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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDA-F (02))
Program Officer
Mccormick, Anna M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Schools of Medicine
United States
Zip Code
Beltrami, Elena; Ruggiero, Antonella; Busuttil, Rita et al. (2013) Deletion of p66Shc in mice increases the frequency of size-change mutations in the lacZ transgene. Aging Cell 12:177-83
Garcia, Ana Maria; Salomon, Robert N; Witsell, Alice et al. (2011) Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila. Genome Biol 12:R121
Garcia, Ana Maria; Calder, R Brent; Dollé, Martijn E T et al. (2010) Age- and temperature-dependent somatic mutation accumulation in Drosophila melanogaster. PLoS Genet 6:e1000950
Maslov, Alexander Y; Vijg, Jan (2009) Genome instability, cancer and aging. Biochim Biophys Acta 1790:963-9
Khrapko, Konstantin; Vijg, Jan (2009) Mitochondrial DNA mutations and aging: devils in the details? Trends Genet 25:91-8
Edman, Ursula; Garcia, Ana Maria; Busuttil, Rita A et al. (2009) Lifespan extension by dietary restriction is not linked to protection against somatic DNA damage in Drosophila melanogaster. Aging Cell 8:331-8
Garcia, Ana Maria; Busuttil, Rita A; Calder, R Brent et al. (2008) Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues. Mech Ageing Dev 129:528-33
Park, Jung Yoon; Cho, Mi-Ook; Leonard, Shanique et al. (2008) Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice. PLoS One 3:e2346
Longo, Valter D; Lieber, Michael R; Vijg, Jan (2008) Turning anti-ageing genes against cancer. Nat Rev Mol Cell Biol 9:903-10
Vijg, Jan (2008) The role of DNA damage and repair in aging: new approaches to an old problem. Mech Ageing Dev 129:498-502

Showing the most recent 10 out of 22 publications