Genetic pathways that regulate ageing in model organisms

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Searches for genes involved in the ageing process have been made in genetically tractable model organisms such as yeast, the nematode Caenorhabditis elegans , Drosophila melanogaster fruitflies and mice. These genetic studies have established that ageing is indeed regulated by specific genes, and have allowed an analysis of the pathways involved, linking physiology, signal transduction and gene regulation. Intriguing similarities in the phenotypes of many of these mutants indicate that the mutations may also perturb regulatory systems that control ageing in higher organisms.

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Figure 1: Ageing in budding yeast.
Figure 2: Caloric restriction in yeast.
Figure 3: Regulation of C. elegans ageing by an elaborate endocrine system.


  1. 1

    Weindruch, R. H., Walford, R. L., Fligiel, S. & Guthrie, D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity, and lifetime energy intake. J. Nutr. 116, 641–654 (1986).

  2. 2

    Harman, D. The aging process. Proc. Natl Acad. Sci. USA 78, 7124–7128 (1981).

  3. 3

    Finch, C. Longevity, senescence, and the genome (Univ. Chicago Press, Chicago, IL, 1990).

  4. 4

    Mortimer, R. K. & Johnston, J. R. Life span of individual yeast cells. Nature 183, 1751 –1752 (1959).

  5. 5

    Egilmez, N. K. & Jazwinski, S. M. Evidence for the involvement of a cytoplasmic factor in the aging of the yeast Saccharomyces cerevisiae . J Bacteriol. 171, 37– 42 (1989).

  6. 6

    Jazwinski, S. M. The genetics of aging in the yeast Saccharomyces cerevisiae. Genetica 91, 35–53 ( 1993).

  7. 7

    Smeal, T., Claus, J., Kennedy, B., Cole, F. & Guarente, L. Loss of transcriptional silencing causes sterility in old mother cells of S. cerevisiae. Cell 84, 633–642 (1996).

  8. 8

    Rine, J. & Herskowitz, I. Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae . Genetics 116, 9–22 (1987).

  9. 9

    Gottschling, D. E., Aparicio, O. M., Billington, B. L. & Zakian, V. A. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 63, 751– 762 (1990).

  10. 10

    Kennedy, B. K., Austriaco, N. R. Jr, Zhang, J. & Guarente, L. Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell 80, 485–486 ( 1995).

  11. 11

    Smith, J. S. & Boeke, J. D. An unusual form of transcriptional silencing in yeast ribosomal DNA. Genes Dev. 11, 241–254 (1997).

  12. 12

    Bryk, M. et al. Transcriptional silencing of Ty1 elements in the RDN1 locus of yeast. Genes Dev. 11, 255– 269 (1997).

  13. 13

    Kaeberlein, M., McVey, M. & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570–2580 (1999).

  14. 14

    Kim, S., Benguria, A., Lai, C.-Y. & Jazwinski, M. Modulation of life span by histone deacetylase genes in S. cerevisiae. Mol. Biol. Cell 10, 3125–3136 (1999).

  15. 15

    Smith, J. S., Caputo, E. & Boeke, J. A genetic screen for ribosomal DNA silencing defects identifies multiple DNA replication and chromatin remodeling factors. Mol. Cell. Biol. 19, 3184–3197 (1999).

  16. 16

    Gottlieb, S. & Esposito, R. E. A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA. Cell 56, 771–776 ( 1989).

  17. 17

    Sinclair, D. & Guarente, L. Extrachromosomal rDNA circles—a cause of aging in yeast. Cell 91, 1033– 1042 (1997).

  18. 18

    Defossez, P. A. et al. Elimination of replication block protein Fob1 extends the life span of yeast mother cells. Mol. Cell 3, 447–455 (1999).

  19. 19

    Heo, S. T., K., Ohsugi, I., Shimamoto, A., Furiuchi, Y. & Ikeda, I. Blooms syndrome gene suppresses premature aging causes by Sgs1 deficiency in yeast. Genes Cells 4, 619–624 (1999).

  20. 20

    Ashrafi, K., Sinclair, D., Gordon, J. & Guarente, L. Passage through stationary phase advances replicative aging in S. cerevisiae. Proc. Natl Acad. Sci. USA 96, 9100– 9105 (1999).

  21. 21

    Sinclair, D., Mills, K. & Guarente, L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science 277, 1313– 1316 (1997).

  22. 22

    Celenza, J. L. A yeast gene that is essential for release from glucose repression encodes a protein kinase. Science 233, 1175– 1180 (1986).

  23. 23

    Ashrafi, K., Lin, S., Manchester, J. & Gordon, J. Sip2p and its partner Snf1p kinase affect aging in S. cerevisiae. Genes Dev. 14, 1872–1885 (2000).

  24. 24

    Brachmann, C. B. et al. The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev. 9, 2888–2902 (1995).

  25. 25

    Frye, R. A. Characterization of five human cDNAs with homology to yeast SIR2 gene: Sir2-like proteins (Sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem. Biophys. Res. Commun. 260, 273–279 (1999).

  26. 26

    Braunstein, M., Rose, A. B., Holmes, S. G., Allis, C. D. & Broach, J. R. Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 7, 592–604 (1993).

  27. 27

    Tanny, J. C., Dowd, G. J., Huang, J., Hilz, H. & Moazed, D. An enzymatic activity in the yeast SIR2 protein that is essential for gene silencing. Cell 99, 735 –745 (1999).

  28. 28

    Imai, S. I., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein SIR2 is an NAD-dependent histone deacetylase. Nature 403, 795– 799 (2000).

  29. 29

    Smith, J. S. et al. A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family. Proc. Natl Acad. Sci. USA 97, 6658–6663 ( 2000).

  30. 30

    Landry, J. et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc. Natl Acad. Sci. USA 97, 5807–5811 (2000).

  31. 31

    Lin, S., Defossez, P. & Guarente, L. Life span extension by calorie restriction in S. cerevisiae requires NAD and SIR2. Science 289, 2126–2128 (2000).

  32. 32

    Chen, J. B., Sun, J. & Jazwinski, S. M. Prolongation of the yeast life span by the v-Ha-Ras oncogene. Mol. Microbiol. 4, 2081– 2086 (1990).

  33. 33

    Guarente, L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 14, 1021–1026 ( 2000).

  34. 34

    Kirchman, P. A., Sangkyu, K., Lai, C. Y. & Jazwinski, S. M. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics 152, 179–190 ( 1999).

  35. 35

    Parikh, V. S., Morgan, M., Scott, R., Clements, S. & Butow, R. A. The mitochondrial genotype can influence nuclear gene expression in yeast. Science 235, 576 –580 (1987).

  36. 36

    Guarente, L. Do changes in chromosomes cause aging? Cell 86, 9–12 (1996).

  37. 37

    Wareham, K. A., Lyon, M. F., Glenister, P. H. & Williams, E. D. Age related reactivation of an X-linked gene. Nature 327, 725–727 (1987).

  38. 38

    Kimura, K. D., Tissenbaum, H. A., Liu, Y. & Ruvkun, G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942–946 (1997).

  39. 39

    Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A C. elegans mutant that lives twice as long as wild type. Nature 366, 461– 464 (1993).

  40. 40

    Larsen, P. L., Albert, P. S. & Riddle, D. L. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139, 1567–1583 (1995).

  41. 41

    Morris, J. Z., Tissenbaum, H. A. & Ruvkun, G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382, 536–539 ( 1996).

  42. 42

    Paradis, S. & Ruvkun, G. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev. 12, 2488 –2498 (1998).

  43. 43

    Paradis, S., Ailion, M., Toker, A., Thomas, J. H. & Ruvkun, G. A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans . Genes Dev. 13, 1438– 1452 (1999).

  44. 44

    Ogg, S. & Ruvkun, G. The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol. Cell 2, 887–893 ( 1998).

  45. 45

    Gil, E. B., Link, E. M., Liu, L. X., Johnson, C. D. & Lees J. A. Regulation of the insulin-like developmental pathway of Caenorhabditis elegans by a homolog of the PTEN tumor suppressor gene. Proc. Natl Acad. Sci. USA 96, 2925 –2930 (1999).

  46. 46

    Rouault, J. P. et al. Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN. Curr. Biol. 9, 329–332 ( 1999).

  47. 47

    Mihaylova, V. T., Borland, C. Z., Manjarrez, L., Stern, M. J. & Sun, H. The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc. Natl Acad. Sci. USA 96, 7427–7432 (1999).

  48. 48

    Friedman, D. B. & Johnson, T. E. Three mutants that extend both mean and maximum life span of the nematode, Caenorhabditis elegans, define the age-1 gene. J. Gerontol. 43, 102–109 (1988).

  49. 49

    Dorman, J. B., Albinder, B., Shroyer, T. & Kenyon, C. The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics 141, 1399–1406 (1995).

  50. 50

    Kawano, T. et al. Molecular cloning and characterization of a new insulin/IGF-like peptide of the nematode Caenorhabditis elegans. Biochem. Biophys. Res. Comm. 273, 431–436 (2000).

  51. 51

    Gems, D. et al. Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans . Genetics 150, 129– 155 (1998).

  52. 52

    Lin, K., Dorman, J. B., Rodan, A. & Kenyon, C daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278, 1319–1322 (1997).

  53. 53

    Ogg, S. et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994–999 (1997).

  54. 54

    Nakae, J., Park, B. & Accili, D. Insulin stimulates phosphorylation of the Forkhead transcription factor FKHR on serine 253 through a wortmannin-sensitive pathway. J. Biol. Chem. 274, 15982–15985 (1999).

  55. 55

    Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).

  56. 56

    Rena, G., Guo, S., Cichy, S. C., Unterman, T. G. & Cohen, P. Phosphorylation of the transcription factor Forkhead family member FKHR by protein kinase B. J. Biol. Chem. 274, 17179–17183 (1999).

  57. 57

    Kops, G. J. et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398, 630– 634 (1999).

  58. 58

    Biggs, W. H. III, Meisenhelder, J., Hunter, T., Cavenee, W. K. & Arden, K. C. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc. Natl Acad. Sci. USA 96, 7421–7460 ( 1999).

  59. 59

    Riddle, D. L. & Albert, P. S. in C. elegans Vol. II (eds Riddle, D. L., Blumenthal, T., Meyer, B. J. & Priess, J. R.) 739–768 (Cold Spring Harbor Laboratory Press, 1997).

  60. 60

    Tissenbaum, H. A. & Ruvkun, G. An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans. Genetics 148, 703– 717 (1998).

  61. 61

    Vanfleteren, J. R. & De Vreese, A. The gerontogenes age-1 and daf-2 determine metabolic rate potential in aging Caenorhabditis elegans. FASEB J. 9, 1355–1361 (1995).

  62. 62

    Van Voorhies, W. A. & Ward, S. Genetic and environmental conditions that increase longevity in Caenorhabditis elegans decrease metabolic rate. Proc. Natl Acad. Sci. USA 96, 11399–11403 (1999).

  63. 63

    Gottlieb, S. & Ruvkun, G. daf-2, daf-16 and daf-23: genetically interacting genes controlling dauer formation in Caenorhabditis elegans. Genetics 137, 107–120 (1994).

  64. 64

    Vowels, J. J. & Thomas, J. H. Genetic analysis of chemosensory control of dauer formation in C. elegans. Genetics 130, 105–123 (1992)

  65. 65

    Apfeld, J. & Kenyon, C. Cell nonautonomy of C. elegans DAF-2 function in the regulation of diapause and life span. Cell 95, 199–210 ( 1998).

  66. 66

    Larsen, P. L. Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 90, 8905– 8909 (1993).

  67. 67

    Lithgow, G. J., White, T. M., Melov, S. & Johnson, T. E. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc. Natl Acad. Sci. USA 92, 7540 –7544 (1995).

  68. 68

    Murakami, S. & Johnson, T. E. A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics 143, 1207–1218 (1996).

  69. 69

    Apfeld, J. & Kenyon, C. Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature 402, 804–809 (1999).

  70. 70

    Ailion, M., Inoue, T., Weaver, C. I., Holdcraft, R. W. & Thomas, J. H. Neurosecretory control of aging in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 96, 7394–7397 (1999).

  71. 71

    Hsin, H. & Kenyon, C. Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399, 362–366 (1999).

  72. 72

    Antebi, A., Yeh, W., Tait,, D., Hedgecock, E. M. & Riddle, D. L. daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans. Genes Dev. 14, 1512–1527 (2000).

  73. 73

    Sgro, C. M. & Partridge, L. A delayed wave of death from reproduction in Drosophila. Science 286, 2521– 2524 (1999).

  74. 74

    Lin, Y. J., Seroude, L. & Benzer, S. Extended life-span and stress resistance in the Drosophila mutant methuselah. Science 282 , 943–946 (1998).

  75. 75

    Arking, R., Buck, S., Berrios, A., Dwyer, S. & Baker, G. T. Elevated paraquat resistance can be used as a bioassay for longevity in a genetically based long-lived strain of Drosophila. Dev. Genet. 12, 362–370 (1991).

  76. 76

    Service, P. M., Hutchinson, E. W., MacKinley, M. D. & Rose, M. R. Resistance to environmental stress in Drosophila melanogaster selected for postponed senescence. Physiol. Zool. 58, 380–389 (1985).

  77. 77

    Sohal, R. S. & Weindruch, R. Oxidative stress, caloric restriction, and aging. Science 273, 59– 63 (1996).

  78. 78

    Migliaccio, E. et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402 , 309–313 (1999).

  79. 79

    Taub, J. et al. A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-2 and clk-1 mutants. Nature 399, 162–166 (1999).

  80. 80

    Honda, Y. & Honda, S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J. 13, 1385–1393 (1999).

  81. 81

    Ishii, N. et al. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 394 , 694–697 (1998).

  82. 82

    Melov, S. et al. Extension of life-span with superoxide dismutase/catalase mimetics . Science 289, 1567–1569 (2000).

  83. 83

    Sun, J. & Tower, J. FLP recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the life span of adult Drosophila melanogaster flies. Mol. Cell. Biol. 19, 216–228 ( 1999).

  84. 84

    Parkes, T. L. et al. Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nature Genet. 19, 171–174 (1998).

  85. 85

    Branicky, R., Benard, C. & Hekimi S. clk-1, mitochondria, and physiological rates. BioEssays 22, 48–56 ( 2000).

  86. 86

    Klass, M. R. Aging in the nematode C. elegans: major biological and environmental factors influencing life span. Mech. Ageing Dev. 6, 413–429 (1977).

  87. 87

    Avery, L. The genetics of feeding in Caenorhabditis elegans. Genetics 133, 897–917 ( 1993).

  88. 88

    Lakowski, B. & Hekimi, S. The genetics of caloric restriction in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 95, 13091–13096 (1998).

  89. 89

    Murakami, S. & Johnson, T. E. Life extension and stress resistance in Caenorhabditis elegans modulated by the tkr-1 gene. Curr. Biol. 9, 791–795 ( 1998).

  90. 90

    Wu, W. et al. Mutations in PROP1 cause familial combined pituitary hormone deficiency . Nature Genet. 18, 147– 149 (1998).

  91. 91

    Brown-Borg, H. M., Borg, K. E., Meliska, C. J. & Bartke, A. Dwarf mice and the aging process. Nature 384, 33 (1996).

  92. 92

    Bartke, A. et al. Does growth hormone prevent or accelerate aging? Exp. Gerontol. 33, 675–687 (1998)

  93. 93

    Kopchick, J. J. & Laron, Z. Is the Laron mouse an accurate model of Laron syndrome? Molec. Gen. Metab. 68, 232–236 (1999)

  94. 94

    Hunter, W. S., Croson, W. B., Bartke, A., Gentry, M. V. & Meliska, C. J. Low body temperature in long-lived Ames dwarf mice at rest and during stress. Physiol. Behav. 67, 433–437 (1999).

  95. 95

    Brown-Borg, H. M. & Rakoczya, S. G. Catalase expression in delayed and premature aging mouse models. Exp. Geron. 35, 199–212 (1999).

  96. 96

    Hauck, S. J. & Bartke, A. Effects of growth hormone on hypothalamic catalase and Cu/Zn superoxide dismutase. Free Radical Biol. Med. 28, 970–978 ( 2000).

  97. 97

    Wolkow, C. A., Kimura, K. D., Lee, M.-S. & Ruvkun, G. Regulation of C. elegans life-span by insulin like signaling in the nervous system. Science 290, 147– 150 (2000).

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Note added in proof. Recently, Wolkow et al.97 have shown that expression of the C. elegans daf-2 receptor or age-1 PI(3)K only in neurons can confer normal life span, and that expression of daf-2 only in endoderm has a significant, but lesser, effect. These findings are in accord with previous mosaic analysis65. An important caveat is that the levels of DAF-2 and AGE-1 produced in these transgenic animals may differ from endogenous levels, possibly altering the level of downstream signal. Wolkow et al. also demonstrate that expressing daf-2 or age-1 only in neurons can be sufficient for normal fat metabolism in the intestine. This is consistent with earlier findings that daf-2 activity in the ectoderm can be necessary and sufficient for normal intestinal pigmentation65, although it should be noted that genetic mosaic animals with a nervous system that is almost completely wild type but internal tissues that are daf-2 often have a Daf-2 intestinal phenotype. Finally, the new study reported that the altered intestinal metabolism of insulin/IGF-1 pathway mutants is not required for longevity, as had been shown previously by analysing intestinal pigmentation and life span in genetic mosaics65 (see text).

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