Normal telomerase levels are needed to maintain telomeres and prevent bone marrow failure. Each stem cell division results in loss of telomere repeats explaining why the average telomere length in various cell types including granulocytes and lymphocytes declines with age (Figure 3). (A) Illustrative representation of the hematopoietic stem cell hierarchy. (B-C) In normal individuals, an occasional stem cell drops out of the stem cell pool (B, red circle) when too many short telomeres relative to the limited repair capacity provided by telomerase accumulate. In patients with reduced telomerase levels, for example, as a result of mutations in telomerase genes, stem cells start dropping out during development (C), putting a strain on remaining stem cells, which have to undergo more divisions to make up the pool (hence, shorter telomeres) as illustrated in panel D. The net result of this negative feed-forward loop is (1) very short telomeres in patients with telomerase deficiency and (2) eventual loss of stem cells resulting in bone marrow failure.