Genomic instability, transcriptional deregulation and aging

From Santa Fe Institute Event Wiki

Genome instability has been implicated as a cause of cancer and aging. Using a transgenic mouse model harboring lacZ mutation reporter genes as part of plasmids integrated head-to-tail at one or more chromosomal locations, we demonstrated that mutations accumulate in different tissues and organs of aging mice. A sizable fraction of these mutations, depending on the organ, were large genome rearrangements. In contrast to point mutations, these large rearrangements were independent of replication. Increased mutation accumulation in mice with defects in antioxidant defense or DNA repair was found to be associated with increased cancer and/or symptoms of premature aging. One possible mechanism by which increased genome instability can lead to cellular degeneration and death is by stochastic deregulation of gene expression. To test this hypothesis we dissociated single cardiomyocytes from fresh heart samples of young and old mice, followed by global mRNA amplification and real-time PCR quantitation of mRNA levels of a panel of housekeeping and heart-specific genes. While gene expression levels already varied among cardiomyocytes from young heart, this heterogeneity was significantly elevated at old age. To confirm that increased stochasticity of gene expression could be a result of increased genome instability, we treated mouse embryonic fibroblasts in culture with hydrogen peroxide. Such treatment resulted in a significant increase in cell-to-cell variation in gene expression, which was found to parallel the induction and persistence of genome rearrangement mutations at the lacZ reporter locus. These results underscore the stochastic nature of the aging process and could provide a mechanism for cellular age-related degeneration and death in tissues of multicellular organisms.