Inside Salk; Salk Institute

Hungering for longevity

Substantial evidence suggests that lifespan is increased if an organism restricts its daily calorie intake, a spartan regime that some say works by just making life seem longer. A team of scientists from the lab of Andrew Dillin, however, has discovered a molecular switch flipped by hunger that could not only make longevity more appetizing but identify drug targets for patients with aging-related diseases such as type 2 diabetes or cancer.

Researchers already knew that hunger promoted longevity by activating an enzyme called AMPK, which senses that food is scarce and pushes cells into a low energy state (see "Recycling cellular fuel," left). But they but didn't know what it was talking to. To define the circuitry, Dillin joined forces with Reuben Shaw, who has a long-term interest in AMPK's role in mammalian metabolism. "It was clear that one pathway that regulated cell growth was AMPK signaling," says Shaw. "Studies had also suggested that AMPK might regulate lifespan in worms. What was not known was what factors downstream of AMPK mediated those effects."

Together they searched the genome of the roundworm 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. When they fed roundworms an inhibitory RNA engineered to deplete them of CRTC1 protein, the worms' lifespan—normally about three weeks—was a whopping 40 percent longer, suggesting that AMPK retards aging by antagonizing CRTC1 activity. The group also discovered how AMPK silences CRTC1.

The good news for the burger and fries crowd is that the entire pathway and a host of interacting factors may operate similarly in worms and humans. "Whether you are talking about yeast, worms, Labradors or rhesus monkeys, dietary restriction is the best intervention we have so far against age-related conditions like neurodegeneration, cancer and diabetes," says postdoctoral researcher William Mair. "Our goal now is to use information we have derived from worm studies to find a way to treat many of these diseases with one magic bullet."

With any luck, that magic bullet will be maximally effective when taken on a full stomach.