A simple model system for age-dependent DNA damage and cancer.
Aging is the major risk factor for many human cancers. However, the mechanisms responsible for the effect of aging on tumor incidence are poorly understood, in part because few model systems are available to study age-dependent genomic instability. Furthermore, the role of DNA mutations in "normal aging" and "life span extension" is unclear. Our laboratory has developed a novel method to study aging in yeast based on the survival of non-dividing populations (chronological life span). Two major pathways have been identified that control chronological aging: the Ras/PKA/Msn2/4 and the Sch9 pathways. The downregulation of either of them promotes life span extension. Importantly, similar pathways (insulin/IGF-I-like), regulate longevity in higher eukaryotes suggesting a common evolutionary origin for the life span-regulatory mechanisms. Moreover, both Ras and Sch9 are functional homologs of two major mammalian oncogenes (Ras and Akt), which underlines the close link between cancer and aging. By combining chronological life span with simple assays for the detection of DNA mutations and dedifferentiation we have developed a powerful system to identify genes that regulate genomic instability and understand the fundamental mechanisms that may be responsible for age-dependent DNA mutations and cancer in mammals. Here, we describe the use of this system to monitor the age-dependent accumulation of different types of DNA mutations including base substitutions, frame-shift mutations, and gross chromosomal rearrangements (GCRs).
Madia
F
F
Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, United States.
Gattazzo
C
C
Fabrizio
P
P
Longo
V D
VD
D000375:Aging / Q000502:physiology*; D000818:Animals; D004249:DNA Damage / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D012441:Saccharomyces cerevisiae / Q000235:genetics