Journal
MECHANISMS OF AGEING AND DEVELOPMENT
Volume 130, Issue 7, Pages 420-428Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mad.2009.04.004
Keywords
Calorie restriction; FOXO1; Longevity; Gadd 45 alpha; Glutamine synthase
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Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT, Tokyo, Japan)
- Japanese Ministry of Health, Labour and Welfare
- Mitsui Sumitomo insurance Welfare Foundation
- Organization for Pharmaceutical Safety and Research (OPSR, Osaka, Japan)
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Caloric restriction (CR) is the most robust and reproducible intervention that can extend lifespan in rodents. Studies in invertebrates have led to the identification of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signaling pathway, including DAF-16 (C. elegans) and dFOXO (Drosophila). Mice subjected to CR for 8 weeks showed an increase in FOXO1 mRNA and other longevity-related genes: Gadd 45 alpha, glutamine synthase, and catalase in skeletal muscle. To investigate whether FOXO1 expression affects longevity in mammals, transgenic mice were studied that overexpress FOXO1 in their skeletal muscle (FOXO1 mice), and in which muscle atrophy occurs. FOXO1 mice showed increases in Gadd 45(x, and glutamine synthase proteins in skeletal muscle. In FOXO1 mice, the phosphorylation/dephosphorylation state of the p70 S6K and 4E-BP1 proteins were not altered, suggesting that translation initiation of protein synthesis might not be suppressed. The lifespan of FOXO1 mice was similar to their wild-type littermates. FOXO1 overexpression could not prevent aging-induced reduction in catalase, CuZu-SOD, and Mn-SOD mRNA in skeletal muscle. These data suggest that an increase in FOXO1 protein and its activation in skeletal muscle does not extend lifespan in mice. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
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