2 replies to this topic

[olaf.larsson]

Do you have any idea by wich mechanism modification of IGF-pathway leads to extended lifespan?

[John Schloendorn]

Short answer is I don't. Longer answer is, there are pleiotropic effects on independent aging biomarkers, therefore it may be that multiple fairly independent mechanisms are at work. But this doesn't tell us much about "how" these biomarkers get affected.

[ferbeyre]

The interest in the IGF-1 pathway came originally from work in worms. Scientists discovered that worms with mutations in the gene coding for something that looks like the insulin/IGF-1 receptor lived longer. If we believe that we and worms get old for the same reasons then this work is giving us a terrific hint at aging. Interestingly, flies seem to live longer when this pathway is disabled. Both in flies and worms the insulin/IGF-1 pathway blocks the action of transcription factors of the forkhead family. These transcription factors induce genes that mediate defenses against ROS, malfolded proteins and perhaps other kinds of damage. This in in short the current answer.
This seems to work in mice. LeBouc and colleagues inactivated one copy of the IGF-1R in mice. The females lived 33% longer and the males 16% longer. These numbers are not as impressive as those reported in worms with similar mutations but we all know that mice are more complicated. This complexity, among other things, makes the insulin/IGF1 pathway more important in mammals and therefore its inactivation may have unwanted effects. In fact complete ablation of the IGF1R in mice is lethal so the longevity study by LeBouc et al was done in a mouse strain with one mutated copy and one normal copy. I’ll finish with a question myself:
Why worms, flies and perhaps mice use IGF-1 signaling to turn down genes that help to resist to stress?