Abstract
Telomeres have been receiving attention given their roles in cancer and aging. Germline genetic variants that result in accelerated telomere dysfunction are often associated with bone marrow diseases, with bone marrow failure being the main cause of death for dyskeratosis congenita. It is well-established that telomere dysfunction activates tumor suppression pathways, thus limiting cell viability. Hartwig and Collares recently reviewed the literature on the differential roles of senescence and apoptosis in detecting telomere dysfunction, proposing biological models regarding tissue renewal impairment and cancer. Based on this paper, the present commentary extends the hypothesis to levels of telomerase activity/telomere integrity others than down-regulated, thus adding to the understanding of the effects of the interactions of senescence and apoptosis. Given the relevance of the bone marrow for the clinical manifestation of telomere syndromes, this commentary focuses on the implications of the proposed extensions for bone marrow impairments, suggesting a hematopoietic stem cell-based model according to which environmental factors plausibly add an extra degree of complexity to the effects of the interactions between telomere biology and tumor suppression responses on the balance between hematopoietic stem cell impairment and hematological malignancies in both telomere syndromes and physiological aging.
Highlights
According to the World Health Organization, the age structure of most populations worldwide is changing, with an increase in the over 60 years-old group in almost every country
Telomerase activity is limited to a few cell types [3,4], including adult stem cells (ASCs), which are of great relevance for aging-related diseases
Telomerase activity promotes telomere (5’ TTAGGG 3’ DNA tandem repeats associated with six proteins called shelterin) [5] elongation through de novo DNA synthesis by reverse transcription, which is essential to allow a cell to continue to proliferate for several mitotic rounds and the fact that critically shortened telomeres elicited DNA damage responses that results in cell cycle arrest or cell death [6]
Summary
According to the World Health Organization, the age structure of most populations worldwide is changing, with an increase in the over 60 years-old group in almost every country. The results of this study support the notion that increased tumor suppression in a wild-type telomerase background has effects in the same direction This has been considered to occur by restraining ASCs proliferation and preventing accumulation of DNA damaged-ASCs (which is in accordance to the roles of both age-dependent DNA damage accumulation as a physiological limiting factor for HSC function [15] and tumor suppression responses in sensing telomere dysfunction and DNA damaging stresses) [16,17], resulting in the elaboration of stem cell-based models for longevity based on telomerase activity and tumor suppression capacity [17]. This, in combination with other studies (well-reviewed elsewhere [19]), evidenced that senescence and apoptosis are redundant regarding tumor suppression activated by telomere dysfunction, while senescence is the major determinant of loss of regenerative capacities due to short
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