Mechanisms of telomere attrition. (A) Physiological telomere attrition in normal individual hematopoietic cells is the result of balance between telomerase mediated telomere elongation and telomere loss with each cell division. Gradual decrease in mean telomere content occurs with age. (B) Germ-line mutations in a telomere repair gene lead to a reduced stem cell pool and severe telomere loss during replication. (C) Regenerative replicative stress during bone marrow failure, recovery after chemotherapy, or hematopoietic transplant also leads to telomere loss due to increased mitotic activity in stem cells and/or progenitors. (D) Reactive oxygen species (generated from radiation, toxins, and inflammation) cause DNA damage and telomere loss as a direct effect on the telomere. HSC, hematopoietic stem cell.