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• W2009716680 abstract "A gene that controls growth rate, radiation resistance and lifespan in the nematode Caenorhabditis elegans has been found to encode a homologue of a yeast telomere maintenance factor, raising the possibility that checkpoint control, telomere maintenance and aging may be linked in unanticipated ways. A gene that controls growth rate, radiation resistance and lifespan in the nematode Caenorhabditis elegans has been found to encode a homologue of a yeast telomere maintenance factor, raising the possibility that checkpoint control, telomere maintenance and aging may be linked in unanticipated ways. “In youth we run into difficulties. In old age difficulties run into us.” Josh Billings The difficulties we encounter in life make us feel older for good reason: cellular stresses accelerate aging and limit our lifespan. With the recognition that life is inevitably followed by a precisely invariant endpoint, we have pondered ways to deflect the inexorable progress of aging. Most aging researchers (and commentators on the subject) have already experienced the degenerative changes that progress with time, and quietly hope that a molecular understanding of aging will soon — very soon — lead to the development of longevity-promoting drugs. While aging is a broadly defined biological process, many of the molecular events of the aging process have been revealed in the past decade, particularly from the emergence of systems in which longevity can be manipulated genetically [1.Guarente L. Kenyon C.J. Genetic pathways that regulate ageing in model organisms.Nature. 2000; 408: 255-262Crossref PubMed Scopus (1064) Google Scholar]. Among the influences on aging and mortality, such processes as metabolic rate, oxidative damage, DNA repair and checkpoint control, gene silencing and telomere maintenance have received particular attention. A startling outcome from these discoveries is that senescence of unicellular yeast cells and aging in multicellular animals are influenced by some of the same molecular control systems [1.Guarente L. Kenyon C.J. Genetic pathways that regulate ageing in model organisms.Nature. 2000; 408: 255-262Crossref PubMed Scopus (1064) Google Scholar]. Two processes that affect aging are mechanistically intertwined: several proteins involved in DNA checkpoint control, which causes cell-cycle arrest or apoptosis in response to DNA damage, also function in maintenance of telomeres, the specialized ends of linear chromosomes [2.Gasser S.M. A sense of the end.Science. 2000; 288: 1377-1379Crossref PubMed Scopus (60) Google Scholar]. For example, the yeast protein Tel1, required for normal telomere length, is the homologue of human ataxia telangiectasia kinase, a mediator of DNA damage checkpoint control. Moreover, resistance to radiation in the budding yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans requires a protein — Rad17 in yeast, Mrt-2 in worms — which activates checkpoint control [3.Gartner A. Milstein S. Ahmed S. Hodgkin J. Hengartner M.O. A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans.Mol. Cell. 2000; 5: 435-443Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar]. Rad17/Mrt-2 also functions in telomere maintenance: C. elegans cells deficient for this protein show progressive telomere shortening and chromosome fusion [4.Ahmed S. Hodgkin J. MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans.Nature. 2000; 403: 159-164Crossref PubMed Scopus (205) Google Scholar]. Given that improper telomere maintenance can cause cells to senesce, and that increased telomerase activity can immortalize some cells (reviewed in [5.Blackburn E.H. Telomere states and cell fates.Nature. 2000; 408: 53-56Crossref PubMed Scopus (1029) Google Scholar]), it is not surprising that lesions in this gene also cause late-onset sterility. Cells of the germline — an immortal lineage in all non-extinct species — lose their immortality in telomerase mutants, concomitant with progressive telomere shortening and ultimately senescence [4.Ahmed S. Hodgkin J. MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans.Nature. 2000; 403: 159-164Crossref PubMed Scopus (205) Google Scholar]. Recent findings by three groups [6.Bénard C. McCright B. Zhang Y. Felkai S. Lakowski B. Hekimi S. The C. elegans maternal-effect gene clk-2 is essential for embryonic development, encodes a protein homologous to yeast Tel2p and affects telomere length.Development. 2001; 128: 4045-4055Crossref PubMed Google Scholar, 7.Ahmed S. Alpi A. Hengartner M.O. Gartner A. C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein.Curr. Biol. 2001; 11: 1934-1944Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 8.Lim C.-S. Mian S. Dernburg A.F. Campisi J. C. elegans clk-2, a gene that limits life span, encodes a regulator of telomere metabolism similar to the yeast telomere binding protein Tel2p.Curr. Biol. 2001; 11: 1706-1710Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] further underscore the potential link between telomere maintenance, checkpoint control and longevity, but in rather unanticipated ways (Fig. 1). C. elegansclk-2 is one of four genes identified on the basis of their ‘slow’ mutant phenotype: clk mutants show delayed development, slower cell division rates and slowed neuronal cycles [9.Lakowski B. Hekimi S. Determination of life-span in Caenorhabditis elegans by four clock genes.Science. 1996; 272: 1010-1013Crossref PubMed Scopus (401) Google Scholar]. They are also longevity mutants, living up to 30% longer than wild-type worms. An allele of clk-2, called rad-5, was identified many years earlier in a separate screen for radiation-sensitive mutations [10.Hartman P.S. Herman R.K. Radiation-sensitive mutants of Caenorhabditis elegans.Genetics. 1982; 102: 159-178Crossref PubMed Google Scholar], and was later found to abrogate radiation-induced checkpoint control — both cell-cycle arrest and apoptosis — in the germline [3.Gartner A. Milstein S. Ahmed S. Hodgkin J. Hengartner M.O. A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans.Mol. Cell. 2000; 5: 435-443Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar]. Finally, clk-2 was also picked out in a screen through existing longevity mutants for those with abnormal telomere lengths [8.Lim C.-S. Mian S. Dernburg A.F. Campisi J. C. elegans clk-2, a gene that limits life span, encodes a regulator of telomere metabolism similar to the yeast telomere binding protein Tel2p.Curr. Biol. 2001; 11: 1706-1710Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. Thus it was that three separate groups [6.Bénard C. McCright B. Zhang Y. Felkai S. Lakowski B. Hekimi S. The C. elegans maternal-effect gene clk-2 is essential for embryonic development, encodes a protein homologous to yeast Tel2p and affects telomere length.Development. 2001; 128: 4045-4055Crossref PubMed Google Scholar, 7.Ahmed S. Alpi A. Hengartner M.O. Gartner A. C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein.Curr. Biol. 2001; 11: 1934-1944Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 8.Lim C.-S. Mian S. Dernburg A.F. Campisi J. C. elegans clk-2, a gene that limits life span, encodes a regulator of telomere metabolism similar to the yeast telomere binding protein Tel2p.Curr. Biol. 2001; 11: 1706-1710Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar], motivated by the distinct problems of aging/biological timing, checkpoint control and telomere function, respectively, all cloned clk-2/rad-5 and found that it encodes a homologue of Tel2, a protein required for normal telomere length in yeast. Tel2 was identified in screens for yeast mutations that result in abnormally short telomeres [11.Runge K.W. Zakian V.A. TEL2, an essential gene required for telomere length regulation and telomere position effect in Saccharomyces cerevisiae.Mol. Cell Biol. 1996; 16: 3094-3105Crossref PubMed Scopus (81) Google Scholar]. The telomeres of tel2 mutant yeast cells are stably much shorter than normal telomeres. Like clk-2 mutants of C. elegans, viable tel2 mutant yeast cells grow slowly. Given the defining phenotype for yeast tel2 mutants, it is therefore not surprising that Lim et al.[8.Lim C.-S. Mian S. Dernburg A.F. Campisi J. C. elegans clk-2, a gene that limits life span, encodes a regulator of telomere metabolism similar to the yeast telomere binding protein Tel2p.Curr. Biol. 2001; 11: 1706-1710Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] found that a clk-2 allele results in shortened telomeres. However, the story is not so simple: Bénard et al.[6.Bénard C. McCright B. Zhang Y. Felkai S. Lakowski B. Hekimi S. The C. elegans maternal-effect gene clk-2 is essential for embryonic development, encodes a protein homologous to yeast Tel2p and affects telomere length.Development. 2001; 128: 4045-4055Crossref PubMed Google Scholar] found that telomeres were reproducibly longer in the clk-2 mutants, that this effect was rescued by the wild-type gene, and that overexpression of the intact gene caused shortened telomeres. Finally, as though to ensure the longevity of the debate, Ahmed et al.[7.Ahmed S. Alpi A. Hengartner M.O. Gartner A. C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein.Curr. Biol. 2001; 11: 1934-1944Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar] found no trend in either direction. The latter investigators explained the discrepancy by noting that extensive, apparently stochastic, heterogeneity in telomere length is seen between, and even within, individual strains of C. elegans. Even if there is no effect of clk-2 mutations on telomere length, this does not mean a priori that telomere maintenance defects are not responsible for the phenotypes of clk-2 mutants. Telomere length was originally thought to be the critical parameter in telomere function that protects against senescence. For example, the replicative potential, or longevity, of dividing cells has been correlated with their ability to maintain telomeres at a sufficient length, a function requiring telomerase, which is necessary, and in some cases sufficient, for longevity of dividing cells [5.Blackburn E.H. Telomere states and cell fates.Nature. 2000; 408: 53-56Crossref PubMed Scopus (1029) Google Scholar]. However, it has since been shown that it is not the length of telomeres, but rather a stabilizing process, or capping, that is critical for proper telomere function and continued propagation of cells (reviewed in [5.Blackburn E.H. Telomere states and cell fates.Nature. 2000; 408: 53-56Crossref PubMed Scopus (1029) Google Scholar]). Clk-2/Rad-5 might function in telomere capping, which protects the double-strand ends of chromosomes from fusing to other such ends by the machinery that repairs double-strand DNA breaks. Consistent with such a notion, yeast Tel2 binds to telomere sequences [12.Kota R.S. Runge K.W. The yeast telomere length regulator TEL2 encodes a protein that binds to telomeric DNA.Nucleic Acids Res. 1998; 26: 1528-1535Crossref PubMed Scopus (26) Google Scholar], suggesting that its telomere-maintenance function might involve direct interaction with telomeres. On the surface, then, one might imagine that Clk-2/Rad-5/Tel2 influences longevity by affecting the maintenance of telomeres in somatic nuclei. This seems unlikely, however. First, Bénard et al.[6.Bénard C. McCright B. Zhang Y. Felkai S. Lakowski B. Hekimi S. The C. elegans maternal-effect gene clk-2 is essential for embryonic development, encodes a protein homologous to yeast Tel2p and affects telomere length.Development. 2001; 128: 4045-4055Crossref PubMed Google Scholar] made the surprising observation that a Clk-2 fusion protein resides in the cytoplasm, not the nucleus as expected for a protein that acts by binding to telomeres. Of course, some of the protein might be nuclear but undetectable, or it may function indirectly in telomere maintenance. Even so, it is difficult to imagine how telomere maintenance might affect longevity of somatic tissues in an organism such as C. elegans, where all adult somatic cells arise by a limited and fixed number of cell divisions [13.Sulston J.E. Schierenberg E. White J.G. Thomson J.N. The embryonic cell lineage of the nematode Caenorhabditis elegans.Dev Biol. 1983; 100: 64-119Crossref PubMed Scopus (2636) Google Scholar]. The longevity of yeast, vertebrate cells and the immortal C. elegans germline is defined by, or requires, continued mitosis of non-senescing cells, which necessitates continuous telomere maintenance [5.Blackburn E.H. Telomere states and cell fates.Nature. 2000; 408: 53-56Crossref PubMed Scopus (1029) Google Scholar]. In contrast, senescence of worms occurs long after cell division has ceased and longevity does not (and cannot) depend on replacement of somatic cells. The longevity of clk-2/rad-5 mutants may be attribut-able not to telomere maintenance but to another aging-related process — DNA repair. Clk-2/Rad-5 defines a new checkpoint component required for resistance to radiation-induced DNA damage [3.Gartner A. Milstein S. Ahmed S. Hodgkin J. Hengartner M.O. A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans.Mol. Cell. 2000; 5: 435-443Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar, 7.Ahmed S. Alpi A. Hengartner M.O. Gartner A. C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein.Curr. Biol. 2001; 11: 1934-1944Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar]. However, this phenotype is paradoxical: DNA repair extends lifespan, and defects in it should diminish rather than extend lifespan. Indeed, that is exactly what is seen for mutations in other checkpoint genes, including mutations of the p53 tumor suppressor, which reduce lifespan in both worms [14.Derry W.B. Putzke A.P. Rothman J.H. Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance.Science. 2001; 294: 591-595Crossref PubMed Scopus (357) Google Scholar, 15.Schumacher B. Hofmann K. Boulton S. Gartner A. The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis.Curr Biol. 2001; 11: 1722-1727Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar] and mice [16.Tyner S.D. Venkatachalam S. Choi J. Jones S. Ghebranious N. Igelmann H. Lu X. Soron G. Cooper B. Brayton C. et al.p53 mutant mice that display early ageing-associated phenotypes.Nature. 2002; 415: 45-53Crossref PubMed Scopus (1115) Google Scholar], and mutations in mrt-2, which extinguish the immortality of the C. elegans germline [4.Ahmed S. Hodgkin J. MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans.Nature. 2000; 403: 159-164Crossref PubMed Scopus (205) Google Scholar]. A compli-cating factor is that the clk-2/rad-5/tel2 mutations are not null mutations in either yeast or worms, and the mutations studied might alter the protein in quite different ways, accounting for the discrepancy in phenotypes [6.Bénard C. McCright B. Zhang Y. Felkai S. Lakowski B. Hekimi S. The C. elegans maternal-effect gene clk-2 is essential for embryonic development, encodes a protein homologous to yeast Tel2p and affects telomere length.Development. 2001; 128: 4045-4055Crossref PubMed Google Scholar, 7.Ahmed S. Alpi A. Hengartner M.O. Gartner A. C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein.Curr. Biol. 2001; 11: 1934-1944Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 11.Runge K.W. Zakian V.A. TEL2, an essential gene required for telomere length regulation and telomere position effect in Saccharomyces cerevisiae.Mol. Cell Biol. 1996; 16: 3094-3105Crossref PubMed Scopus (81) Google Scholar]. As elimination of the gene in either organism is lethal, its absolute roles in checkpoint control, telomere function and lifespan are not readily assessed. DNA checkpoint control and telomere maintenance are linked in another way which could account for the longevity of clk-2 mutants: some proteins involvedin both processes also act in silencing of telomere-proximal genes [1.Guarente L. Kenyon C.J. Genetic pathways that regulate ageing in model organisms.Nature. 2000; 408: 255-262Crossref PubMed Scopus (1064) Google Scholar]. Normally silent subtelomeric genes are desilenced in aging yeast, resulting in their sterility, and silencing of ribosomal (r)DNA leads to increased lifespan. This silencing is mediated by Sir proteins, which are telomere-associated in young yeast cells and move to the nucleolus in old cells. Remarkably, increasing the dosage of Sir2, the NAD-dependent histone deacetylase activity of which is responsible for silencing, increases lifespan in both yeast and in worms [17.Tissenbaum H.A. Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans.Nature. 2001; 410: 227-230Crossref PubMed Scopus (1500) Google Scholar]. Caloric restriction, which extends lifespan, may act in part by increasing NAD levels, thereby activating Sir2's gene silencingfunction [1.Guarente L. Kenyon C.J. Genetic pathways that regulate ageing in model organisms.Nature. 2000; 408: 255-262Crossref PubMed Scopus (1064) Google Scholar]. A mutation in yeast tel2 reduces subtelomeric gene silencing, thus linking clk-2/rad-5/tel2 gene anda process that influences aging. Again, however, the clk-2 mutant phenotype is the opposite of what might be expected, as desilencing in yeast is associated with decreased longevity. Perhaps many of the rad-5/clk-2 phenotypes in worms arise from desilencing of telomere-proximal genes, including genes that slow neuronal cycles or enhance longevity. Such a mechanism could explain how a telomere maintenance function might regulate longevity of non-dividing somatic cells in C. elegans. Given their slowed growth and development, clk-2 mutants may be metabolically depressed, a condition that increases longevity irrespective of any effects on checkpoint control or telomere maintenance. Indeed, clk-2 mutant adults are generally sickly and sluggish, suggesting reduced metabolic rates [6.Bénard C. McCright B. Zhang Y. Felkai S. Lakowski B. Hekimi S. The C. elegans maternal-effect gene clk-2 is essential for embryonic development, encodes a protein homologous to yeast Tel2p and affects telomere length.Development. 2001; 128: 4045-4055Crossref PubMed Google Scholar]. In fact, although clk-2/rad-5 is the only clk gene known to affect checkpoint control [7.Ahmed S. Alpi A. Hengartner M.O. Gartner A. C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein.Curr. Biol. 2001; 11: 1934-1944Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar], and the molecular identities of the clk-1–clk-3 gene products indicate that they are involved in quite different molecular processes, mutations in ten clk genes have been identified based on slow growth phenotypes, and all extend lifespan [18.Hekimi S. Burgess J. Bussière F. Meng Y Bénard C. Genetics of lifespan in C. elegans: molecular diversity, physiological complexity, mechanistic simplicity.Trends Genet. 2001; 17: 712-718Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]. Moreover, worms are no exception in showing longer lifespan as a result of caloric restriction: for example, semi-starved ‘eat’ mutants show extended lifespan and appear to be defective in the same aging pathway as clk-1[19.Lakowski B. Hekimi S. The genetics of caloric restriction in Caenorhabditis elegans.Proc. Natl. Acad Sci. U.S.A. 1998; 95: 13091-13096Crossref PubMed Scopus (683) Google Scholar]. This does not, however, explain why checkpoint control and/or telomere maintenance defects lead to slow growth. Perhaps slow growth results from an unidentified checkpoint function that attenuates cell-cycle progression in response to damage accumulating in the absence of the Rad-5/Clk-2-mediated checkpoint. The slow neuronal cycles might be explained if damaged differentiated cells have mechanisms to reduce metabolic rates. A major regulatory process for aging in C. elegans is an insulin-like hormonal signaling system that limits lifespan [1.Guarente L. Kenyon C.J. Genetic pathways that regulate ageing in model organisms.Nature. 2000; 408: 255-262Crossref PubMed Scopus (1064) Google Scholar]. This pathway is apparently separate from that affected by the caloric restriction/clk pathway. But while the effect of the hormonal pathway on longevity may be separable from its role in metabolic regulation, it does appear to affect longevity through the oxidative stress which arises from electron transport [20.Feng J. Bussière F. Hekimi S. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans.Dev Cell. 2001; 1: 633-644Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar]. Thus, once again the aging mechanism relates back to stress-management systems and metabolism. Teasing apart the function of factors that influence the complex process of aging and perform multiple activities within cells poses great challenges. Which of the activities are truly aging-relevant? Do clk-2/rad-5 mutations extend longevity by affecting telomere maintenance, gene silencing, altered DNA repair/checkpoint control or simply by slowing growth and metabolism (Fig. 1)? The degree to which the controls over DNA damage checkpoints, the abrupt ends of chromosomes and the finite span of life are intimately intertwined will be illuminated once the field reaches an advanced age. Many of us hope that will occur before we ourselves have arrived at that same stage." @default.
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• W2009716680 title "Aging: From Radiant Youth to an Abrupt End" @default.
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