Collapse of Telomere Homeostasis in Hematopoietic Cells Caused by Heterozygous Mutations in Telomerase Genes

Abstract

Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain telomere length with proliferation in vitro and with age in vivo. We performed a detailed study of the telomere length by flow FISH analysis in leukocytes from 835 healthy individuals and 60 individuals with reduced telomerase activity. Healthy individuals showed a broad range in average telomere length in granulocytes and lymphocytes at any given age. The average telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. Gender differences between leukocyte telomere lengths were observed for all cell subsets studied; interestingly, this trend could already be detected at birth. Heterozygous carriers for mutations in either the telomerase reverse transcriptase (hTERT) or the telomerase RNA template (hTERC) gene displayed striking and comparable telomere length deficits. Further, non-carrier relatives of such heterozygous individuals had somewhat shorter leukocyte telomere lengths than expected; this difference was most profound for granulocytes. Failure to maintain telomere homeostasis as a result of partial telomerase deficiency is thought to trigger cell senescence or cell death, eventually causing tissue failure syndromes. Our data are consistent with these statements and suggest that the likelihood of similar processes occurring in normal individuals increases with age. Our work highlights the essential role of telomerase in the hematopoietic system and supports the notion that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall telomere shortening, are nevertheless crucial to maintain telomere homeostasis with age.

The Effect of Physical Activity Agains The Telomere Length in The Leukocytes Cells of KONI (Indonesian National Sports Committee) Athletes

“…(Aubert et al, 2012). This is supported by other studies that also reported the difference in telomere length lomere length athletes are no different from nonathletes, while in old age, telomere length was significantly different.…”

Leukocyte and Skeletal Muscle Telomere Length and Body Composition in Monozygotic Twin Pairs Discordant for Long-term Hormone Replacement Therapy

“…This is especially important with regard to telomeres, as it is known that telomere length is highly heritable (Broer et al, 2013;Hjelmborg et al, 2015) and majority of the attrition occurs during first two decades, when cells divide and differentiate rapidly due to growth and development (Aubert et al, 2012;Zeichner et al, 1999). Our results from a genetically controlled sample suggest that long term HRT is not associated with telomere length in older age.…”

Telomere attrition in beta and alpha cells with age

“…Recently, Lansdorp and colleagues provided further confirmative data by flow FISH analysis, demonstrating that individuals showed a broad range in average telomere length in granulocytes and lymphocytes at any given age and the average telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. (Aubert et al 2012). …”

“…Regression analysis of NTCRs and age was carried out using piecewise linear fits to the NTCRβ and NTCRα values with a break point at age 18 years, as described previously (Aubert et al 2012). F tests were used to compare the fit of the model to the test data.…”