Premature Aging and Reduced Cancer Incidence Associated with Near-Complete Body-WideMycInactivation

Abstract

SummaryMYCproto-oncogene dysregulation alters metabolism, translation and other functions in ways that support tumor induction and maintenance. AlthoughMyc+/-mice are healthier and longer-lived than control mice, the long-term ramifications of more completeMycloss remain unknown. We now describe the chronic consequences of body-wideMycinactivation initiated postnatally. “MycKO” mice acquire numerous features of premature aging including altered body composition and habitus, metabolic dysfunction, hepatic steatosis and the dysregulation of numerous gene sets involved in functions that normally deteriorate with aging. Yet,MycKO mice have extended life spans that correlate with a 3-4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also down-regulate Myc and gradually deregulate many of the same Myc target gene sets that are dysregulated inMycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc and its target genes and can be genetically separated.