Genetic analysis of hemopoietic cell cycling in mice suggests its involvement in organismal lifespan

Abstract

Normal somatic cells undergo replicalive senescence in vitro but the significance of this process in organismic aging remains controversial. We have shown previously that hemopoietic stern cells of common inbred strains of mice vary widely in cycling activity and that this parameter is inversely correlated with straindependent mouse lifespan. To assess whether progenitor cell cycling and organismic lifespan are causally related, genes thai affect both traits have to be identified. As a first step towards this goal we searched for quantitative trait loci (QTLs) that contributed to these traits in young BXD recombinant inbred mice. These mice are derived from long-lived/low-cycling C57BL/6 and shortlived/high-cycling DBA/2 mice, and can be used in genetic linkage analysis studies. Also in BXD mice a significant inverse correlation between progenitor cell cycling and lifespan was observed. Two QTLs, mapping to exactly the same intervals on chromosomes 7 and 11, were identified that contributed to both lifespan and cycling. This strongly suggests that genes affecting cell cycling also contribute to variation in lifespan. The locus on chromosome 11 mapped to the cytokine cluster, a segment that shows synteny with human chromosome 5q, deletions of which are strongly associated with a late-onset type of myelodysplastic syndrome. These data indicate that cell cycle kinetics, here measured in hemopoielic progenitor cells, have a profound effect on the rate of organismic aging in mammals.