Grant: Operating Grant

Both genetic and environmental factors are thought to contribute to growth, healthy aging and longevity. Studies in worms and flies have clearly demonstrated that the insulin signaling has a negative effect on longevity. Seemingly counterintuitive evidence has also been presented that mice lacking the insulin receptor in fat also have improved lifespan. However, there has been no direct demonstration that insulin itself modulates tissue growth or longevity in mammals. An ideal way to test this hypothesis would be to vary the amount of insulin in genetically engineered mice. The total lack of Insulin genes leads to diabetes at birth, but mice live normally with only one copy of the Insulin gene. Mice have two insulin genes: Insulin 2, which has a broad tissue distribution like human insulin and Insulin, which is restricted to the pancreas. The Insulin 1 gene is therefore an ideal tool to examine the specific effects of circulating insulin on metabolism and longevity. We have taken advantage of this and begun to characterize mice with two of the four copies of the insulin gene, as well as mice with only one insulin gene copy. Our preliminary data suggest that mice lacking all but 1 insulin gene allele are smaller but healthier than controls with reduced fat and lower blood sugar levels. Since these are all features of mice with extended lifespan, we have good reason to properly examine longevity in a controlled study. Our data also provide novel evidence that insulin negatively controls energy expenditure in fat tissue. Our findings have the potential to change multiple paradigms in the fields of aging and metabolism, but directly implicating insulin in this integrated system. The findings are likely to translate to humans, where high circulating insulin is a prominent feature of the emerging worldwide epidemics of obesity and type 2 diabetes and human lifespan is predicted to fall for the first time in recorded history.