Mammals have four insulin-like growth factor receptor genes. Earlier studies by Morris White‘s lab at Harvard Medical School had established that deletion of one of these, Irs2, caused mice to develop diabetes-like insulin resistance. The White lab (Taguchi et al., “Brain IRS2 signaling Coordinates Lifespan and Nutrient Homeostasis,” Science, July 19, 2007) has re-examined the role of Irs2 in light of recent findings about insulin signaling in the control of aging.

Heterozygous nulls of Irs2 (Irs2+/-) showed essentially normal development and metabolism in youth but in old age proved surprisingly responsive to insulin, with lower levels of glucose and insulin upon fasting. Consistent with the insulin resistance theory of aging, Irs2+/- mice lived ~17% longer than wild type controls. But where does lower insulin signaling mediate these effects? Drawing on work by Cathy Wolkow in C. elegans, Taguchi et al. tested whether decreased Irs2 levels in the brain could influence longevity by using a Cre-Lox-mediated knockout of Irs2 in broad swaths of the brain. The result was quite paradoxical— brain-specific disruption of Irs2 recapitulated the diabetes-like obesity and insulin resistance of the whole body knockouts but nevertheless extended lifespan. Moreover, like the surprisingly fast fat guy on my swimming team, these ostensibly diabetic mice were still quite energetic and active in old age, as measured through a number of arcane metabolic assays.

Another curious feature of the brain-specific Irs2 knockouts is that they have markedly smaller brains. Fortunately, another recent paper shows that a small brain per se is no impediment to a normal family life or even a career in the civil service.

These findings challenge a number of ideas about the insulin resistance theory of aging. Brain-specific disruption of Irs2 makes mice display some of the supposedly causative features of aging (obesity, insulin resistance, glucose intolerance) but yet these mice are both more active and longer-lived than age-matched wild type animals. Does this mean that regardless of the state of the body, lifespan extension is all in the head? Can we have our cake and eat it, too? Eat that, caloric restriction suckas!