Piper et al. have a nice comprehensive review on IGF-I signaling and genetic control of longevity. The authors are especially interested in moving beyond the genetic phenomenology and drilling down into the mechanistic details of how single-gene mutations can radically influence lifespan in widely separated species (emphasis is mine):

Separating cause from effect: how does insulin/IGF signalling control lifespan in worms, flies and mice?

Ageing research has been revolutionized by the use of model organisms to discover genetic alterations that can extend lifespan. In the last 5 years alone, it has become apparent that single gene mutations in the insulin and insulin-like growth-factor signalling pathways can lengthen lifespan in worms, flies and mice, implying evolutionary conservation of mechanisms. Importantly, this research has also shown that these mutations can keep the animals healthy and disease-free for longer and can alleviate specific ageing-related pathologies. These findings are striking in view of the negative effects that disruption of these signalling pathways can also produce. Here, we summarize the body of work that has lead to these discoveries and point out areas of interest for future work in characterizing the genetic, molecular and biochemical details of the mechanisms to achieving a longer and healthier life.

The underscored passage brings up an issue that we’ve discussed here previously: Why is it that IGF-I pathway mutations can confer long healthy lives on organisms, even though supplementation with IGF-I is often quite beneficial, and depletion of IGF-I is often bad for individual organ systems? Indeed, according to another recent study, low doses of IGF-I appear to protect the mitochondria in aging rodents — why then do completely IGF-I-deficient animals enjoy extended and healthy lives?

It’s a mystery, and not one that this review answers — but it’s well worth thinking about, especially as we begin to consider pharmaceutical intervention in the aging process itself. When choosing between alternatives that might alter lifespan by 20-50%, it would be a damn shame to get the sign wrong.