The Jackson Laboratory

One theory of aging posits that accumulation of DNA damage or chromosomal abnormalities with age leads to decline or derangement of normal cellular processes. In support of this hypothesis, mice deficient for DNA damage response or repair often show phenotypes resembling accelerated aging, especially tumor development. However, natural aging and age-specific pathologies, such as cancer, are complex and variable phenomena that may be considered quantitative traits.

We have taken advantage of a comprehensive collection of aging inbred mouse strains that were generated at The Jackson Laboratory with support from The Ellison Foundation and the NIH Nathan Shock Center of Excellence in the Basic Biology of Aging to probe the connection between DNA damage and natural aging. We have found that endogenous genotoxic stress, and the magnitude of the resulting apoptotic response, varies dramatically among different inbred strains of mice, at least in the tissues we tested. This suggests that either the underlying susceptibility to DNA damage or the nature of the response is under genetic control. Intriguingly, we have found that apoptosis and spontaneous chromosomal instability appear to be inversely correlated, suggesting that some strains more effectively avoid genomic instability by mounting a stronger apoptotic reaction to damage. Moreover, we have found that this apoptosis/instability relationship also correlates with the average lifespan characteristics of individual strains, suggesting that DNA damage, chromosomal instability and cellular genotoxicity may relate to some aspects of overall organismal aging. We are now taking agenetics approach to begin dissecting the pathways governing these phenotypes.