Insulin Signaling Gene Expression in Long-lived Mice
We hypothesize that the remarkable longevity of Ames dwarf (Prop1df) mice and growth hormone receptor knockout (GHR-KO) mice is due to reduced insulin levels and enhanced sensitivity to insulin. We believe that these physiological changes are reflected in altered gene expression in the pancreas and in different insulin/IGF-1 target organs (e.g. muscle, liver, heart), and result in a slowing of the aging process and increases in the efficiency of mechanisms important to long term survival, e.g. stress resistance. Our initial and principal objective in the present application is to identify which genes show changes in expression in life-extended mutant and calorically restricted mice, focusing principally, but not exclusively, on loci sensitive to insulin signaling. Particular attention will be paid to those changes in gene expression that are common to three different models of extended longevity (implying fundamental importance) and are consistent with findings in other animal models and in human subjects. These results will then serve as a basis for future experiments in which the role of newly identified candidate genes in longevity and aging will be tested in human subjects (the long term goal of the Consortium) and in genetically manipulated mice. The Specific Aims of this proposal are to:
- Identify effects of Prop1df mutation in Ames dwarf mice on the expression of genes related to insulin signaling in different insulin target organs.
- Identify effects of disruption of GHR gene in GHR-KO mice on the expression of genes related to insulin signaling in different insulin target organs;
- Identify effects of caloric restriction on the expression of the same genes;
- To use results of microarray studies to identify alterations in pathways not directly related to insulin action, but associated with extended longevity.
- On the basis of individual and comparative results obtained from the above experiments, identify candidate longevity genes for the study of single nucleotide polymorphisms and haplotypes in relevant human populations.