. Although the evolutionary biology of ageing is well understood, the mechanisms that limit lifespan are unknown. The isolation and analysis of single-gene mutations which extend lifespan (Age mutations) is likely to reveal processes which influence ageing. Caenorhabditis elegans is the only metazoan in which Age mutations have been identified. The Age mutations not only prolong life, but also confer a complex array of other phenotypes. Some of these phenotypes provide clues to the evolutionary origins of these genes while others allude to mechanisms of lifespan-extension. Many of the Age genes interact and share a second common phenotype, that of stress resistance. Rather than invertebrate ageing being determined by a 'clock mechanism', a picture is emerging of ageing as a non-adaptive process determined, in part, by resistance to intrinsic stress mediated by stress-response genes.
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TL;DR: This work discloses that expression of Hsps can occur in nature, all species have hsp genes but they vary in the patterns of their expression, and Hsp expression can be correlated with resistance to stress, and species' thresholds for HSP expression are correlated with levels of stress that they naturally undergo.
Abstract: Molecular chaperones, including the heat-shock proteins (Hsps), are a ubiquitous feature of cells in which these proteins cope with stress-induced denaturation of other proteins. Hsps have received the most attention in model organisms undergoing experimental stress in the laboratory, and the function of Hsps at the molecular and cellular level is becoming well understood in this context. A complementary focus is now emerging on the Hsps of both model and nonmodel organisms undergoing stress in nature, on the roles of Hsps in the stress physiology of whole multicellular eukaryotes and the tissues and organs they comprise, and on the ecological and evolutionary correlates of variation in Hsps and the genes that encode them. This focus discloses that (a) expression of Hsps can occur in nature, (b) all species have hsp genes but they vary in the patterns of their expression, (c) Hsp expression can be correlated with resistance to stress, and (d) species' thresholds for Hsp expression are correlated with levels of stress that they naturally undergo. These conclusions are now well established and may require little additional confirmation; many significant questions remain unanswered concerning both the mechanisms of Hsp-mediated stress tolerance at the organismal level and the evolutionary mechanisms that have diversified the hsp genes.
3,841 citations
TL;DR: Phosphoinositide 3-kinases generate lipids that are implicated in receptor-stimulated signalling and in the regulation of membrane traffic and their potential signalling pathways have been elucidated and PI3K function is now being characterised in several model organisms.
982 citations
TL;DR: The most direct test of the Free Radical/Oxidative Stress Theory of Aging is to specifically alter the age-related increase in oxidative damage and determine how this alteration affects life span.
597 citations
TL;DR: The nature of genetic variation for Drosophila longevity in a population of recombinant inbred lines was investigated, providing support for the pleiotropy theory of senescence and the hypothesis that variation for longevity might be maintained by opposing selection pressures in males and females and variable environments.
Abstract: The nature of genetic variation for Drosophila longevity in a population of recombinant inbred lines was investigated by estimating quantitative genetic parameters and mapping quantitative trait loci (QTL) for adult life span in five environments: standard culture conditions, high and low temperature, and heat-shock and starvation stress. There was highly significant genetic variation for life span within each sex and environment. In the analysis of variance of life span pooled over sexes and environments, however, the significant genetic variation appeared in the genotype x sex and genotype x environment interaction terms. The genetic correlation of longevity across the sexes and environments was not significantly different from zero in these lines. We estimated map positions and effects of QTL affecting life span by linkage to highly polymorphic roo transposable element markers, using a multiple-trait composite interval mapping procedure. A minimum of 17 QTL were detected; all were sex and/or environment-specific. Ten of the QTL had sexually antagonistic or antagonistic pleiotropic effects in different environments. These data provide support for the pleiotropy theory of senescence and the hypothesis that variation for longevity might be maintained by opposing selection pressures in males and females and variable environments. Further work is necessary to assess the generality of these results, using different strains, to determine heterozygous effects and to map the life span QTL to the level of genetic loci.
329 citations
Cites background from "Invertebrate gerontology: the age m..."
...1988; Graves et al. 1992; Lin et al. 1998), and thermal and UV-irradiation stress (Lithgow 1996; Lin et al.tion in life span segregate, and at what fraction of the QTL is variation attributable to the segregation of rare, 1998), implicating oxidative stress and heat-shock response genes as…...
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...…as a modelet Biologie des Populations, Université Claude Bernard Lyon1, 43 bd. 11 novembre, 69622 Villeurbanne Cedex, France. system, by testing whether genetic variation in fitness Genetics 154: 213–227 ( January 2000) components increases with age, as predicted by the mu- notypes (Lithgow 1996)....
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TL;DR: A significant activation of the Raf/MEK/ERK signaling pathway and upregulation of cell protective molecules, including superoxide dismutase are demonstrated and suggest that AC is a fundamentally important mechanism regulating lifespan and stress resistance.
328 citations
Cites background from "Invertebrate gerontology: the age m..."
...In addition, increased lifespan in nematodes (Feng et al., 2001; Ishii, 2000; Lithgow, 1996) and Drosophila (Morrow et al....
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...In addition, increased lifespan in nematodes (Feng et al., 2001; Ishii, 2000; Lithgow, 1996) and Drosophila (Morrow et al., 2004) also has been attributed at least in part to increased resistance to oxidative stress....
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References
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TL;DR: It seems possible that one factor in aging may be related to deleterious side attacks of free radicals (which are normally produced in the course of cellular metabolism) on cell constituents.
Abstract: The phenomenon of growth, decline and death—aging—has been the source of considerable speculation (1, 8, 10). This cycle seems to be a more or less direct function of the metabolic rate and this in turn depends on the species (animal or plant) on which are superimposed the factors of heredity and the effects of the stresses and strains of life—which alter the metabolic activity. The universality of this phenomenon suggests that the reactions which cause it are basically the same in all living things. Viewing this process in the light of present day free radical and radiation chemistry and of radiobiology, it seems possible that one factor in aging may be related to deleterious side attacks of free radicals (which are normally produced in the course of cellular metabolism) on cell constituents.* Irradiation of living things induces mutation, cancer, and aging (9). Inasmuch as these also arise spontaneously in nature, it is natural to inquire if the processes might not be similar. It is believed that one mechanism of irradiation effect is through liberation of OH and HO 2 radicals (12). There is evidence, although indirect, that these two highly active free radicals are produced normally in living systems. In the first place, free radicals are present in living cells; this was recently demonstrated in vivo by a paramagnetic resonance absorption method (3). Further, it was shown that the concentration of free radicals increased with increasing metabolic activity in conformity with the postulates set forth some years ago that free radicals were involved in biologic oxidation-reduction reactions (11, 13). Are some of these free radicals OH and/or HO2, or radicals of a similar high order of reactivity, and where might they arise in the cell? The most likely source of OH and HO2 radicals, at least in the animal cell, would be the interaction of the respiratory enzymes involved
7,917 citations
TL;DR: August Weismann's theory is subject to a number of criticisms, the most forceful of which are: 1) The fallacy of identifying senescence with mechanical wear, 2) the extreme rarity, in natural populations, of individuals that would be old enough to die of the postulated death-mechanism, 3) the failure of several decades of gerontological research to uncover any deathmechanisms, and 4) the difficulties involved in visualizing how such a feature could be produced
Abstract: A new individual entering a population may be said to have a reproductive probability distribution. The reproductive probability is zero from zygote to reproductive maturity. Later, perhaps shortly...
3,981 citations
Journal Article•
TL;DR: A new individual entering a population may be said to have a reproductive probability distribution as discussed by the authors, where the reproductive probability is zero from zygote to reproductive maturity, i.e., the individual will have no reproductive capability from birth to maturity.
Abstract: A new individual entering a population may be said to have a reproductive probability distribution. The reproductive probability is zero from zygote to reproductive maturity. Later, perhaps shortly...
3,800 citations
TL;DR: Finding that mutations in the gene daf-2 can cause fertile, active, adult Caenorhabditis elegans hermaphrodites to live more than twice as long as wild type raises the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation.
Abstract: We have found that mutations in the gene daf-2 can cause fertile, active, adult Caenorhabditis elegans hermaphrodites to live more than twice as long as wild type. This lifespan extension, the largest yet reported in any organism, requires the activity of a second gene, daf-16. Both genes also regulate formation of the dauer larva, a developmentally arrested larval form that is induced by crowding and starvation and is very long-lived. Our findings raise the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation. daf-2 and daf-16 provide entry points into understanding how lifespan can be extended.
3,146 citations
TL;DR: A basis for the theory that senescence is an inevitable outcome of evolution is established and the model shows that higher fertility will be a primary factor leading to the evolution of higher rates ofsenescence unless the resulting extra mortality is confined to the immature period.
1,966 citations