Age related microsatellite instability in T cells from healthy individuals

Svetlana Krichevsky, Graham Pawelec, Alexander Gural, Rita B. Effros, Amiela Globerson, Dina Ben Yehuda, Arie Ben Yehuda*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Many immune functions decline with age and may jeopardize the elderly, as illustrated, for example by the significantly higher mortality rate from influenza in old age. Although innate and humoral immunity are affected by aging, it is the T cell compartment, which manifests most alterations. The mechanisms behind these alterations are still unclear, and several explanations have been offered including thymic involution and Telomere attrition leading to cell senescence. Age related accumulation of mutations has been documented and could serve as an additional mechanism of T cell dysfunction. One effective repair mechanism capable of rectifying errors in DNA replications is the mismatch repair (MMR) system. We previously reported a comparative examination of individual DNA samples from blood cells obtained at 10 year intervals from young and old subjects. We showed significantly higher rates of microsatellite instability (MSI), an indicator of MMR dysfunction in older subjects, compared to young. In the present study we confirm this result, using direct automated sequencing and in addition, we demonstrate that as CD8 lymphocytes from aged individuals, undergo repeated population doublings (PDs) in culture, they develop MSI. CD4 clones that also undergo repeated PDs in culture develop significant MSI as well. Elucidation of this previously unexplored facet of lymphocyte dynamics in relation to aging may help identify novel mechanisms of immunosenescence and pathways that could serve as targets for interventions to restore immune function.

Original languageAmerican English
Pages (from-to)507-515
Number of pages9
JournalExperimental Gerontology
Volume39
Issue number4
DOIs
StatePublished - Apr 2004
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by grants from the TEVA company, and from the HWZOA (Hadassah Women Zionist Organization of America).

Keywords

  • Microsatellite instability
  • Mismatch repair
  • Population doublings

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