Insulin exposure and aging theory.

Abstract

The underlying mechanism of calorie restriction (CR) extension of mammalian life spans operates by altering the rate of decline in reserve capacity (with time) as well as the exposure to growth stimulus, two mechanisms that seem to be related to the central genetically determined mechanism that controls mammalian life span over a 50-fold range. While genetic control is principally exerted at the level of metabolic rate and entrained protective defenses, CR appears to alter the rate of decline in reserve capacity and the exposure to growth stimulus without appreciable alteration of metabolic rate. CR accomplishes this by lowering the nutritionally driven level of insulin exposure, which in turn lowers overall growth factor exposure, improves age-declining maintenance of mitochondrial maximal function, and maintains a longer-term favorable balance of the insulin:growth hormone antagonism. Obtaining the 'halved' insulin exposure in calorie-restricted animals (relative to ad libitum fed) can be specifically targeted in non-obese ad libitum fed humans by multiple techniques, a situation that may confer most of the life span extension of CR without restricting calories. The prospect for even further extension of the human life span is considered.