Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Lessons from human progeroid syndromes

Abstract

A number of human genes have been identified in which mutations can lead to the accelerated emergence of features of senescence. Studies of these genes, and of the functions of their protein products, may lead to a clearer understanding of the nature of senescence, and could provide clues for ways in which ageing might be retarded.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: RecQ helicases.

Similar content being viewed by others

References

  1. Rose, M. R. Evolutionary Biology of Aging (Oxford Univ. Press, Oxford, 1991).

    Google Scholar 

  2. Martin, G. M. Genetic Effects on Aging Vol. II (ed. Harrison, D. E.) 493–520 (Telford Press, Caldwell, NJ, 1990).

    Google Scholar 

  3. Grist, S. A., McCarron, M., Kutlaca, A., Turner, D. R. & Morley, A. A. In vivo human somatic mutation: frequency and spectrum with age. Mutat. Res. 266, 189–196 (1992).

    Article  CAS  Google Scholar 

  4. Martin, G. M. et al. Somatic mutations are frequent and increase with age in human kidney epithelial cells. Hum. Mol. Genet. 5, 215–221 (1996).

    Article  CAS  Google Scholar 

  5. Crow, J. F. Spontaneous mutation in man. Mutat. Res. 437, 5–9 (1999).

    Article  CAS  Google Scholar 

  6. Yu, C. E. et al. Positional cloning of the Werner's syndrome gene. Science 272, 258–262 ( 1996).

    Article  ADS  CAS  Google Scholar 

  7. Fukuchi, K., Martin, G. M. & Monnat, R. J. Jr Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc. Natl Acad. Sci. USA 86, 5893–5897 ( 1989). [Published erratum appears in Proc. Natl Acad. Sci. USA 86, 7994 (1989).]

    Article  ADS  CAS  Google Scholar 

  8. Epstein, C. J., Martin, G. M., Schultz, A. L. & Motulsky, A. G. Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Med. Baltimore 45, 177–221 (1966).

    Article  CAS  Google Scholar 

  9. Goto, M., Miller, R. W., Ishikawa, Y. & Sugano, H. Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol. Biomarkers Prev. 5, 239– 246 (1996).

    CAS  PubMed  Google Scholar 

  10. Gimbrone, M. A. Jr Endothelial dysfunction, hemodynamic forces, and atherosclerosis . Thromb. Haemost. 82, 722– 726 (1999).

    Article  CAS  Google Scholar 

  11. Martin, G. M., Sprague, C. A. & Epstein, C. J. Replicative life-span of cultivated human cells. Effects of donor's age, tissue, and genotype. Lab. Invest. 23, 86–92 (1970).

    CAS  PubMed  Google Scholar 

  12. Ogburn, C. E. et al. An apoptosis-inducing genotoxin differentiates heterozygotic carriers for Werner helicase mutations from wild-type and homozygous mutants . Hum. Genet. 101, 121– 125 (1997).

    Article  CAS  Google Scholar 

  13. Castro, E. et al. Polymorphisms at the Werner locus: I. Newly identified polymorphisms, ethnic variability of 1367Cys/Arg, and its stability in a population of Finnish centenarians. Am. J. Med. Genet. 82, 399 –403 (1999).

    Article  CAS  Google Scholar 

  14. Ye, L. et al. Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population. Am. J. Med. Genet. 68, 494–498 ( 1997). [Published erratum appears in Am. J. Med. Genet. 70, 103 (1997).]

    Article  CAS  Google Scholar 

  15. Huang, S. et al. The premature aging syndrome protein, WRN, is a 3′ 5′ exonuclease. Nature Genet. 20, 114– 116 (1998).

    Article  CAS  Google Scholar 

  16. Shen, J. C. et al. Werner syndrome protein. I. DNA helicase and dna exonuclease reside on the same polypeptide. J. Biol. Chem. 273, 34139–34144 (1998).

    Article  CAS  Google Scholar 

  17. Suzuki, N., Shiratori, M., Goto, M. & Furuichi, Y. Werner syndrome helicase contains a 5′ 3′ exonuclease activity that digests DNA and RNA strands in DNA/DNA and RNA/DNA duplexes dependent on unwinding. Nucleic Acids Res. 27, 2361–2368 (1999).

    Article  CAS  Google Scholar 

  18. Poot, M., Hoehn, H., Runger, T. M. & Martin, G. M. Impaired S-phase transit of Werner syndrome cells expressed in lymphoblastoid cell lines. Exp. Cell Res. 202, 267–273 (1992).

    Article  CAS  Google Scholar 

  19. Yan, H., Chen, C. Y., Kobayashi, R. & Newport, J. Replication focus-forming activity 1 and the Werner syndrome gene product . Nature Genet. 19, 375– 378 (1998).

    Article  CAS  Google Scholar 

  20. Lebel, M., Spillare, E. A., Harris, C. C. & Leder, P. The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J. Biol. Chem. 274, 37795–37799 (1999).

    Article  CAS  Google Scholar 

  21. Gray, M. D. et al. The Werner syndrome protein is a DNA helicase. Nature Genet. 17, 100–103 (1997).

    Article  CAS  Google Scholar 

  22. Cooper, M. P. et al. Ku complex interacts with and stimulates the Werner protein . Genes Dev. 14, 907–912 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, B. & Comai, L. Functional interaction between Ku and the Werner syndrome protein in DNA end processing. J. Biol. Chem. 275, 28349–28352 ( 2000).

    Article  CAS  Google Scholar 

  24. Balajee, A. S. et al. The Werner syndrome protein is involved in RNA polymerase II transcription. Mol. Biol. Cell 10, 2655 –2668 (1999).

    Article  CAS  Google Scholar 

  25. Blander, G. et al. Physical and functional interaction between p53 and the Werner's syndrome protein. J. Biol. Chem. 274, 29463 –29469 (1999).

    Article  CAS  Google Scholar 

  26. Hanada, K. et al. RecQ DNA helicase is a suppressor of illegitimate recombination in Escherichia coli. Proc. Natl Acad. Sci. USA 94, 3860–3865 (1997).

    Article  ADS  CAS  Google Scholar 

  27. Yamagata, K. et al. Bloom's and Werner's syndrome genes suppress hyperrecombination in yeast sgs1 mutant: implication for genomic instability in human diseases . Proc. Natl Acad. Sci. USA 95, 8733– 8738 (1998).

    Article  ADS  CAS  Google Scholar 

  28. Fu, Y. H. et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256– 1258 (1992).

    Article  ADS  CAS  Google Scholar 

  29. Tiscornia, G. & Mahadevan, M. S. Myotonic dystrophy: the role of the CUG triplet repeats in splicing of a novel DMPK exon and altered cytoplasmic DMPK mRNA isoform ratios. Mol. Cell 5, 959 –967 (2000).

    Article  CAS  Google Scholar 

  30. Harley, H. G. et al. Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in myotonic dystrophy. Am. J. Hum. Genet. 52, 1164–1174 ( 1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Harnshere, M. G. et al. Myotonic dystrophy: the correlation of (CTG) repeat length in leucocytes with age at onset is significant only for patients with small expansions. J. Med. Genet. 36, 59– 61 (1999).

    Google Scholar 

  32. Klesert, T. R. et al. Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy. Nature Genet. 25, 105 –109 (2000).

    Article  CAS  Google Scholar 

  33. Lee, A. T. & Cerami, A. Role of glycation in aging. Ann. NY Acad. Sci. 663, 63–70 (1992).

    Article  ADS  CAS  Google Scholar 

  34. Seip, M. & Trygstad, O. Generalized lipodystrophy, congenital and acquired (lipoatrophy). Acta Paediatr. Suppl. 413, 2–28 (1996).

    Article  CAS  Google Scholar 

  35. Garg, A., Fleckenstein, J. L., Peshock, R. M. & Grundy, S. M. Peculiar distribution of adipose tissue in patients with congenital generalized lipodystrophy. J Clin. Endocrinol. Metab. 75, 358–361 (1992).

    CAS  PubMed  Google Scholar 

  36. Garg, A., Chandalia, M. & Vuitch, F. Severe islet amyloidosis in congenital generalized lipodystrophy . Diabetes Care 19, 28– 31 (1996).

    Article  CAS  Google Scholar 

  37. Westvik, J. Radiological features in generalized lipodystrophy. Acta Paediatr. Suppl. 413, 44–51 (1996).

    Article  CAS  Google Scholar 

  38. Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45– 51 (1997).

    Article  ADS  CAS  Google Scholar 

  39. Martin, G. M. & Mian, I. New mice for old questions. Nature 390, 18–19 ( 1997).

    Article  ADS  CAS  Google Scholar 

  40. Garg, A. et al. A gene for congenital generalized lipodystrophy maps to human chromosome 9q34. J. Clin. Endocrinol. Metab. 84, 3390–3394 (1999).

    Article  CAS  Google Scholar 

  41. Brown, W. T. Progeria: a human-disease model of accelerated ageing. Am. J Clin. Nutr. 55, 1222S–1224S ( 1992).

    Article  CAS  Google Scholar 

  42. Oshima, J., Brown, W. T. & Martin, G. M. No detectable mutations at Werner helicase locus in progeria. Lancet 348, 1106 (1996).

    Article  CAS  Google Scholar 

  43. Ly, D. H., Lockhart, D. J., Lerner, R. A. & Schultz, P. G. Mitotic misregulation and human ageing. Science 287 , 2486–2492 (2000).

    Article  ADS  CAS  Google Scholar 

  44. Allsopp, R. C. et al. Telomere length predicts replicative capacity of human fibroblasts . Proc. Natl Acad. Sci. USA 89, 10114– 10118 (1992).

    Article  ADS  CAS  Google Scholar 

  45. Wang, S., Nishigori, C., Yagi, T. & Takebe, H. Reduced DNA repair in progeria cells and effects of gamma-ray irradiation on UV-induced unscheduled DNA synthesis in normal and progeria cells. Mutat. Res. 256, 59–66 (1991).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  47. Martin, G. M., Austad, S. N. & Johnson, T. E. Genetic analysis of aging: role of oxidative damage and environmental stresses. Nature Genet. 13, 25–34 (1996).

    Article  CAS  Google Scholar 

  48. Martin, G. M. in Handbook of the Aging Brain (eds Wang, E. & Snyder, D. S.), 126–134 (Academic, New York, 1998).

    Google Scholar 

  49. McKusick, V. A. Mendelian Inheritance in Man, 12th edn (Johns Hopkins Univ. Press, Baltimore, MD, 1998).

    Google Scholar 

  50. Kitao S. et al. Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nature Genet. 22, 82– 84 (1998).

    Article  Google Scholar 

  51. Vennos, E. M. et al. Rothmund-Thomson syndrome: review of the world literature . J Am. Acad. Dermatol. 7, 750– 762 (1992).

    Article  Google Scholar 

  52. Henning, K. A. et al. The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH. Cell 82, 555–564 ( 1995).

    Article  CAS  Google Scholar 

  53. Troelstra, C. et al. ERCC6, a member of a subfamily of putative helicases, is involved in Cockayne's syndrome and preferential repair of active genes. Cell 71, 939–953 ( 1992).

    Article  CAS  Google Scholar 

  54. Nance, M. A. & Berry, S. A. Cockayne syndrome: review of 140 cases. Am. J. Med. Genet. 42, 68– 84 (1992).

    Article  CAS  Google Scholar 

  55. Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749– 1753 (1995).

    Article  ADS  CAS  Google Scholar 

  56. Gatti, R. A. et al. Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis . Medicine 70, 99–117 (1991).

    Article  CAS  Google Scholar 

  57. Varon, R. et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93, 467–476 (1998).

    Article  CAS  Google Scholar 

  58. van der Burgt, I. et al. Nijmegen breakage syndrome. J. Med. Genet. 33, 20–32 (1996).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martin, G., Oshima, J. Lessons from human progeroid syndromes. Nature 408, 263–266 (2000). https://doi.org/10.1038/35041705

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35041705

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing