Telomerase is a ribonucleoprotein enzyme that catalyzes telomere synthesis and other non-telomere lengthening activity. Telomerase activity is tightly regulated during T cell development, differentiation, and activation. With age, telomere shortens in peripheral lymphocytes but it is unknown whether reduction of telomerase activity in lymphocytes also occurs with age. Our previous study of telomerase activity in T and B cells over 200 BLSA participants showed that telomerase activity declined with age in resting and in vitro activated T cells, and in the resting B cells but not in vitro activated B cells. To further understand the basis of this age-related reduction of telomerase activity in lymphocytes, we analyzed mRNA level of the key telomerase component, telomerase reverse transcriptase (TERT) in T cell subsets. TERT serves as a rate-limiting factor and TERT mRNA is detectable in resting T cells and rapidly upregulated upon T cell activation. Because multiple TERT mRNA alternatively spliced products (ASPs) have been detected, it is unclear whether the mRNAs are full-length (FL) and/or loss-of-function ASPs in T cells. We analyzed the full-length (FL) and 3 types of reverse transcriptase-null ASPs (alpha, beta, and alpha+beta) in nave and memory CD4 and CD8 T cells from young (<36 year old) and old (>69 year old) humans. We found that resting nave CD4 T cells (CD4N) expressed highest level of full length hTERT mRNA, followed by CD4 central (CM), nave CD8 T cells, CD8 central (CM), CD4 effector memory (EM) cells. hTERT mRNA was undetectable in CD8 effector memory cells. Upon TCR activation with anti-CD3 + anti-CD28 antibodies, CD4 subsets showed greater hTERT expression than CD8 subsets. Furthermore, nave cells showed greater amounts of hTERT mRNA than memory cells, and CM was greater than EM. Compared to the young subjects, naive CD4 T cells from aged subjects had significantly less FL hTERT mRNA. This finding suggests that reduced full length hTERT mRNA is responsible for reduced telomerase activity in T cells with age. Current studies are trying to understand the mechanism underlying this age-related reduction of hTERT mRNA and to identify small molecules that could extend hTERT mRNA.
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