Elevated ATF4 Function in Fibroblasts and Liver of Slow-Aging Mutant Mice

Work in yeast has shown that longevity extension induced by nutrient deprivation, altered ribosomal function, or diminished target of rapamycin action requires the activity of GCN4. We hypothesized that increased activity of ATF4, the mammalian equivalent of yeast GCN4, might be characteristic of mutations that extend mouse life span. Fibroblasts from the skin of two such mutants (Snell dwarf and PAPP-A knockout) were found to have higher levels of ATF4 protein and expression of several ATF4 target genes in responses to amino acid withdrawal, cadmium, hydrogen peroxide, and tunicamycin. ATF4 pathways were also elevated in liver of both kinds of long-lived mutant mice. Thus, a connection between ATF4 pathways and longevity may have deep evolutionary roots, and further studies of ATF4 mechanisms may provide insights into the links between cellular stress resistance, protein translation control, and aging.