One hypothesis proposes that calorie restriction reduces the creation of toxic reactive oxygen species—free radicals—which are considered to be crucial factors in the aging of cells and tissues. Eat less food and the cells burn less fuel, and so generate fewer free radicals. Oxidative stress proceeds at a slower pace, and we live longer, just as a car will last longer in a dry climate that doesn’t promote rust. Certainly, calorie restriction suppresses free-radical production. And if fruit flies are either fed antioxidants or genetically transformed to overproduce their own antioxidants, they will live up to 50 percent longer. But similar experimental interventions seem to do nothing for rodents. The genetic evidence suggests that something more profound is happening, although this reduction in oxidative stress likely plays some role.

The characteristics that all these long-lived organisms seem to share definitively are reduced insulin resistance, and abnormally low levels of blood sugar, insulin, and insulin-like growth factor. As a result, the current thinking is that a lifelong reduction in blood sugar, insulin, and IGF bestows a longer and healthier life. The reduction in blood sugar also leads to reduced oxidative stress and to a decrease in glycation, the haphazard binding of sugars to proteins, and glycation end-products and all the toxic sequelae that follow. The decrease in insulin and IGF also apparently bestows on the organism an enhanced ability to protect against oxidative stress and to ward off other pathogens.

The most compelling evidence now supporting this hypothesis has emerged since the early 1990s from genetic studies of yeast, worms, and fruit flies, and it has recently been confirmed in mice. In all four cases, the mutations that bestow extreme longevity on these organisms are mutations in the genes that control both insulin and IGF signaling.

Geneticists and developmental biologists refer to yeast, worms, fruit flies, and mice as model organisms because they’re easy to study in the laboratory and what we learn from them about genetics will almost assuredly apply to humans as well. This is considered the fundamental principle underlying modern genetic research: once evolution comes upon a genetic mechanism that works, it reuses it again and again. Those genes that regulate the development and the existence of any single living organism will likely be used in some similar fashion in all of them. “When reduced to essentials,” as the cancer researcher J. Michael Bishop suggested in his 1989 Nobel Prize lecture, “the fruit fly and Homo sapiens are not very different.”