Effect of age and replicative stress on hematopoietic stem cell telomere length
Telomeres and telomerase expression have been implicated in neoplastic progress Ion of human tumors and in replicative senescence of cultured cells. However, their rol& in replicative senescence and aging of cell populations in vivo is less certain. Given that relatively short-lived inbred mice have telomeres several times longer than humans, the relevance of telomere shortening to aging in mice is even more doubtful. Using a flow cytometry-based (Flow-FISH) method of measuring telomere length in individual cells, we have studied the effects of aging and sublethal irradiation on hematopoietic cells of longlived C57BL/6 and short-lived DBA/2 mouse strains. Telomere lengths of hematopoietic stem cells purified from bone marrow of young (2 mo.) animals of both strains showed a consistent strain difference where DBA/2 stem cells had 30% longer telomeres than those of C57BL/6 mice (~ 180 vs. -130 kMESF units). Stem cells purified from old ( 18 mo.) animals of both strains showed no detectable telomere shortening relative to young animals, and the strain difference was maintained. Thus aging had no demonstrable effect on stem cell telomere length in these strains. Because we found that telomere measurements of blood leukocytes accurately reflected telomere lengths of purified stem cells in young and old animals of both strains, we tested the effects of sublethal irradiation on hematopoietic recovery during which blood cells from mice could be repetitively sampled. One month after irradiation (5 Gy), we found no detectable change in telomere lengths of young animals of either strain. However, in old animals of both strains, telomeres shortened dramatically. In C57BL/6 animals, telomeres shortened from a mean of 126 to 97 kMESF units one month after 5 Gy (23%, P<0.05). Old DBA/2 mice showed an even larger reduction (38%, P<0.01 ) in telomere length from a mean of 186 to 116 kMESF units, despite the fact they were given 4 rather than 5 Gy (5 Gy was fatal). We have previously found that the replicative rate of hematopoietic progenitor cells both under steady-state conditions and following transplant or administration of 5-fluorouracil, is significantly higher in DBA/2 mice than in C57BL/6. The dramatic reduction in telomere length following irradiation in old mice of both strains suggests either a lack of repair mechanisms in old mice, accelerated telomere loss per cell division, or a decrease in the number of stem cells. We conclude that aging affects the ability of stem cells to maintain telomeres in vivo in the face of replicative stress.
Manning, EL; Grimes, BA; Baerlocher, GM; Lansdorp, PM; Van Zant, G
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