Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1986 Jul;78(1):40–43. doi: 10.1172/JCI112570

Impaired nuclear responsiveness to cytoplasmic signals in lymphocytes from elderly humans with depressed proliferative responses.

J K Gutowski, J B Innes, M E Weksler, S Cohen
PMCID: PMC329528  PMID: 3722382

Abstract

Lymphocytes from many elderly individuals exhibit depressed proliferative responses to the plant phytohemagglutinin (PHA). We have previously reported that this proliferative defect is not due to a failure to generate a cytoplasmic activator of DNA replication (ADR). In the present study, we tested the DNA synthetic response of nuclei derived from aged cells to an exogenous source of ADR. We found that nuclei from aged lymphocytes exhibiting low PHA responses were impaired in their ability to synthesize DNA in responses to ADR, compared with nuclei from younger adult donors. In contrast, those aged cells maintaining intact PHA responses provided nuclei that were also unimpaired in their response to ADR. The relationship between PHA responsiveness of the intact cells and ADR responsiveness of nuclei derived from these was a linear one. These results suggest that the depressed cellular reactivity of aged lymphocytes to PHA (when seen) may be due to a failure of these nuclei to respond to cytoplasmic stimulatory signals induced by the mitogen.

Full text

PDF
40

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Benz W. C., Strominger J. L. Viral and cellular DNA synthesis in nuclei from human lymphocytes transformed by Epstein-Barr virus. Proc Natl Acad Sci U S A. 1975 Jun;72(6):2413–2417. doi: 10.1073/pnas.72.6.2413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Collins J. M., Chu A. K. Reduction of DNA synthesis in aging but still proliferating cells. J Cell Physiol. 1985 Jul;124(1):165–173. doi: 10.1002/jcp.1041240126. [DOI] [PubMed] [Google Scholar]
  3. Das M. Mitogenic hormone-induced intracellular message: assay and partial characterization of an activator of DNA replication induced by epidermal growth factor. Proc Natl Acad Sci U S A. 1980 Jan;77(1):112–116. doi: 10.1073/pnas.77.1.112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Eda Y., Ohara J., Watanabe T. Restoration of LPS responsiveness of C3H/HeJ mouse lymphocytes by microinjection of cytoplasmic factor(s) from LPS-stimulated normal lymphocytes. J Immunol. 1983 Sep;131(3):1294–1299. [PubMed] [Google Scholar]
  5. Gutowski J. K., Cohen S. Induction of DNA synthesis in isolated nuclei by cytoplasmic factors from spontaneously proliferating and mitogen-activated lymphoid cells. Cell Immunol. 1983 Feb 1;75(2):300–311. doi: 10.1016/0008-8749(83)90328-3. [DOI] [PubMed] [Google Scholar]
  6. Gutowski J. K., Innes J., Weksler M. E., Cohen S. Induction of DNA synthesis in isolated nuclei by cytoplasmic factors. II. Normal generation of cytoplasmic stimulatory factors by lymphocytes from aged humans with depressed proliferative responses. J Immunol. 1984 Feb;132(2):559–562. [PubMed] [Google Scholar]
  7. Gutowski J. K., Mukherji B., Cohen S. The role of cytoplasmic intermediates in IL 2-induced T cell growth. J Immunol. 1984 Dec;133(6):3068–3074. [PubMed] [Google Scholar]
  8. HAYFLICK L., MOORHEAD P. S. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961 Dec;25:585–621. doi: 10.1016/0014-4827(61)90192-6. [DOI] [PubMed] [Google Scholar]
  9. HAYFLICK L. THE LIMITED IN VITRO LIFETIME OF HUMAN DIPLOID CELL STRAINS. Exp Cell Res. 1965 Mar;37:614–636. doi: 10.1016/0014-4827(65)90211-9. [DOI] [PubMed] [Google Scholar]
  10. Hart R. W., Setlow R. B. DNA repair in late-passage human cells. Mech Ageing Dev. 1976 Jan-Feb;5(1):67–77. doi: 10.1016/0047-6374(76)90009-9. [DOI] [PubMed] [Google Scholar]
  11. Hefton J. M., Darlington G. J., Casazza B. A., Weksler M. E. Immunologic studies of aging. V. Impaired proliferation of PHA responsive human lymphocytes in culture. J Immunol. 1980 Sep;125(3):1007–1010. [PubMed] [Google Scholar]
  12. Hori Y., Perkins E. H., Halsall M. K. Decline in phytohemagglutinin responsiveness of spleen cells from aging mice. Proc Soc Exp Biol Med. 1973 Oct 1;144(1):48–53. doi: 10.3181/00379727-144-37524. [DOI] [PubMed] [Google Scholar]
  13. Inkeles B., Innes J. B., Kuntz M. M., Kadish A. S., Weksler M. E. Immunological studies of Aging. III. Cytokinetic basis for the impaired response of lymphocytes from aged humans to plant lectins. J Exp Med. 1977 May 1;145(5):1176–1187. doi: 10.1084/jem.145.5.1176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. JACOBS P. A., COURT BROWN W. M., DOLL R. Distribution of human chromosome counts in relation to age. Nature. 1961 Sep 16;191:1178–1180. doi: 10.1038/1911178a0. [DOI] [PubMed] [Google Scholar]
  15. Jazwinski S. M., Wang J. L., Edelman G. M. Initiation of replication in chromosomal DNA induced by extracts from proliferating cells. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2231–2235. doi: 10.1073/pnas.73.7.2231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Makinodan T., Kay M. M. Age influence on the immune system. Adv Immunol. 1980;29:287–330. doi: 10.1016/s0065-2776(08)60047-4. [DOI] [PubMed] [Google Scholar]
  17. Muggleton-Harris A. L., Hayflick L. Cellular aging studied by the reconstruction of replicating cells from nuclei and cytoplasms isolated from normal human diploid cells. Exp Cell Res. 1976 Dec;103(2):321–330. doi: 10.1016/0014-4827(76)90269-x. [DOI] [PubMed] [Google Scholar]
  18. Niedermüller H. Age dependency of DNA repair in rats after DNA damage by carcinogens. Mech Ageing Dev. 1982 Jul;19(3):259–271. doi: 10.1016/0047-6374(82)90058-6. [DOI] [PubMed] [Google Scholar]
  19. Ord M. J. The separate roles of nucleus and cytoplasm in the synthesis of DNA. Int Rev Cytol Suppl. 1979;(9):221–277. doi: 10.1016/s0074-7696(08)60905-5. [DOI] [PubMed] [Google Scholar]
  20. Preumont A. M., Van Gansen P., Brachet J. Cytochemical study of human lymphocytes stimulated by PHA in function of donor age. Mech Ageing Dev. 1978 Jan;7(1):25–32. doi: 10.1016/0047-6374(78)90050-7. [DOI] [PubMed] [Google Scholar]
  21. Staiano-Coico L., Darzynkiewicz Z., Hefton J. M., Dutkowski R., Darlington G. J., Weksler M. E. Increased sensitivity of lymphocytes from people over 65 to cell cycle arrest and chromosomal damage. Science. 1983 Mar 18;219(4590):1335–1337. doi: 10.1126/science.6828861. [DOI] [PubMed] [Google Scholar]
  22. Tice R. R., Schneider E. L., Kram D., Thorne P. Cytokinetic analysis of the impaired proliferative response of peripheral lymphocytes from aged humans to phytohemagglutinin. J Exp Med. 1979 May 1;149(5):1029–1041. doi: 10.1084/jem.149.5.1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Watanabe T., Ohara J. Functional nuclei of LPS-nonresponder C3H/HeJ mice after transfer into LPS-responder C3H/HeN cells by cell fusion. Nature. 1981 Mar 5;290(5801):58–59. doi: 10.1038/290058a0. [DOI] [PubMed] [Google Scholar]
  24. Weksler M. E., Hütteroth T. H. Impaired lymphocyte function in aged humans. J Clin Invest. 1974 Jan;53(1):99–104. doi: 10.1172/JCI107565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Wright W. E., Hayflick L. Nuclear control of cellular aging demonstrated by hybridization of anucleate and whole cultured normal human fibroblasts. Exp Cell Res. 1975 Nov;96(1):113–121. doi: 10.1016/s0014-4827(75)80043-7. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES