DESCRIPTION (provided by applicant): Genomic instability is the driving force of evolutionary change, but also the cause of cancer and, possibly, aging in multicellular organisms. Using a transgenic mouse model with chromosomally integrated lacZ mutational target genes, we have demonstrated that mutations accumulate with age in an organ-specific manner. To investigate if in a mouse model of extended longevity the rate of mutation accumulation would be slower, and the mutation spectra different, we crossed the lacZ reporter locus into Prop-7 mutant (Ames) dwarf mice. The results indicated a significant reduction in mutation accumulation in liver and kidney already at 7 months of age. Reduced insulin/insulin-like growth factor (IGF) signaling plays a major role in increasing life span in invertebrates and has also been considered to underlie the longevity phenotype in Ames dwarf mice. To test the hypothesis that reduced insulin signaling is the most likely mechanism for the observed reduced genomic instability in Ames dwarf mice, we will compare the lacZ mutation accumulation pattern in cells and tissues of these mice with that in Growth Hormone Receptor (GHR)- and IGF-1 receptor (IGF-1 R)- defective mice. By contrast, we will also test if GH overexpressing mice display increased genomic instability at the lacZ locus. To test if also invertebrates display a reduction in genomic instability at the lacZ locus in response to decreased activity of the IGF-1 axis, we generated a lacZ transgenic fly model, which will be crossed into a Insulin Receptor Substrate (IRS) null mutant (chico) and analyzed for lacZ mutations, similar to the lacZ hybrid mouse models. The availability of the lacZ reporter in both flies and mice would allow, for the first time, an in depth comparison of the fundamental process of genome instability between two disparate metazoa during development and aging, in relation to longevity and its endocrine regulation. This will provide basic insight into genome deterioration in somatic cells and its possible contribution to the efferent pathways by which insulin signaling accelerates aging.
|Effective start/end date||7/15/09 → 6/30/11|
- National Institute on Aging: $253,202.00
- Molecular Medicine
- Endocrinology, Diabetes and Metabolism
- Developmental Biology