Accelerated Aging in Down’s Syndrome: The Concept of Hierarchical Homeostasis in Relation to Local and Global Failure

  • Roy L. Walford
  • Faramarz Naeim
  • Kathleen Y. Hall
  • C. F. Tam
  • Richard A. Gatti
  • Michael A. Medici


A number of diseases are known to manifest various features of accelerated aging, including progeria, Werner’s syndrome, most of the chromosomal instability syndromes (Gatti and Walford, 1981), various other maladies (Martin, 1978) and — reflecting our own particular interests — systemic lypus erythematosus (SLE) (Barnett et al., 1981) and Down’s syndrome (DS) (Walford et al., 1981). Table 1 lists a number of the non-immune hallmarks of aging as seen normally and in various diseases characterized in part by accelerated aging. DS demonstrates many features of accelerated aging: premature greying of hair, degenerative vascular disease, amyloidosis, hypogonadism, senile dementia of the Alzheimer’s type, immune dysfunction, possibly an increased susceptibility to diabetes, and decreased replicative capacity of fibroblasts, among others.


Accelerate Aging Energy Charge Purine Nucleoside Phosphorylase Systemic Lupus Erythe Thymic Hormone 
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  1. Barnett, E.V., Chia, D., Knutson, D., Van Lancker, J., Cheney, K., Weindruch, R. and Walford, R.L., 1981, SLE an accelerated form of aging, in: “Immunological Aspects of Aging,” Segre, D. and Smith, L., eds., Marcel Dekker Inc., New York.Google Scholar
  2. Benda, C.E. and Strassman, G.S., 1965, The thymus in mongolism, J. Ment. Defic. Res., 9:109.PubMedGoogle Scholar
  3. Boss, G.R., Thompson, L.F., Spiegelberg, H.L., Pichler, W.J. and Seegmiller, J.E., 1980, Age-dependency of lymphocyte ‘Ecto-5′-nucleotidase activity, J. Immunol., 125: 679.PubMedGoogle Scholar
  4. Brown, W.T., Epstein, E.J., and Little, J.B, 1976, Progeria cells are stimulated to repair DNA by co-cultivation with normal cells, Exp. Cell. Res., 97:291–296.PubMedCrossRefGoogle Scholar
  5. Cox, D.R., Epstein, L.B. and Epstein, C.J., 1980, Gene coding for sensitivity to interferon (If Rec) and soluble superoxide dysmutase (SODI) are linked in mouse and man and map to mouse chromosome 16, Proc. Nat. Acad. Sci., 77:2168.PubMedCrossRefGoogle Scholar
  6. Epstein, L.B., Lee, S.H.S. and Epstein, C.J., 1980, Enhanced sensitivity of trisomy 21 monocytes to the maturation-inhibiting effect of interferon, Cell. Immunol., 50:191.PubMedCrossRefGoogle Scholar
  7. Gatti, R.A., and Walford, R.L., 1981, Immune function and features of aging in chromosomal instability syndrome, in: “Immunological Aspects of Aging”, Segre, D. and Smith, L., eds., Marcel Dekker Inc., New York.Google Scholar
  8. Gottesman, S., and Walford, R.L., 1980, Autoimmunity theories and aging, in: “Testing the Theories of Aging,” V. XIV in the CRC Uniscience Series Methods in Aging Research, Adelman, R.C. and Roth, C.S., eds., CRC Press, in press.Google Scholar
  9. Griffiths, A.W., and Sylvester, P.E., 1967, Monogols and non-mongols compared to their response to active tetanus immunisation, J. Ment. Defic. Res., 11:263.PubMedGoogle Scholar
  10. Hall, K.Y., Hart, R.W., Benirschke, A.K., and Walford, R.L., 1981a, Correlation of repair of UV-induced DNA damage in primate lymphocytes and fibroblasts with maximum life span, Proc. Natl. Acad. Sci., in press.Google Scholar
  11. Hall, K.Y., Bergmann, K. and Walford, R.L., 1981b, DNA repair, H-2, and aging in NZB and CBA mice, Tissue Antigens, 16:104.Google Scholar
  12. Hall, K.Y., Gatti, R.A., and Walford, R.L., 1981c, Repair of gamma and bleomycin induced DNA damage in ataxia telangiectasia patients and families. J. of Supramolecular Structure and Cellular Biochemistry, Suppl. 5, C.F., Fox, Alan, ed., R. Liss Inc., New York.Google Scholar
  13. Hall, K.Y., Gatti, R.A., and Walford, R.L., 1981d, Excision repair of UV and gamma-induced DNA damage in Down’s syndrome and systemic lupus erythematosus. Abst. Gerontological Society, Toronto, Canada.Google Scholar
  14. Hann, H.W.., Deacon, J.C., and London, W.T., 1979, Lymphocyte surface markers and serum immunoglobulins in persons with Down’s syndrome. Am. J. Mental Deficiency, 85:245.Google Scholar
  15. Hart, R.W., Hall, K.Y., and Daniel, F.B., 1978, DNA repair and mutagenesis in mammalian cells, Photochem Photobioo.Google Scholar
  16. Hart, R.W. and Setlow, R.B., 1974, Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species, Proc. Nat. Acad. Sci. U.S.A., 71:2169.CrossRefGoogle Scholar
  17. Hoar, D.I., and Waghorne, C., 1978, DNA repair in cockayne syndrome, Am. J. Hum. Genet., 30:590.PubMedGoogle Scholar
  18. Inkeles, B., Innes, J.B., Kuntz, M.M., Kadish, A.S., and Weksler, M. E., 1977, Immunological studies of aging. III. Cytokinetic basis for the impaired response of lymphocytes from aged humans to plant lectins, J. Exp. Med., 145:1176.PubMedCrossRefGoogle Scholar
  19. Karran, P., and Ormerod, M.G., 1973, Is the ability to repair damaged DNA related to the proliferative capacity of a cell? The rejoining of X-ray produced strand breaks, Biochem. Biophys. Acta, 299:54.PubMedGoogle Scholar
  20. Kouvalainin, D., 1964, The pathology of the thymus, Ann. Med. Exp. Fenn., 42:177.Google Scholar
  21. Kurnet, D.M., 1980, A molecular approach to Down’s syndrome, Down’s Syndrome, 3:1–2.Google Scholar
  22. Lambert, B., Hansson, K., Bui, T.H., Funes-Cravioto, F. and Lindsten, J., 1976, DNA repair and frequency of X-ray and UV-light induced chromosome aberrations in leukocytes from patients with Down’s Syndrome, Ann. Hum. Genet., 39:293.PubMedCrossRefGoogle Scholar
  23. Leibovitz, A., and Yannet, H., 1942, The production of humoral antibodies by the mongolian, Amer. J. Ment. Defic., 46:304.Google Scholar
  24. Levin, S., Schlesinger, M., Handzel, Z., Hahn, T., Altman, T., Czernobilshy, B. and Boss, J., 1979, Thymic deficiency in Down’s syndrome, Pediatr., 63:80.Google Scholar
  25. Lopez, V., Ochs, H.D., Thuline, H.C., Davis, S.D., and Wedgwood, J.R. J., 1975, Defective antibody response to bacteriophage OX 174 in Down’s syndrome, J. Pediatr., 86:207.PubMedCrossRefGoogle Scholar
  26. Martin, G.M., 1978, Genetic syndromes in man with potential relevance to the pathobiology of aging in: “Genetic Effects on Aging,” D. Bergsma and D.E. Harrison, eds., Alan Liss Inc., N.Y., p. 5–40.Google Scholar
  27. Mattern, M.R., and Cerutti, P.A., 1975, Age-dependent excision repair of damaged thymine from gamma-irradiated DNA by isolated nuclei from human fibroblasts, Nature, London, 254:450.PubMedCrossRefGoogle Scholar
  28. Naeim, F., and Walford, R.L., 1980, Disturbance of redistribution of surface membrane receptors on peripheral mononuclear cells of patients with Down’s syndrome and of aged individuals, J. Gerontol., 35:640.Google Scholar
  29. Naeim, F., Bergmann, K. and Walford, R.L., 1981, Capping and concanavalin A receptors on lymphocytes of aged individuals and patients with Down’s syndrome: enhancing effect of colchicine; possible relation to microtubular system, Age, 4:5.CrossRefGoogle Scholar
  30. O’Brien, R.L., Poon, P., Kline, E., and Parker, J.W., 1971, Susceptibility of chromosomes from patients with Down’s syndrome to 7, 12-dimethyl-benz (a)anthracene-induced aberrations in vitro, Int. J. Cancer, 8:202.PubMedCrossRefGoogle Scholar
  31. Ove, P., and Coetzee, M.L., 1978, A difference in bleomycin-induced DNA synthesis between liver nuclei from mature and old rats, Mech. Age. Develop., 8:363.CrossRefGoogle Scholar
  32. Paffenhalz, V., 1978, Correlation between DNA repair of embryonic fibroblasts and different life span of 3 inbred mouse strains, Mech. Age. Develop., 7:131.CrossRefGoogle Scholar
  33. Pero, R.W., Bryngelsson, C., Mitelman, F., Kornfalt, R., Thulin, T., and Norden, A., 1979, Interindividual variation in the responses of cultured human lymphocytes to exposure from DNA damaging chemical agents, Interindividual variation to carcinogen exposure, Mutation Res., 53:327.Google Scholar
  34. Rainbow, A.J., and Howes, M., 1977, Decreased repair of gamma ray damaged DNA in progeria, Biochem. Biophys. Res. Commun., 74:714.PubMedCrossRefGoogle Scholar
  35. Rosen, E., 1981, Dynamical aspects of senescence, in: “Biological Mechanisms in Aging, “Conference,” Bethesda, Md., in press.Google Scholar
  36. Sacher, G.A., and Hart, R.W., 1978, Longevity, aging and comparative cellular and molecular biology of the house mouse, Mus musculus, and the white-footed mouse, Peromyscus leucopus. in: “Genetic effects on Aging”, D. Bergsma and Harrison, D.E., Alan R. Liss, Inc, New York.Google Scholar
  37. Scholar, E.M., Rashidian, M., and Heidrick, M.L., 1980, Adenosine deaminase and purine nucleoside Phosphorylase activity in spleen cells of aged mice, Mech. Age. Develop., 12:323.CrossRefGoogle Scholar
  38. Sechadri, R.S., Morley, A.A., Trainor, K.J., and Sorrell, J., 1979, Sensitivity of human lymphocytes to bleomycin increases with age, Experientia, 35:233.CrossRefGoogle Scholar
  39. Siegel, M., 1948, Susceptibility of mongoloids to infection. I. Incidence of pneumonia, influenza A and shigella dysenteriae (Sonne), Amer. J. Hyg., 48–53.Google Scholar
  40. Tam, C.F., and Walford, R.L., 1980, Alterations in cyclic nucleotides and cyclase specific activities in T-lymphocytes of aging normal humans and patients with Down’s syndrome, J. Immunol., 125:1665.PubMedGoogle Scholar
  41. Tam, C.F., Cheung, M., Mock, D.C., Verity, A.M., and Walford, R.L., 1980, Energy charge values and adenine nucleotides in resting peripheral T-cells from young, normal aged, SLE and Down’s subjects, The Gerontologist 20, Part 2:211, abstr.Google Scholar
  42. Tam, C.F., Mock, D.C. and Walford, R.L., 1980, Alterations in cyclic nucleotide metabolism in resting peripheral T-cells from young and old, Down’s and SLE subjects, Human Immunology, 1:291, abstr.CrossRefGoogle Scholar
  43. Thorn, H., and McKay, E., 1972, Gm antigenic titres in adults with Down’s syndrome (mongolism), non-mongoloid mental defectives and healthy blood donors, Clin. Exp. Immunol., 12:515.Google Scholar
  44. Walford, R.L., 1976, When is a mouse “old”? J. Immunol., 117:352.PubMedGoogle Scholar
  45. Walford, R.L., Barnett, E.V., Chia, D., Fahey, J.L., Gatti, R.A., Gossett, T.C., Grossman, H., Medici, M.A., Motola, M., Naeim, F., Sparkes, R.S., Spina, C., Tam, C.F., Tomura, T. and Van Lancker, J., 1981, Immunological and biochemical studies of Down’s syndrome as a model for accelerated aging, in: “Immunological Aspects of Aging,” Segre, D., and Smith, L., eds., Marcel Dekker, Inc., p.Google Scholar
  46. Weindruch, R., Cheung, M.K., Verity, M.A., and Walford, R.L. 1980, Modification of mitochondrial respiration by aging and dietary restriction, Mech. Age. and Develop., 12:375.CrossRefGoogle Scholar
  47. Yotti, L.P., Glover, T.W., Trosko, J.E. and Segel, D.J., 1980, Comparative study of X-ray and UV induced cytotoxicity, DNA repair, and mutagenesis in Down’s syndrome and normal fibroblasts, Pediatric Res., 2:88.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Roy L. Walford
    • 1
  • Faramarz Naeim
  • Kathleen Y. Hall
  • C. F. Tam
  • Richard A. Gatti
  • Michael A. Medici
  1. 1.The Department of Pathology, UCLA Medical School and Pediatric OncologyCedars-Saint HospitalLos AngelesUSA

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