Journal
REJUVENATION RESEARCH
Volume 11, Issue 6, Pages 1001-1011Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/rej.2008.0747
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Funding
- National Institutes of Health [RO1 AG 15043, ROT AT 57266]
- General Clinical Research Center [MO1 RR00039]
- Noble Foundation
- Aging Registry
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The ability to mount adaptive immune responses to vaccinations and viral infections declines with increasing age. To identify mechanisms leading to immunosenescence, primary CD4 T cell responses were examined in 60- to 75-year-old individuals lacking overt functional defects. Transcriptome analysis indicated a selective defect in zinc homeostasis. CD4 T cell. activation was associated with zinc influx via the zinc transporter Zip6, leading to increased free cytoplasmic zinc and activation of negative feedback loops, including the induction of zinc-binding metallothioneins. In young adults, activation-induced cytoplasmic zinc concentrations declined after 2 days to below prestimulation levels. In contrast, activated naive CD4 T cells from older individuals failed to downregulate cytoplasmic zinc, resulting in excessive induction of metallothioneins. Activation-induced metallothioneins regulated the redox state in activated T cells and accounted for an increased proliferation of old CD4 T cells, suggesting that regulation of T cell zinc homeostasis functions as a compensatory mechanism to preserve the replicative potential of naive CD4 T cells with age.
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