Roundworms low on insulin tend to live longer, and a new study identifies a protein that helps explain the effect. Low insulin levels increase this protein's activity in the gut, where the protein can extend longevity by helping cells avoid damage.

Humans and other mammals have a similar group of proteins, suggesting that insulin probably affects the proteins' activity in people as well, the researchers say. The discovery could help explain why calorie-restricted diets extend life span in animals and why diabetes reduces life expectancy.

"The link with insulin is tantalizing," says study leader T. Keith Blackwell of the Joslin Diabetes Center at Harvard Medical School in Boston. However, "we'll need more research to show if this [link] has anything to do with dietary restriction or diabetes."

Scientists have known since the 1930s that yeast and many animal species live 30 to 50 percent longer when they are fed a spartan diet, containing about one-third fewer calories than normal. One frequently observed effect of this extreme diet is an improved sensitivity to insulin. This sensitivity causes the body to produce less of the hormone. At the other extreme, people with type 2 diabetes have poor insulin sensitivity, so their bodies ramp up insulin production to compensate.

Blackwell and his colleagues studied how insulin regulates a protein called SKN-1 in roundworms. This protein orchestrates a family of detoxification enzymes that protect cells by removing free radicals—vandals of the cellular world that can shorten life span. The team found that insulin decreases the activity of SKN-1, throttling down these detoxification enzymes and leaving cells less protected.

Boosting SKN-1 levels by adding extra copies of the gene for SKN-1 extended the worms' life spans by 25 to 30 percent, the researchers report in the March 21 Cell.

"The fact that having more SKN-1 around is sufficient to extend life span is a very important result," comments Matt Kaeberlein, a longevity researcher at the University of Washington in Seattle. "That's proof that SKN-1 is really involved in aging."

A study published last year in Nature did show that SKN-1 within nerve cells in roundworms' heads is essential for the life-extending effects of calorie restriction (SN: 6/30/07, p. 414), but the new study shows a variant of the protein in the gut influences aging in a different way—one that's controlled by insulin.

One explanation for why insulin appears to shorten an animal's life span could be that insulin requires an oxidizing chemical environment-friendly to free radicals—to do its primary function of regulating blood sugar. To disarm free radicals, the detoxification enzymes create the opposite environment, a reducing one. So the body might be trading a bit of cellular damage for the sake of improving insulin's ability to do its job, Blackwell suggests.

The mammalian versions of SKN-1 could provide new targets for researchers trying to develop drugs that extend life span, Blackwell says.

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