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• W2023442907 abstract "The process of aging influences our poetry, our art, our lifestyle, and our happiness, yet we know surprisingly little about it. Genetics has taught us a great deal about gene regulation, development, and the cell cycle. Can it teach us how we age? First, why assume the aging process is subject to genetic control at all? One observation in support of this idea is that different species can have very different life spans. For example, mice, canaries, and bats are all small warm-blooded animals. Yet a mouse lives 2 years, a canary 13, and a bat 30 or more (4Finch C.E. Longevity, Senescence, and the Genome. The University of Chicago Press, Chicago1990Google Scholar). How might these differences be established (reviewed by4Finch C.E. Longevity, Senescence, and the Genome. The University of Chicago Press, Chicago1990Google Scholar)? There is a tendency to think that organisms age the way cars do—they just break down from accumulated wear and tear. In this case, different species may differ in their resistance to damage. However, it is also possible that the aging process is not controlled in a haphazard fashion but rather by a dedicated regulatory mechanism, analogous to the mechanisms that control pattern formation or the cell cycle. For example, one could think of aging as a temporal control system equipped with a regulatory dial that has different settings (see Figure 1). The temporal control system would govern and coordinate the overall aging process, although the timing of certain age-related events could also be subject to specific gene activities or environmental factors. In principle, such a temporal control mechanism could also regulate physiological changes that are age-related, such as puberty and menopause. The setting of the regulatory dial, a key feature of this system, would determine the rate at which the temporal control system runs the aging process. The dial would be set differently in different species, causing animals like dogs to go through the entire process of development and senescence in a single decade, but allowing humans to take a century. There are two different ways to learn more about the regulation of aging. The first is to identify changes that occur in older cells, such as telomere shortening and increased levels of DNA damage, and to ask whether any of these changes is not simply correlated with aging but actually causes it. Alternatively, one can identify genes that might regulate aging by looking for mutants with altered rates of aging. An advantage of the genetic approach is that it is model independent. It doesn't matter what causes aging or whether it is regulated in a deliberate or a haphazard way. From the types of genes identified (or not identified) in a genetic screen, one can make valuable inferences about how the aging process takes place. Investigators have looked for mutations affecting life span in two quite different ways. First, they have carried out selective breeding experiments by crossing long-lived individuals from natural populations for many generations. In this way, the life span of Drosophila has been increased more than 30% (14Rose M.R. Can. J. Zool. 1984; 62: 1661-1667Crossref Google Scholar, 4Finch C.E. Longevity, Senescence, and the Genome. The University of Chicago Press, Chicago1990Google Scholar). These natural polymorphisms may prove to be informative. However, key regulatory genes will not necessarily be identified by selective breeding, because these genes may not be polymorphic in natural populations. The aging field now contains a small number of enthusiastic geneticists who are generating and analyzing life span mutants in the laboratory. Mutations have been identified that change the rate of aging substantially (10Klass M. Mech. Aging Dev. 1983; 22: 279-286Crossref PubMed Scopus (279) Google Scholar, 9Kenyon C.J. Chang J. Gensch E. Rudner A. Tabtiang R. Nature. 1993; 366: 461-464Crossref PubMed Scopus (2291) Google Scholar, 3D'mello N.P. Childress A.M. Franklin D.S. Kale S.P. Pinswasdi C. Jazwinski S.M. J. Biol. Chem. 1994; 269: 15451-15459Abstract Full Text PDF PubMed Google Scholar, 11Larsen P.L. Albert P.S. Riddle D.L. Genetics. 1995; 139: 1567-1583Crossref PubMed Google Scholar, 8Kennedy B.K. Austriaco Jr., N.R. Zhang J. Guarente L. Cell. 1995; 80: 485-496Abstract Full Text PDF PubMed Scopus (383) Google Scholar), which supports the hypothesis that the rate of aging is under genetic control. One mutation, which affects the aging process in yeast, is interesting because it alters a gene that normally silences gene expression. A second set of mutations, which affect the life span of Caenorhabditis elegans, are thought-provoking because they affect genes that also regulate an alternative developmental state that is long-lived. The identification of single-site mutations that coordinately affect many aspects of the aging process argues strongly for the existence of a mechanism that regulates aging. These yeast and nematode aging mutants are discussed in more detail in this minireview. In yeast, the aging process is manifested by failure to undergo cell division. A new yeast bud cell becomes a mother cell that can divide to produce new bud cells for 13–30 generations, depending on the strain (8Kennedy B.K. Austriaco Jr., N.R. Zhang J. Guarente L. Cell. 1995; 80: 485-496Abstract Full Text PDF PubMed Scopus (383) Google Scholar). To identify mutations affecting life span, Kennedy et al. took advantage of the finding that long-lived strains of yeast are relatively heat resistant. Because screening for heat-resistant mutants is straightforward, they looked for this type of mutant in hopes of identifying genes affecting life span. Although this screening procedure was admittedly biased, it did identify several new life span mutants. One mutation was a gain-of-function allele of SIR4, a gene that regulates silencing. The SIR4 gene is required for silencing of gene expression within certain chromosomal domains, including telomeres and the silent mating-type loci. The SIR4 life span mutant exhibits the same spectrum of phenotypes seen in SIR4 loss-of-function mutants; however, they also exhibit increased life span. Whereas normal yeast mother cells go though about 16 cell divisions on average, the SIR4 mutant goes through about 25. How does this SIR4 mutation influence life span? First, it seems unlikely that the longevity of the mutant is caused by a change in telomere length, because telomere shortening is not observed in old yeast cells (Smeal et al., 1996 [this issue of Cell]). It is also unlikely that heat tolerance is related to longevity, because SIR4 null mutations are heat resistant but not long-lived. In the wild typeSIR4 forms a silencing complex with products of three other genesSIR1 SIR2, and SIR3. The SIR1–SIR3 gene products are also required for the longevity of the SIR4 gain-of-function mutation. This suggests that the SIR4 gain-of-function mutation somehow prevents the SIR complex from silencing its normal targets (thereby producing the loss-of-function SIR phenotypes) and also causes the silencing complex to acquire a new activity. One possibility is that in young wild-type yeast cells, the SIR complex silences a gene that promotes senescence. This model postulates that in older yeast cells, silencing is reduced, thereby causing expression of the senescence gene(s). Consistent with this model, the same group has now made the interesting discovery that gene silencing is lost in old yeast cells (15Smeal T. Claus J. Kennedy B. Cole F. Guarente L. Cell. 1996; 84 (this issue)Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar). Do SIR4 loss-of-function mutants age prematurely? When a large number of mutant cells are analyzed, one can detect a statistically significant decrease in life span, although the effect is quite small. A key question is whether the targets of the SIR4 complex in the long-lived gain-of-function mutant are genes normally regulated by SIR4 or whether they are novel genes (see Figure 2). The latter possibility cannot be ruled out, especially since the mutant complex fails to silence any of its known targets. It should be possible to address this issue by identifying the targets of the silencing complex in the long-lived mutant. In addition to raising the possibility that gene silencing plays a role in the aging process, the genetic approach seems likely to implicate other types of proteins in the yeast aging process. For example, by looking for genes expressed differentially in old cells, 3D'mello N.P. Childress A.M. Franklin D.S. Kale S.P. Pinswasdi C. Jazwinski S.M. J. Biol. Chem. 1994; 269: 15451-15459Abstract Full Text PDF PubMed Google Scholar have identified a different, novel protein that may influence yeast life span. And the SIR4 gain-of-function mutation was only one of eight long-lived mutants found in the selection for heat tolerance. Life span mutants have also been identified in C. elegans. C. elegans normally grows to adulthood, ages, and dies in just over 2 weeks. The first C. elegans life span mutant, called age-1, was identified in a screen for mutants that live longer than normal (10Klass M. Mech. Aging Dev. 1983; 22: 279-286Crossref PubMed Scopus (279) Google Scholar). The age-1 mutant looks and behaves normally, but was found to live 60% longer than wild type. The mutant does undergo senescence, but at a slower rate than normal (7Johnson T.E. Science. 1990; 249: 908-912Crossref PubMed Scopus (302) Google Scholar). Only one independent age-1 mutation was identified in this screen, indicating that it did not reach saturation (10Klass M. Mech. Aging Dev. 1983; 22: 279-286Crossref PubMed Scopus (279) Google Scholar, 5Friedman D.B. Johnson T.E. Genetics. 1988; 118: 75-86Crossref PubMed Google Scholar). More recently, mutations in two additional genes have also been found to affect C. elegans' life span. Mutations in the gene daf-2 (Kenyon et al., 1992) can double the life span of C. elegans, and mutations in another daf genedaf-23 (6Gottlieb S. Ruvkun G. Genetics. 1994; 137: 107-120Crossref PubMed Google Scholar), also lengthen life span substantially (11Larsen P.L. Albert P.S. Riddle D.L. Genetics. 1995; 139: 1567-1583Crossref PubMed Google Scholar). daf-2 and daf-23 were initially identified because they affect the process of dauer formation, which is an alternative developmental process regulated by environmental signals (12Riddle, D.L. (1988). In The Nematode Caenorhabditis elegans, W.B. Wood, ed. (Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press), pp. 393–414.Google Scholar). A dauer is C. elegans' version of a spore. A worm that hatches in an uncrowded environment with ample food grows to adulthood, ages, and dies after about 2 weeks. In contrast, when food is scarce, young larvae crowd together, which causes the concentration of a constitutively produced dauer pheromone to rise. As a consequence, the animals enter the dauer state instead of growing to adulthood. The dauer is a larval form that is developmentally arrested, sexually immature, and protected from desiccation by a special cuticle. It does not eat or grow. Unlike the adult, it lives for months. When it encounters food, it exits the dauer stage, grows to adulthood, and, over the course of about 2 weeks, senesces and dies. Two types of mutations affect dauer formation. daf-d (dauer-defective) mutations block dauer formation, and daf-c (dauer-constitutive) mutations induce dauer formation even under favorable living conditions. daf-2 and daf-23 mutations were originally identified in screens for daf-c mutants (12Riddle, D.L. (1988). In The Nematode Caenorhabditis elegans, W.B. Wood, ed. (Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press), pp. 393–414.Google Scholar). When these gene activities are eliminated, the animals enter the dauer stage (12Riddle, D.L. (1988). In The Nematode Caenorhabditis elegans, W.B. Wood, ed. (Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press), pp. 393–414.Google Scholar, 6Gottlieb S. Ruvkun G. Genetics. 1994; 137: 107-120Crossref PubMed Google Scholar). However, when the activity levels of these genes are only partially lowered, the animals do not become dauers, but instead become adults with extended life spans (9Kenyon C.J. Chang J. Gensch E. Rudner A. Tabtiang R. Nature. 1993; 366: 461-464Crossref PubMed Scopus (2291) Google Scholar, 11Larsen P.L. Albert P.S. Riddle D.L. Genetics. 1995; 139: 1567-1583Crossref PubMed Google Scholar). Not all daf-c mutations extend life span. daf-c mutations in genes located upstream of daf-2 and daf-23 in the dauer pathway have no effect on life span, even under the most stringent experimental conditions (9Kenyon C.J. Chang J. Gensch E. Rudner A. Tabtiang R. Nature. 1993; 366: 461-464Crossref PubMed Scopus (2291) Google Scholar, 11Larsen P.L. Albert P.S. Riddle D.L. Genetics. 1995; 139: 1567-1583Crossref PubMed Google Scholar). The reason for this difference is not clear; however, it argues that daf-2 and daf-23 play a specific role in life span control. It is important to emphasize that the long-lived daf animals are not dauers. For example, animals carrying the daf-2 mutation e1370 growing at 20°C are normal-sized adults (dauers are much smaller and thinner); they eat normally, and they have normal or nearly normal brood sizes. The life span phenotype of these animals is striking: at an age when the wild type is decrepit, immobile, and close to death or dead already, these mutants still move and feed actively and appear youthful. Overall, the long-lived daf mutants appear to undergo the same type of senescence as wild type; however, it occurs over a longer period of time. This implies that in the wild type, the products of the daf-2 and daf-23 genes accelerate the aging process. Are there any gene activities that can slow the aging process? daf-16 is a gene that is required for dauer formation; it acts downstream of daf-2 and daf-23 in the dauer pathway. This gene is also required for the longevity of daf-2 and daf-23 adults (9Kenyon C.J. Chang J. Gensch E. Rudner A. Tabtiang R. Nature. 1993; 366: 461-464Crossref PubMed Scopus (2291) Google Scholar, 11Larsen P.L. Albert P.S. Riddle D.L. Genetics. 1995; 139: 1567-1583Crossref PubMed Google Scholar). Thus, wild-type daf-16 gene activity can extend life span. A second gene required for dauer formationdaf-18, also appears to be required for the longevity of daf-2 and daf-23 mutants (2Dorman J.B. Albinder B. Shroyer T. Kenyon C. Genetics. 1995; 141: 1399-1406Crossref PubMed Google Scholar, 11Larsen P.L. Albert P.S. Riddle D.L. Genetics. 1995; 139: 1567-1583Crossref PubMed Google Scholar). Both daf-16 and daf-18 functions are also required for the longevity of the original C. elegans life span mutationage-1 (2Dorman J.B. Albinder B. Shroyer T. Kenyon C. Genetics. 1995; 141: 1399-1406Crossref PubMed Google Scholar, 11Larsen P.L. Albert P.S. Riddle D.L. Genetics. 1995; 139: 1567-1583Crossref PubMed Google Scholar). Together these findings suggest that all of these genes may act in a single genetic pathway to regulate life span. What is the connection between dauer formation and adult life span? Why do single genes affect both processes? It may simply be a coincidence. Alternatively, perhaps weak mutations in daf-2 and daf-23 uncouple the expression of a life span extension process normally only induced in the dauer from other dauer features, such as the dauer's special cuticle. This uncoupling could occur if different features of the dauer have different thresholds for expression. At this time, it is not possible to distinguish between these two possibilities. One way to resolve this issue might be to identify targets of daf-16 and daf-18 that mediate life span extension and then ask whether mutations in these downstream genes also affect the life spans of dauers. How is the life span extension seen in daf-2 and daf-23 mutants related to normal life span? This is a key question. There are at least two possibilities (Figure 2 ). Firstdaf-2 and daf-23 mutations might elicit an alternative life span–extending process that overrides the normal control system and extends life span in a new way. Alternatively, it is possible that the daf-2 and daf-23 mutations simply turn the hypothetical life span dial of C. elegans to a longer life span setting. If the dial can be set differently in different species, perhaps there are ways of changing its setting within a single individual. The process of dauer formation in C. elegans is reminiscent of the curious effect of caloric restriction on mammalian life span. If the caloric intake of rats is very low, they will live up to 60% longer than normal (reviewed by4Finch C.E. Longevity, Senescence, and the Genome. The University of Chicago Press, Chicago1990Google Scholar). These animals are fit, healthy, and disease resistant, suggesting that an alternative physiological state has been induced. Calorically restricted animals do not produce progeny. However, once food is restored, they become fertile, even if they have reached an age at which control rats would be postreproductive. How is caloric restriction related to dauer formation? Perhaps all animals have mechanisms that allow them to outlast environmental hardships and to postpone reproduction when the young are unlikely to survive. A mechanism like this could have evolved early in evolution. In modern-day rats, caloric restriction would have two effects: it would extend life and delay fertility. In modern-day worms it would initiate the full-blown dauer syndrome. How do the daf mutations lengthen life span of adult worms? It seems unlikely that the daf mutations extend life span simply by starving the worms. This is because the long-lived daf adults are fertile, and they do not have the pale, thin appearance characteristic of worms that cannot eat properly (1Avery L. Genetics. 1993; 133: 897-917Crossref PubMed Google Scholar). It is possible, however, that the daf genes (and possible homologs of these genes in other organisms) do function in a conserved pathway leading from environmental signals to longer life span, but at a relatively downstream position. Once the daf-2 and daf-23 genes are cloned, we may be able to infer their molecular activities. We will also be able to ask whether homologous genes influence life span in other organisms and, if so, whether their activity levels are set differently in different species. Are there other pathways for life span control in C. elegans? A second set of life span mutants, called clk (clock) mutants, may extend the life span of C. elegans in a different way (17Wong A. Boutis P. Hekimi S. Genetics. 1995; 139: 1247-1259Crossref PubMed Google Scholar). The clk mutations have not been reported to affect dauer formation. Furthermore, unlike the daf and age-1 mutationsclk mutations decrease the rates of many developmental and periodic processes, including the rate of cell division, pumping (chewing), and defecation. Thus, it seems possible that these mutations affect a second pathway that regulates the rate of aging. How likely is it that genetic analysis of organisms such as yeast and nematodes will provide insights into the mechanisms by which humans age? There is no way to answer this question definitively at this time. By identifying homologs of genes identified in these small organisms, it should be possible to test their relevance to vertebrates directly. Possibly the strongest argument for conservation comes from the remarkable level of evolutionary conservation that has been found to exist in other biological processes, such as the control of pattern formation, apoptosis, and the cell cycle. Again and again we discover that different types of organisms use the same mechanisms to control their growth and differentiation. In this light, it would be surprising if the mechanisms that control a process as fundamental and universal as aging were not conserved at some level. If we are lucky, the control of life span will be as elegant and discrete as the control of development and equally accessible to genetic analysis. There still have not been any large-scale unbiased screens carried out for life span mutants in any organism, so we have no idea how many life span genes will be found to exist. We should get going before it is too late." @default.
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• W2023442907 title "Ponce d'elegans: Genetic Quest for the Fountain of Youth" @default.
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