Genetic factors play a role in the determination of longevity of all species, but the identities and modes of actions of actions of relevant loci remain enigmatic. In mice we have recently identified and mapped 3 distinct loci associated with lifespan (Scp1, Scp2 and Life1) by recombinant inbred analysis of long-lived C57BL/6 and short-lived and short-lived DBA/2 inbred strains. In parallel studies of the same strains we also showed that SCP1 and SCP2 are associated with the steady-state cell cycle kinetics of hematopoietic progenitor cells, thereby suggesting a cause-effect relationship between longevity and cell cycle kinetics. We were able to extend these results to other strains by showing a strong correlation between the same 2 parameters among commonly used inbred mouse strains. Life1, the 3rd longevity locus which we recently defined and mapped, imparts variability in the temporal range over which genetically identical mice of the same strain die. Thus, the focus of this proposal is a study of the 3 genes affecting longevity according to the following specific aims: 1. In order to study the physiological effects of each gene in isolation from background genetic variation, we will generate congenic strains of mice in which the individual loci we have mapped have been moved onto a common genetic background. We will determine the phenotype imparted by each and, through study of cell cycle kinetics and telomeres, whether genetically determined mitotic histories play a role in longevity. 2. We will construct and study chimeric mice by aggregating embryos of strains congenic for SCP1, Scp2 and Life1 with selected partner. This approach will provide insight into the modes of action of the putative genes. For example, it will resolve whether a gene acts in a cell intrinsic or extrinsic manner by admixing cell populations with specified dissimilarities (congenic) into the common in vivo environment of a chimera. Through such studies we also plan to identify which tissues are affected by the congenic loci and determine which are longevity-limiting. Thus our primary hypotheses are a) that generating mice congenic for our loci will provide models for the systematic study of their physiological mechanisms of action and will ultimately aid in their cloning and b) that study of chimeras compounded from congenic strains will shed light on the genetic mechanisms of longevity determination in vivo.
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