Tolerance: pregnancy matters.

progenitor cell functional assays were included in the studies by Calado et al. Although it is logical that increasing TERT activity would increase hematopoietic stem/progenitor cell function, no direct studies addressed this critical question. Understanding whether androgen/estradiol-induced TERT activation also occurs in hematopoietic stem/progenitors is crucial because it is loss of these cells that is at the crux of genetic and acquired bone marrow failure conditions. Whereas the investigators used bone marrow CD34 cells, which are enriched for stem/progenitors, this cell population is very heterogeneous. They contain a low frequency of stem/progenitor cells. In addition, pharmacologic doses of hormones were used in their studies. It is unclear whether the concentrations of the hormones used are achieved clinically. Therefore, future clinical studies assessing TERT activity in peripheral blood cells from patients before and after androgen therapy would be very interesting. Moreover, comparing increased TERT activity in patients who have a hematologic response after androgen therapy with patients who are androgen nonresponders and have no change in TERT activity would provide considerable evidence that the novel mechanism identified by these authors is evident in vivo. Given the data presented by Calado et al, it is intriguing to speculate whether other tissuespecific stem/progenitor cells may enhance TERT activity in response to endogenously produced hormones. As one example, it is well established that premenopausal women have lower rates of cardiovascular disease compared with men, although those rates increase after menopause when estrogen levels are lower, coinciding with lower telomere lengths in hematopoietic cells.5,6 Could stem/progenitor cells of the vascular system also be dependent on estrogen to activate TERT, thereby enhancing cell lifespan, survival, and proliferation? Many similar provocative questions regarding aging and cancer arise from the studies by Calado et al, an attribute ascribed to groundbreaking scientific investigation. Conflict-of-interest disclosure: The author declares no competing financial interests. ■