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The aging of lympho-hematopoietic stem cells

Nature Immunology volume 3, pages 329–333 (2002)Cite this article

Abstract

The extensive self-renewal capacity of hematopoietic stem cells (HSCs) implies that this cell population may not age and thus may provide undiminished replenishment of blood cells throughout the lifespan of an organism. In contrast, accumulating experimental evidence supports the premise that HSCs show signs of aging and may have a limited functional lifespan. We summarize here the evidence for HSC aging, discuss the possible molecular mechanisms that may be involved and show evidence of a genetic connection between the effects of age on blood-forming cells and the longevity of mice. We speculate that age-related functional decline in adult tissue HSCs limits longevity in mammals.

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Figure 1: HSC-autonomous aging in embryo-aggregated chimeric mice.
Figure 2: Intrinsic and extrinsic models of HSC aging.

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References

  1. Harrison, D. E. Normal function of transplanted mouse erythrocyte precursors for 21 months beyond donor life spans. Nature New Biology 237, 220–222 (1972).

    Article  CAS  PubMed  Google Scholar 

  2. Ploemacher, R. E. & Brons, N. H. C. Isolation of hemopoietic stem cell subsets from murine bone marrow: I. Radioprotective ability of purified cell suspensions differing in the proportion of day-7 and day-12 CFU-S. Exp. Hematol. 16, 21–26 (1988).

    CAS  PubMed  Google Scholar 

  3. Spangrude, G. J., Heimfeld, S. & Weissman, I. L. Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62 (1988).

    Article  CAS  PubMed  Google Scholar 

  4. Baum, C. M., Weissman, I. L., Tsukamoto, A. S., Buckle, A.-M. & Peault, B. Isolation of a candidate human hematopoietic stem-cell population. Proc. Natl Acad. Sci. USA 89, 2804–2808 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Morrison, S. & Weissman, I. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1, 661–673 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Zhao, Y. et al. Murine hematopoietic stem cell characterization and its regulation in BM transplantation. Blood 96, 3016–3022 (2000).

    CAS  PubMed  Google Scholar 

  7. Morrison, S. J., Wandycz, A. M., Akashi, K., Globerson, A. & Weissman, I. L. The aging of hematopoietic stem cells. Nature Med. 2, 1011–1016 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Sudo, K., Ema, H., Morita, Y. & Nakauchi, H. Age-associated characteristics of murine hematopoietic stem cells. J. Exp. Med. 192, 1273–1280 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. de Haan, G. & Van Zant, G. Dynamic changes in mouse hematopoietic stem cell numbers during aging. Blood 93, 3294–3301 (1999).

    CAS  PubMed  Google Scholar 

  10. Harrison, D., Astle, C. & Stone, M. Numbers and functions of transplantable primitive immunohemtopoietic stem cells. Effects of age. J. Immunol. 142, 3833–3840 (1989).

    CAS  PubMed  Google Scholar 

  11. Ross, E., Anderson, N. & Micklem, H. S. Serial depletion and regeneration of the murine hematopoietic system. Implications for hematopoietic organization and the study of cellular aging. J. Exp. Med. 155, 432–444 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Harrison, D. Long-term erythropoietic repopulating ability of old, young and fetal stem cells. J. Exp. Med. 157, 1496–1504 (1983).

    Article  CAS  PubMed  Google Scholar 

  13. Rebel, V. I., Miller, C. L., Eaves, C. J. & Lansdorp, P. M. The repopulation potential of fetal liver hematopoietic stem cells in mice exceeds that of their adult bone marrow counterparts. Blood 87, 3500–3507 (1996).

    CAS  PubMed  Google Scholar 

  14. Micklem, H. S., Ford, C. E., Evans, E. P., Ogden, D. A. & Papworth, D. S. Competitive in vivo proliferation of foetal and adult hematopoietic cells in lethally irradiated mice. J. Cell Physiol. 79, 293–298 (1972).

    Article  CAS  PubMed  Google Scholar 

  15. Harrison, D. E., Zhong, R. K., Jordan, C. T., Lemischka, I. R. & Astle, C. M. Relative to adult marrow, fetal liver repopulates nearly five times more effectively long-term than short-term. Exp. Hematol. 25, 293–297 (1997).

    CAS  PubMed  Google Scholar 

  16. Chen, J., Astle, B. A. & Harrison, D. E. Development and aging of primitive hematopoietic stem cells in BALB/cBy mice. Exp. Hematol. 27, 928–935 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Chen, J., Astle, C. M. & Harrison, D. E. Genetic regulation of primitive hematopoietic stem cell senescence. Exp. Hematol. 28, 442–50 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Lansdorp, P., Dragowska, W. & Manyani, H. Ontogeny-related changes in proliferative potential of human hematopoietic cells. J. Exp. Med. 178, 787–791 (1993).

    Article  CAS  PubMed  Google Scholar 

  19. Van Zant, G., Holland, B. P., Eldridge, P. W. & Chen, J.-J. Genotype-restricted growth and aging patterns in hematopoietic stem cell populations of allophenic mice. J. Exp. Med. 171, 1547–1565 (1990).

    Article  CAS  PubMed  Google Scholar 

  20. Mintz, B. & Silvers, W. K. “Intrinsic” immunological tolerance in allophenic mice. Science 158, 1484–1486 (1967).

    Article  CAS  PubMed  Google Scholar 

  21. Van Zant, G., Scott-Micus, K., Thompson, B. P., Fleischman, R. A. & Perkins, S. Stem cell quiescence/activation is reversible by serial transplantation and is independent of stromal cell genotype in mouse aggregation chimeras. Exp. Hematol. 20, 470–475 (1992).

    CAS  PubMed  Google Scholar 

  22. Campisi, J. Replicative senescence: An old lives' tale? Cell 84, 497–500 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Campisi, J. The biology of replicative senescence. Eur. J. Cancer 33, 703–709 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. de Haan, G. et al. Distinct functional properties of highly purified hematopoietic stem cells from mouse strains differing in stem cell numbers. Blood 96, 1374–1379 (2000).

    CAS  PubMed  Google Scholar 

  26. Wineman, J., Moore, K., Lemischka, I. & Muller-Sieburg, C. Functional heterogeneity of the hematopoietic microenvironment: rare stromal elements maintain long-term repopulating stem cells. Blood 87, 4082–4090 (1996).

    CAS  PubMed  Google Scholar 

  27. Cashman, J., Eaves, A. C. & Eaves, C. J. Regulated proliferation of primitive hematopoietic progenitor cells in long-term human marrow cultures. Blood 66, 1002–1005 (1985).

    CAS  PubMed  Google Scholar 

  28. Mauch, P., Botnick, L. E., Hannon, E. C., Obbagy, J. & Hellman, S. Decline in bone marrow proliferative capacity as a function of age. Blood 60, 245–252 (1982).

    CAS  PubMed  Google Scholar 

  29. Chertkov, J. L. & Gurevitch, O. A. Age-related changes in hemopoietic microenvironment. Enhanced growth of hemopoietic stroma and weakened genetic resistance of hemopoietic cells in old mice. Exp. Gerontol. 16, 195–198 (1981).

    Article  CAS  PubMed  Google Scholar 

  30. Hotta, T., Hirabayashi, N., Utsumi, M., Murate, T. & Yamada, H. Age related changes in the function of hemopoietic stroma in mice. Exp. Hematol. 8, 933–936 (1980).

    CAS  PubMed  Google Scholar 

  31. Jiang, D., Fei, R.-G., Pendergrass, W. & Wolf, N. An age-related reduction in the replicative capacity of two murine hematopoietic stroma cell types. Exp. Hematol. 20, 1216–1222 (1992).

    CAS  PubMed  Google Scholar 

  32. Aspinall, R. & Andrew, D. Thymic involution in aging. J. Clin. Immunol. 20, 250–256 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Globerson, A. Thymocytopoiesis in aging: The bone marrow thymus axis. Arch. Gerontol. Geriatr. 24, 141–155 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Aspinall, R. Longevity and the immune response. Biogerontology 1, 273–278 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Aspinall, R. & Andrew, D. Age-associated thymic atrophy is not associated with a deficiency in the CD44+CD25−CD3−CD4−CD8− thymocyte population. Cell. Immunol. 212, 150–157 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Andrew, D. & Aspinall, R. Age-associated thymic atrophy is linked to a decline in IL-7 production. Exp. Gerontol. 37, 455–463 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Bhatia, S. K., Tygrett, L. T., Grabstein, K. H. & Waldschmidt, T. J. The effect of in vivo IL-7 deprivation on T cell maturation. J. Exp. Med. 181, 1399–1409 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Miller, R. A. Effect of aging on T lymphocyte activation. Vaccine 18, 1654–1660 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Miller, R. A. The aging immune system: primer and prospectus. Science 273, 70–74 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Effros, R. B. Replicative senescence in the immune system: impact of the Hayflick limit on T-cell function in the elderly. Am. J. Hum. Genet. 62, 1003–1007 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hsu, H. C. et al. Aged mice exhibit in vivo defective peripheral clonal deletion of D(b)/H-Y reactive CD8(+) T cells. Mech. Ageing Dev. 122, 305–326 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. de Haan, G. & Van Zant, G. Genetic analysis of hemopoietic cell cycling in mice suggests its involvement in organismal life span. FASEB J. 13, 707–713 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Geiger, H., True, J. M., de Haan, G. & Van Zant, G. Age- and stage-specific regulation patterns in the hematopoietic stem cell hierarchy. Blood 98, 2966–2972 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. de Haan, G. & Van Zant, G. Intrinsic and extrinsic control of hemopoietic stem cell numbers: Mapping of a stem cell gene. J. Exp. Med. 186, 529–536 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. J. Exp. Cell Res. 25, 585–621 (1961).

    Article  CAS  Google Scholar 

  46. Hayflick, L. How and why we age. Exp. Gerontol. 33, 639–653 (1997).

    Article  Google Scholar 

  47. Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).

    Article  CAS  PubMed  Google Scholar 

  48. Vaziri, H. et al. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc. Natl Acad. Sci. USA. 91, 9857–9860 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hemann, M. T. & Greider, C. W. Wild-derived inbred mouse strains have short telomeres. Nucleic Acids Res. 28, 4474–4478 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Morrison, S. J., Prowse, K. R., Ho, P. & Weissman, I. L. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5, 207–216 (1996).

    Article  CAS  PubMed  Google Scholar 

  51. Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Kennedy, B. K. et al. Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Cell 89, 381–391 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Lin, S. J., Defossez, P. A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000).

    CAS  Google Scholar 

  54. Wright, W. E. & Shay, J. W. Cellular senescence as a tumor-protection mechanism: the essential role of counting. Curr. Opin. Genet. Dev. 11, 98–103 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Lundberg, A. S., Hahn, W. C., Gupta, P. & Weinberg, R. A. Genes involved in senescence and immortalization. Curr. Opin. Cell. Biol. 12, 705–709 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Kruk, P. A., Rampino, N. J. & Bohr, V. A. DNA damage and repair in telomeres: relation to aging. Proc. Natl Acad. Sci. USA 92, 258–62 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Imai, T., Jiang, M., Kastner, P., Chambon, P. & Metzger, D. Selective ablation of retinoid X receptor α in hepatocytes impairs their lifespan and regenerative capacity. Proc. Natl Acad. Sci. USA 98, 4581–6 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dolle, M. et al. Rapid accumulation of genome rearrangements in liver but not in brain of old mice. Nature Genet. 17, 431–434 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Dolle, M. E., Snyder, W. K., Gossen, J. A., Lohman, P. H. M. & Vijg, J. Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine. Proc. Natl Acad. Sci. USA 97, 8403–8408 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, Y. et al. Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication. Proc. Natl Acad. Sci. USA 98, 4022–4027 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hamilton, M. L. et al. Does oxidative damage to DNA increase with age? Proc. Natl Acad. Sci. USA 98, 10469–10474 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hasty, P. The impact energy metabolism and genome maintenance have on longevity and senescence: lessons from yeast to mammals. Mech. Ageing Dev. 122, 1651–1662 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Bohr, V., Anson, R. M., Mazur, S. & Dianov, G. Oxidative DNA damage processing and changes with aging. Toxicol. Lett. 103, 47–52 (1998).

    Article  Google Scholar 

  64. Anson, R. M., Hudson, E. & Bohr, V. A. Mitochondrial endogenous oxidative damage has been overestimated. FASEB J. 14, 355–360 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Jacobson, L. O., Marks, E. K., Robson, M. J., Gaston, E. O. & Zirkle, R. E. Effect of spleen protection on mortality following x-irradiation. J. Lab. Clin. Med. 34, 1538–1543 (1949).

    Google Scholar 

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Acknowledgements

Supported by the Bundesministerium für Bildung und Forschung by Leopoldina (H. G.) and NIH grant AG16653.

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  1. Departments of Medicine and Physiology, University of Kentucky, Lexington, 40536-0093, KY, USA

    Hartmut Geiger & Gary Van Zant

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  1. Hartmut Geiger
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Correspondence to Gary Van Zant.

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Geiger, H., Van Zant, G. The aging of lympho-hematopoietic stem cells. Nat Immunol 3, 329–333 (2002). https://doi.org/10.1038/ni0402-329

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