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Werner’s syndrome: An underdiagnosed disorder resembling premature aging

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Abstract

Werner’s syndrome is an inheritable segmental progeroid syndrome manifested by a premature senescent appearance. Juvenile cataract formation and cutaneous atrophy are the most common features of this disease. Differences in geographic prevalence of this disease appear to reflect varying levels of consanguinity. The diagnosis of this disorder is made less frequently than the frequency suggested by genetic analyses. Our review reveals that there is an inverse relationship between age and in vitro replicative lifespan of cultured fibroblasts from these patients. Greater than 91% of Werner’s syndrome fibroblasts have in vitro lifespans of less than 20 cumulative cell population doublings while only 4.8% of control fibroblasts have in vitro replicative lifespans so reduced. Cultured fibroblasts from other segmental progeroid syndromes are not nearly as reduced in replicative lifespans. Urinary hylauronir acid is increased in Werner’s syndrome, and may be useful, along with fibroblast culturing, as a potential diagnostic aid for this unique and apparently underdiagnosed disorder.

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References

  1. Werner, O.: Uber kataract in verbindung mit sklerodermie. Doctoral Dissertation, Kiel University. Schmidt and Klaunig, Kiel, 1904.

    Google Scholar 

  2. Oppenheimer, B.S. and Kugel, V.H.: Werner’s syndrome: Heredofamilial disorders with scleroderma, bilateral juvenile cataract, precocious graying of the hair and endocrine stigmatization. Trans. Assoc. Am. Physicians, 49: 358–370, 1934.

    Google Scholar 

  3. Thannhauser, S.J.: Werner’s syndrome (progeria of adults) and Rothmund sundrome: 2 types of closely related heredofamilial atrophic dermatoses with juvenile cataracts and endocrine features: Critical study of 5 new cases. Ann. Intern. Med., 23: 559–626, 1945.

    Google Scholar 

  4. Epstein, C.J., Martin, G.M., Schultz, A.L., and Motulsky, A.G.: Werner’s syndrome. A review of its symptomatology, natural history, pathologic features, genetics and relationships to the natural aging process. Medicine, 45: 177–221, 1966.

    PubMed  CAS  Google Scholar 

  5. Martin, G.M.: Genetic syndromes in man with potential relevance to the pathobiology of aging. Birth Defects, 14: 5–39, 1978.

    PubMed  CAS  Google Scholar 

  6. Tokunaga, M., Futami, T., Wakamatsu, E., Endo, M., and Yosizawa, Z.: Werner’s syndrome as “hyaluronuria”. Clin. Chim. Acta, 62: 89–96, 1975.

    Article  PubMed  CAS  Google Scholar 

  7. Tokunaga, M., Wakamatsu, E., and Yosizawa, Z.: Excretion of glucose containing oligosaccharides in urines of orthopedic patients. Tohoku J. Exp. Med., 128: 71–79, 1979.

    Article  PubMed  CAS  Google Scholar 

  8. Basler, J.W., David, J.D., and Agris, P.F.: Deteriorating collagen synthesis and cell ultrastructure accompanying senescence of human normal and Werner’s syndrome fibroblast cell strains. Exp. Cell. Res., 118: 73–84, 1979.

    Article  PubMed  CAS  Google Scholar 

  9. Tajima, T., Iijima, K., and Watanabe, T.: Collagen synthesis of cultured fibroblasts from Werner’s syndrome of premature aging. Experientia, 34: 1459–1460, 1978.

    Article  PubMed  CAS  Google Scholar 

  10. Rabbiosi, G. and Barroni, G.: Werner’s syndrome: Seven cases in one family. Dermatologica, 158: 355–360, 1979.

    Article  PubMed  CAS  Google Scholar 

  11. Salk, D.: Can we learn about aging from a study of Werner’s syndrome? J. Am. Geriatr. Soc., 30: 334–339, 1982.

    PubMed  CAS  Google Scholar 

  12. Goto, M., Tanimoto, K., Horiuchi, Y., and Sasazuji, T.: Family analysis of Werner’s syndrome: A survey of 42 Japanese families with a review of the literature. Clin. Genet., 19: 8–15, 1981.

    Article  PubMed  CAS  Google Scholar 

  13. Murata, K. and Nakashima, H.: Werner’s syndrome: Twenty-four cases with a review of the Japanese medical literature. J. Am. Geriatr. Soc., 30: 303–308, 1982.

    PubMed  CAS  Google Scholar 

  14. Cerimele, D., Cottoni, F., Scappaticci, S., et al.: High prevalence of Werner’s syndrome in Sardinia. Description of six patients and estimate of the gene frequency. Human Genet., 62: 25–30, 1982.

    Article  CAS  Google Scholar 

  15. Goto, M., Horiuchi, Y., Tanimoto, K., Ishii, T., and Nakashima, H.: Werner’s syndrome: Analysis of 15 cases and a review of the Japanese literature. J. Am. Geriatr. Soc., 26: 341–347, 1978.

    PubMed  CAS  Google Scholar 

  16. Nakao, Y., Kishihara, M., Yoshimi, H., et al.: Werner’s syndrome, in vivo and in vitro characteristics as a model of aging. Am. J. Med., 65: 919–932, 1978.

    Article  PubMed  CAS  Google Scholar 

  17. Zala, J.A.: Werner’s syndrome. Cutis, 25: 275–278, 1980.

    Google Scholar 

  18. Goto, M. and Murata, K.: Urinary excretion of macromolecular acidic glycosaminoglycans in Werner’s syndrome. Clin. Chim. Acta, 85: 101–106, 1978.

    Article  PubMed  CAS  Google Scholar 

  19. Murata, K.: Urinary acidic glycosaminoglycans in Werner’s syndrome. Experientia, 38: 313–314, 1982.

    Article  PubMed  CAS  Google Scholar 

  20. Varada, D.P., Cifonelli, J.A., and Dorfman, A.: The acid mucopolysaccharides in normal urine. Biochim. Biophys. Acta, 141: 103–107, 1967.

    Google Scholar 

  21. Nakao, Y., Hattori, T., Takasuki, K. et al.: Immunological studies on Werner’s syndrome. Clin. Exp. Immunol., 42: 10–19, 1980.

    PubMed  CAS  Google Scholar 

  22. Gupta, S.: Subpopulations of human T lymphocytes. Gerontol., 27: 181–186, 1981.

    Article  CAS  Google Scholar 

  23. Goto, M., Horiuchi, Y., Okumura, K., Tada, T., Kawata, M., and Ohmori, K.: Immunological abnormalities of aging: An analysis of T lymphocyte subpoputations of Werner’s syndrome. J. Clin. Invest, 64: 695–699, 1979.

    Article  PubMed  CAS  Google Scholar 

  24. Glohme, G. and Smith, U.: Metabolic studies in a case of Werner’s syndrome. Diabetes Metab., 51: 119–124, 1979.

    Google Scholar 

  25. Hayflick, L. and Moorhead, P.S.: The serial cultivation of human diploid cell strains. Exp. Cell. Res., 25: 585–621, 1961.

    Article  Google Scholar 

  26. Cristofalo, V.: Animal cell cultures as a model system for the study of aging. Adv. Gerontol. Res., 4: 45–79, 1972.

    CAS  Google Scholar 

  27. Hayflick, L.: The cellular basis for biological aging, by Finch, C.E. and Hayflick, L., in Handbook of the Biology of Aging, edited by New York, Van Nostrand Reinhold Co., 1977, pp. 159–186.

    Google Scholar 

  28. Goldstein, S.: Senescence, in Endocrinology, edited by DeGroot, L.J., Cahill, G.F., Martini, L. et al. New York, Grune and Stratton, 1978, pp. 2201–2225.

    Google Scholar 

  29. Hayflick, L.: The limited in vitro lifetime of human diploid cell strains. Exp. Cell. Res., 37: 614–636, 1965.

    Article  PubMed  CAS  Google Scholar 

  30. Ebbesen, P.: Experimental studies of premature ageing. Danish Med. Bulletin, 27: 248–250, 1980.

    CAS  Google Scholar 

  31. Goldstein, S.: Human genetic disorders which feature accelerated aging, in The Genetics of Aging, edited by Schneider, E.L., New York, Plenum, 1978, pp. 171–224.

    Google Scholar 

  32. Wertz, R.L., Hartwig, G.B., Frost, A.P., Brophy, J.J., Atwater, S.K., and Roses, A.D.: Patients with myotonic dystrophy have fibroblasts with normal limits for in vitro lifespan and growth characteristics. J. Cell. Physiol., 107: 255–260, 1981.

    Article  PubMed  CAS  Google Scholar 

  33. Goldstein, S.: Lifespan of cultured cells in progeria. Lancet, 1: 424, 1969.

    Article  PubMed  CAS  Google Scholar 

  34. Goldstein, S., Littlefield, J.W., and Soeldner, J.S.: Diabetes mellitus and aging: Diminished plating efficiency of cultured human fibroblasts. Proc. Natl. Acad. Sci. USA, 64: 155–160, 1969.

    PubMed  CAS  Google Scholar 

  35. Martin, G.M., Sprague, C.A., and Epstein, C.J.: Replicative life-span of cultivated human cells. Lab. Invest. 23: 86–92, 1970.

    PubMed  CAS  Google Scholar 

  36. Goldstein, S. and Moerman, E.L.: Defective proteins in normal and abnormal human fibroblasts during aging in vitro. Interdiscipl. Topics of Gerontol., 10: 24–43, 1976.

    CAS  Google Scholar 

  37. Goldstein, S., Stotland, D., and Cordiero, R.A.J.: Decreased proteolysis and increased amino acid efflux in aging human fibroblasts. Mech. Age. Devel., 5: 221–233, 1976.

    Article  CAS  Google Scholar 

  38. Schneider, E.L., Braunschweiger, K., and Mitsui, Y.: The effect of serum batch on the in vitro lifespans of cell cultures derived from old and young human donors. Exp. Cell Res., 115: 47–52, 1978.

    Article  PubMed  CAS  Google Scholar 

  39. Woztyk, R.I. and Goldstein, S.: Fidelity of protein synthesis does not decline during aging of cultured human fibroblasts. J. Cell. Physiol., 103: 299–303, 1980.

    Article  Google Scholar 

  40. Wertz, R.L. and Roses, A.D.: Premature aging of fibroblasts from patients with Duchenne muscular dystrophy. Pediatr. Res., 16: 589–590, 1982.

    PubMed  CAS  Google Scholar 

  41. Nienhaus, A.J., DeJong, B., and Ten Kate, L.P.: Fibroblast culture in Werner’s syndrome. Humangenetik, 13: 244–246, 1971.

    Article  PubMed  CAS  Google Scholar 

  42. Norwood, T.H., Hoehn, H., Salk, D., and Martin, G.M.: Cellular ageing in Werner’s syndrome: A unique phenotype? J. Invest. Dermatol., 78: 92–96, 1979.

    Article  Google Scholar 

  43. Goldstein, S. and Singal, D.P.: Alteration of fibroblast gene products in vitro from a subject with Werner’s syndrome. Nature, 251: 719–721, 1974.

    Article  PubMed  CAS  Google Scholar 

  44. Holliday, R., Porterfield, J.S., and Gibbs, D.D.: Premature aging and occurrence of altered enzyme in Werner’s syndrome fibroblasts. Nature, 248: 762–763, 1974.

    Article  PubMed  CAS  Google Scholar 

  45. Goldstein, S. and Moerman, E.J.: Heat-labile enzymes in Werner’s syndrome fibroblasts. Nature, 255: 159, 1975.

    Article  PubMed  CAS  Google Scholar 

  46. Beadle, G.F., Mackay, K.R., Whittingham, S., Taggert, G., Harris, A.W., and Harrison, LC.: Werner’s syndrome, a model of premature aging? J. Med., 9: 377–403, 1978.

    PubMed  CAS  Google Scholar 

  47. Goldstein, S. and Harley, C.B.: In vitro studies of age-associated diseases. Fed. Proc., 38: 1862–1867, 1979.

    PubMed  CAS  Google Scholar 

  48. Basler, J.W., David, J.D., and Agris, P.F.: Deteriorating collagen synthesis and cell ultrastructural accompanying senescence of human normal and Werner’s syndrome fibroblast cell strains. Exp. Cell. Res., 118: 73–84, 1979.

    Article  PubMed  CAS  Google Scholar 

  49. Houben, A., Houbion, A., and Remacle, J.: Lysosomal and mitochondrial heat labile enzymes in Werner’s syndrome fibroblasts. Exp. Geront., 15: 629–631, 1980.

    Article  CAS  Google Scholar 

  50. Salk, D., Bryant, E., Au, K., Hoehn, H., and Martin, G.M.: Systematic growth rates, co-cultivation, and cell hybridization studies of Werner’s syndrome cultured skin fibroblasts. Human Genet., 58: 310–316, 1981.

    Article  CAS  Google Scholar 

  51. Scappaticci, S., Cerimele, D., and Fraccaro, M.: Clonal structural rearrangements in primary fibroblast cultures and in lymphocytes of patients with Werner’s syndrome. Human Genet., 61: 16–24, 1982.

    Article  Google Scholar 

  52. Tollefsbol, T.O., Zaun, J.R., and Gracy, R.W.: Increased lability of triosephosphate isomerase in progeria and Werner’s syndrome fibroblasts. Mech. Age. Devel., 20: 93–101, 1982.

    Article  CAS  Google Scholar 

  53. Danes, B.S.: Progeria: A cell culture study on aging. J. Clin. Invest., 50: 2000–2023, 1971.

    PubMed  CAS  Google Scholar 

  54. Goldstein, S. and Moerman, E.J.: Heat-labile enzymes in skin fibroblasts from subjects with progeria. N. Engl. J. Med., 292: 1305–1309, 1975.

    Article  PubMed  CAS  Google Scholar 

  55. Goldstein, S. and Moerman, E.J.: Defective proteins in normal and abnormal human fibroblasts during aging in vitro. Interdiscipl. Topics Geront., 10: 24–43, 1976.

    CAS  Google Scholar 

  56. Rautenstrauch, T., Shigula, F., Kreig, T., Gay, S., and Muller, P.V.: Progeria: A cell culture study and clinical report of familial incidence. Eur. J. Pediat., 124: 101–111, 1977.

    Article  CAS  Google Scholar 

  57. Goldstein, S.: Studies on age-related diseases in cultured skin fibroblasts. J. Invest. Derm., 73: 19–23, 1979.

    Article  PubMed  CAS  Google Scholar 

  58. Harley, C.B., Pollard, J.W., Chamberlain, J.W., Stanners, C.P., and Goldstein, S.: Protein synthetic errors do not increase during aging of cultured human fibroblasts. Proc. Natl. Acad. Sci. USA, 77: 1885–1889, 1980.

    PubMed  CAS  Google Scholar 

  59. Goldstein, S., Ballantyne, S.R., Robson, A.L., and Moerman, E.J.: Energy metabolism in cultured human fibroblasts during aging in vitro. J. Cell. Phys., 112: 419–424, 1982.

    Article  CAS  Google Scholar 

  60. Schneider, E.L. and Epstein, C.J.: Replication rate and lifespan of cultured fibroblasts in Downs syndrome. PRoc. Soc. Exp. Biol. Med., 141: 1092–1094, 1972.

    PubMed  CAS  Google Scholar 

  61. Hoehn, H., Bryant, E.M., Au, K., Norwood, T.H., Boman, H., and Martin, G.M.: Variegated translocation mosaicism in human skin fibroblast cultures. Cytogenet. Cell Genet., 15: 282–298, 1975.

    PubMed  CAS  Google Scholar 

  62. Salk, D., Au, K., Hoehn, H., and Martin, G.M.: Cytogenetics of Werner’s syndrome cultured skin fibroblasts: Variegated translocation mosaicism. Cytogenet. Cell Genet., 30: 92–107, 1981.

    PubMed  CAS  Google Scholar 

  63. Orgel, L.E.: The maintenance of the accuracy of protein synthesis and its relevance to aging. Proc. Natl. Acad. Sci. USA, 49: 517–521, 1963.

    PubMed  CAS  Google Scholar 

  64. Goldstein, S. and Niewiarowski, S.: Increased procoagulant activity in cultured fibroblasts from progeria and Werner’s syndrome of premature ageing. Nature, 260: 711–713, 260.

    Google Scholar 

  65. Tollefsbol, T.O., Zaun, M.R., and Gracy, R.W.: Decreased protcolysis and the accumulation of deamidated enzymes in progeria and Werner’s syndrome fibroblasts. Mech. Age. Devel., In press, 1983.

  66. Iijima, K. and Watanabe, T.: Collagen synthesis of cultured fibroblasts from Werner’s syndromes of premature aging. Experientia, 34: 1459–1460, 1978.

    Article  PubMed  Google Scholar 

  67. Salk, D.: Werner’s syndrome: A review of recent research with an analysis of connective tissue metabolism, growth control of cultured cells, and chromosomal aberrations. Hum. Genet., 62: 1–15, 1982.

    Article  PubMed  CAS  Google Scholar 

  68. Hayflick, L.: The biology of human aging. Plastic and Reconst. Surgery, 67: 536–560, 1981.

    CAS  Google Scholar 

  69. Fujiwara, Y., Higashikawa, T., and Tatsumi, M.: A retarded rate of DNA replication and normal level of DNA repair in Werner’s syndrome fibroblasts in culture. J. Cell Physiol., 92: 365–374, 1977.

    Article  PubMed  CAS  Google Scholar 

  70. Yatscoff, R.W., Goldstein, S., and Freeman, K.B.: Conservation of genes coding for proteins synthesized in human mitochondria. Somatic Cell Genet., 4: 633–645, 1978.

    Article  PubMed  CAS  Google Scholar 

  71. Marklund, S., Nordensson, I., and Back, O.: Normal CuZn superoxide dismutase, Mn superoxide dismutase, catalase and glutathione peroxidase in Werner’s syndrome. J. Geront., 36: 405–409, 1981.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Geriatric Research, Education, and Clinical Center, VA Medical Center, Durham, North Carolina, 27705

    Trygve O. Tollefsbol D.O., Ph.D. & Harvey Jay Cohen M.D.

  2. Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina, 27710

    Trygve O. Tollefsbol D.O., Ph.D. & Harvey Jay Cohen M.D.

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  1. Trygve O. Tollefsbol D.O., Ph.D.
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  2. Harvey Jay Cohen M.D.
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Tollefsbol, T.O., Cohen, H.J. Werner’s syndrome: An underdiagnosed disorder resembling premature aging. AGE 7, 75–88 (1984). https://doi.org/10.1007/BF02432205

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