Genes affecting aging stem cell populations

增龄是以多器官系统功能衰退为特征的。乍一看，造血系统似乎并没有反映出衰老的影响，因为正常的血细胞计数会一直保持到老年。然而，在对需要加速血细胞形成的压力的反应中，与年龄相关的功能下降是明显的。造血干细胞群体处于这种反应的核心，虽然能够维持稳定的血液形成，但它对需求增加的反应是迟钝的。尽管干细胞群体在血液形成中起着关键作用，而且对其在年轻人中的作用的了解也在不断增加，但我们对老化干细胞的了解仍存在很大差距。我们假设，淋巴-造血干细胞种群的有害变化，可能还有其他器官的干细胞，限制了生物的寿命。我们已经在老鼠身上绘制了一个基因位点，它可以调节老年动物的干细胞数量，但不能调节幼年动物的干细胞数量。因此，它被认为是一种“衰老基因”。该基因座的等位基因差异导致长寿C57BL/6(B6)小鼠在衰老过程中干细胞数量增加了3倍以上，而在短寿命DBA/2(DBA)小鼠的衰老过程中干细胞数量下降了20%。我们假设该基因是干细胞对老年动物的造血需求作出反应的重要决定因素，从而影响生物的寿命。该项目的目标是以一种能够在下一阶段在分子水平上进行定位克隆的分辨率对该基因进行精细定位。为此，我们为DBA衍生的CHR端粒片段产生了一株B6菌株。2藏匿于此轨迹。我们建议在同源区间内创造大量的重组，从而创造同源亚株，使我们能够将基因座缩小到0.5 cM以下。对现有同源基因株的初步研究表明，在骨髓移植的严格要求下，可以在幼年动物的干细胞中观察到该基因座的作用。因此，为了帮助将来对该基因座的研究，我们建议通过使用移植试验来开发一种幼鼠衰老表型的替代测量方法。

Advancing age is characterized by the functional decline of multiple organ systems. At first glance, the blood-forming system does not seem to reflect the effects of aging in that normal blood cell counts are maintained into old age. However, an age-related decline in function is apparent in the response to stresses requiring accelerated blood cell formation. The hematopoietic stem cell population lies at the heart of this response and, while able to maintain steady-state blood formation, its response to increased demand is blunted. Despite the key role of the stem cell population in blood formation, and increasing knowledge about its function in the young, there are large gaps in our knowledge of aging stem cells. We hypothesize that deleterious changes in the lympho-hematopoietic stem cell population, and perhaps in stem cells of other organs, limit organismal longevity. We have mapped a genetic locus in the mouse that regulates stem cell numbers in old animals, but not in young animals. It thus qualifies as an 'aging gene'. Allelic differences at this locus prescribe over a 3-fold increase in stem cells during aging of long-lived C57BL/6 (B6) mice and a 20 percent decline in stem cells during the same period in short-lived DBA/2 (DBA) mice. We hypothesize that this locus is an important determinant of the response of stem cells to hematopoietic demands in old animals and thus influences organismal longevity. The goal of this project is to genetically fine map the locus at a resolution that will permit positional cloning at the molecular level in the next phase. To this end, we have generated a B6 strain congenic for the DBA-derived telomeric segment of Chr. 2 harboring the locus. We propose to create a large number of recombinations within the congenic interval, and thus to create congenic sub-strains, enabling us to narrow the locus to less than 0.5 cM. Preliminary studies of the existing congenic strain have shown that the effect of the locus can be observed in stem cells of young animals under the rigorous demands of bone marrow transplantation. Thus, to aid in the future study of this locus, we propose developing a surrogate measure of the aging phenotype in young mice by using a transplantation assay.