CRTC1 in the Calorie Restriction Response
The investigation of the mechanisms of calorie restriction continues apace. Here, researchers "report for the first time that deactivation of a protein called CRTC1 in roundworms increases their lifespan, most likely mediating the effects of calorie restriction. Previously, researchers knew hunger promoted longevity by activating an enzyme called AMPK, which senses that food is scarce and pushes cells into a low energy state. ... We knew AMPK was a major energy sensor but didn't know what it was talking to. Our goal was to understand the genetic circuitry that registered that response. ... It was clear that one pathway that coordinated metabolism with growth in response to nutrients was AMPK signaling. Studies had also suggested that AMPK might regulate lifespan in worms. What was not known was what factors downstream of AMPK mediated those effects. ... they searched the genome of Caenorhabditis elegans for likely AMPK targets, and identified one suspect encoding a protein called CRTC1, which was expressed at the same time and place as AMPK. To determine if CRTC1 played any role in lifespan, the team fed worms an inhibitory RNA engineered to deplete them of CRTC1 protein. When they measured the worms' lifespan-normally about 3 weeks-they found that worms fed the anti-CRTC1 RNA lived a whopping 40% longer, suggesting that AMPK retards aging by antagonizing CRTC1 activity. ... AMPK deactivated CRTC1 by adding phosphates to a specific region of the CRTC1 protein, an effect equivalent to eliminating CRTC1 altogether. Likewise, when the worms were fed an inhibitory RNA depleting them of an enzyme that lops off the CRTC1 phosphates, they lived longer, showing that AMPK and the lopper - known to scientists as calcineurin - determine lifespan by controlling the extent to which CRTC1 is phosphorylated."