The ultimate evidence, at least so far, that insulin and insulin-like growth factor affect longevity and disease comes from a type of transgenic animal experiment known as a knockout. The working assumption of such experiments is that the function of a gene can be elucidated by creating an animal that lacks the gene entirely—the gene has been knocked out—or has only one copy instead of the usual two. In January 2003, Martin Holzenberger and his colleagues from the Institut National de la Santé et de la Recherche Médicale in Paris reported that they had created mice with only a single copy of the gene for the IGF receptor, which meant that the cells of such mice would be comparatively unresponsive to any IGF that might be available in the circulation. The result was that these mice lived 25 percent longer than their littermates who had both copies of the gene, despite the fact that their weights were effectively identical. That same month, C. Ronald Kahn and his colleagues at the Joslin Diabetes Center published the results of their research on mice that they had genetically engineered to lack the insulin receptor only on their fat cells. With their fat tissue immune to the effect of insulin, Kahn’s mice weighed 25 percent less than normal mice. These mice remained lean, even when forced to overeat. They were simply incapable of putting on fat. As Kahn later explained, this wasn’t surprising, since fat cells require insulin for fat synthesis. If they have no receptor to detect the insulin that’s present, then no fat can accumulate. The transgenic mice lived almost 20 percent longer than normal mice.

These experiments have led to the working hypothesis that insulin and insulin-like growth factor emerged in simple organisms in part to promote the survival of the species when food is hard to come by. These hormone/growth factors regulate metabolism and fat storage and reproduction. The IGF regulates cell division and growth, while the insulin regulates metabolism by apportioning or partitioning the food we consume into those calories that will be used immediately for fuel and those that will be stored for use at a later time. When food is plentiful, activity in the insulin and IGF pathways increases and pushes the animal to grow, mature, and reproduce. When food is scarce, activity in these pathways is reduced, and this shifts the organism into a mode that favors long-term survival over immediate reproduction. As Cynthia Kenyon explains: