Healthy Life Extended in Obese Mice

Red Wine Component Inhibits Ill Effects of Excess Weight

A compound that increases the life span of yeast, worms, and fruit flies now has been shown to improve health and survival in mice fed a high-calorie diet. Treatment with resveratrol, a plant-derived molecule found in red wine, prevented many of the health consequences of obesity, even as mice gained weight. David Sinclair, who led the research, said that resveratrol “reduced the deleterious effects of a high-calorie diet. The mice were statistically similar to mice fed a lean diet.”

Photo by Graham Ramsay

David Sinclair (left) and Joseph Baur found that resveratrol, which can extend the lives of lower organisms, also keeps overfed mice healthy.

An HMS associate professor of pathology, Sinclair first identified resveratrol in a screen of molecules that enhance the activity of Sirt1, the mammalian version of the protein Sir2 that has been shown to affect life span in yeast and other lower organisms. Since then, treatment with resveratrol has been demonstrated to increase life span in worms, flies, and fish. This study, published online in Nature on Nov. 1, is the first in a series of studies by Sinclair’s group to determine whether resveratrol has the same impact on mammals.

Living Lean
So far, the most reliable way to extend life span of an organism is through caloric restriction. Since Sir2 seems to mediate the effects of caloric restriction in some lower organisms, Sinclair’s team has been investigating whether manipulating the equivalent pathway in mammals can achieve the same benefits without cutting back on food. Joseph Baur, a postdoctoral fellow in Sinclair’s lab and first author on the paper, said that studying the compound’s effects in high-fat diets also makes sense given the prevalence of overweight and its known health risks. “Obesity tends to accelerate a lot of aging-related diseases,” he said.

The study compared three groups of mice: one fed a normal diet; another that began a high-calorie, high-fat diet at middle age; and a group that began the same high-calorie diet but were simultaneously treated with resveratrol. The researchers do not yet have final numbers on the total life span of the animals, since some are still alive. But after six months of treatment, mice that received resveratrol had a significantly higher survival rate. At 114 weeks of age, 42 percent of treated mice had died, compared with 58 percent of their untreated peers fed a high-calorie diet

Resveratrol did not prevent mice from gaining weight on a richer diet, but it did prevent health problems that arise with obesity. Most noticeable were differences in the livers of the two sets of mice. Untreated mice who followed the high-calorie diet had swollen livers filled with fat deposits—the livers of the treated mice, however, looked normal. Pathologists who examined the hearts of the mice also found that the group treated with resveratrol had healthier hearts, comparable to those of normal mice. Treated mice also had lower levels of glucose and insulin in their blood and higher insulin sensitivity. In a test of motor skills, the -resveratrol-treated mice outperformed untreated overweight peers and even showed improvement with age.

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.

Missing Pieces
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

When mice were fed a high-calorie, high-fat diet, their livers were swollen and filled with fat deposits (center) compared with those of mice fed a normal diet (left). Treating mice with resveratrol while they were on a high-calorie diet, however, prevented many of the liver abnormalities (right).

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.

—Courtney Humphries

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