State of HMS
“We need to find out what the exact targets are that resveratrol is hitting within fat tissue and organs.”
The team also examined gene expression changes in the liver tissue of the
mice. They ran the data through a database from the Broad Institute that
groups genes into functional pathways. Through that, the team identified
153 pathways that were significantly changed by either the high-calorie diet
alone or the high-calorie diet plus resveratrol. In 144 of them, resveratrol
produced an effect opposite that of a high-calorie diet; in other words,
said Baur, “If a pathway went up in comparison to a standard diet,
resveratrol made it go down,”
and vice versa.
One of the study’s surprises is that resveratrol seems to have uncoupled the health consequences of being overweight from the fat itself. “By looking at the physiology of these mice, you would think they are lean healthy mice, but they’re fat healthy mice,” Sinclair said. The implication, he said, is that “fat isn’t necessarily bad if you can block its effects.”
Matt Kaeberlein, assistant professor of pathology at the University of Washington, said the study suggests that taking resveratrol or a similar compound could be beneficial for people who are obese or are eating a high-fat diet—which unfortunately includes a majority of people in the United States and other developed countries. But the study leaves open many questions, such as how resveratrol works and whether it can mimic the effects of calorie restriction in lean animals, which Sinclair’s lab is currently testing. The attempt to translate the pathways controlling life span in lower organisms into mammals has generated a great deal of debate. “Because the biology is so complicated, many of these pathways tie together,” said Kaeberlein. “It’s difficult to untangle.”
Sinclair believes that the compound is keeping mice healthy by triggering the same life-extending response that a strict diet does. “We’ve been going up the tree of life from yeast to worms to flies, showing this molecule extends their life and mimics calorie restriction,” he said. However, Sinclair added, “There’s a lot to figure out about how resveratrol is working.” His team used a proxy measure of Sirt1 activity to show that the enzyme was more active in mice treated with resveratrol. He doesn’t rule out that other pathways may be involved, and the team is currently testing Sirt1’s role by treating Sirt1--knockout mice.
Photo courtesy of Joseph Baur
Sinclair believes that because resveratrol is produced when plants are stressed, it may be one of many plant compounds that can trigger a “survival response” in animals that consume them. “It could be that we’ve evolved to sense molecules from the plant world.” He said that certain components of plants are not just beneficial as antioxidants or anti-inflammatories but are actually sending signals that change physiology. However, the daily dose of resveratrol given to mice in this study is the equivalent in humans of 100 glasses of wine, so its role at normal dietary levels is unknown.
Rafael de Cabo, the study’s co-senior author and an investigator at the National Institute on Aging’s Laboratory of Experimental Gerontology, said that he hopes this study will spur new methods for testing the effects of aging in the body. Using longevity as an endpoint is onerous because studies on mammals can take years or, in the case of primates, decades. “We need to find out what the exact targets are that resveratrol is hitting within fat tissue and organs,” de Cabo said, as well as understand how caloric restriction affects the entire body of an animal. Only then can scientists start to unravel the puzzle of how these interventions extend life.