Genes affecting aging stem cell populations

随着年龄的增长，多个器官系统的功能下降。 乍一看，血液形成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一直维持到老年。 然而，与年龄相关的功能下降在对需要加速血细胞形成的压力的反应中是明显的。 造血干细胞群体是这种反应的核心，虽然能够维持稳态血液形成，但其对增加的需求的反应是迟钝的。 尽管干细胞群体在血液形成中的关键作用，以及关于其在年轻人中的功能的知识越来越多，但我们对衰老干细胞的知识仍存在很大的差距。 我们推测，淋巴造血干细胞群的有害变化，也许在其他器官的干细胞，限制生物体的寿命。我们已经在老鼠身上绘制了一个基因位点，它调节老年动物的干细胞数量，但不调节年轻动物的干细胞数量。 因此，它有资格作为“老化基因”。 该基因座的等位基因差异导致长寿C57 BL/6（B6）小鼠衰老期间干细胞增加3倍以上，而短命DBA/2（DBA）小鼠在同一时期干细胞减少20%。 我们假设，这个位点是一个重要的决定因素的干细胞的造血需求在老年动物的反应，从而影响生物体的寿命。该项目的目标是在一个决议，将允许在下一阶段的分子水平上的定位克隆的基因精细定位。 为此，我们已经产生了一个B6菌株同源的DBA衍生端粒片段的Chr.2窝藏的轨迹。 我们建议在同源间隔内创建大量重组，从而创建同源亚株，使我们能够将基因座缩小到小于0.5 cM。 对现有同类菌株的初步研究表明，在骨髓移植的严格要求下，可以在年轻动物的干细胞中观察到该位点的作用。 因此，为了帮助在未来的研究这个位点，我们建议开发一个替代措施的老化表型在年轻的小鼠通过使用移植试验。

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.