After healthy human cells convert nutrients into energy, there are some molecules left over. Some of these are useful and are integrated into the cell, but others are highly reactive and ready to wreak havoc. Called free radicals, these molecules have an unpaired electron in their atomic structure. To stabilize themselves, free radicals donate or steal an electron from whatever other molecule is close by, setting off a cascade of chemical reactions that can eventually damage DNA and other critical cellular components.

Luckily, cells can normally keep free radicals under control. But when exposed to damaging agents such as sunlight, cigarette smoke, pollution, or radiation, so many free radicals are formed in cells that normal control mechanisms can’t get rid of all of them. Because of the potential damage they can do, such free radicals are considered bad guys in biology. Antioxidants, molecules that can block the formation of free radicals, have become popular ingredients in dietary supplements, hailed as a way to prevent diseases from cancer to Alzheimer’s. But two new pieces of research by School of Medicine scientists show how important free radicals are to normal cell biology. And too many antioxidants, the papers suggest, can thwart important signaling pathways. It might be time to give the bad guys a break.

Over the past decade, scientists have shown that blocking a cell-signaling pathway called TOR extends the lifespan of yeast, roundworms, fruit flies, and mice. Gerald S. Shadel, Ph.D., professor of pathology and genetics, suspected that mitochondria—the energy-generating powerhouse of cells—played a role in this longevity. After all, when mitochondria finalize the metabolism of glucose, they make reactive oxygen species (ROS), which are free radicals centered around oxygen atoms, and ROS are already known to affect aging.

“Reactive oxygen species in the mitochondria have been implicated in aging for many years,” says Shadel. “These molecules are known to cause dysfunction of cells and tissues over time.”

But when Shadel and members of his lab looked at a strain of yeast in which tor signaling is reduced, he discovered something surprising. As the team reports in the June issue of Cell Metabolism, the lowered TOR signaling that increases this yeast strain’s lifespan actually causes their mitochondria toproducea small burst of ROS. To see if these ROS molecules were necessary for the yeast’s longevity or just a side effect, Shadel blocked ROS production in the yeast’s mitochondria, and found that the yeast lived no longer than usual. But if mitochondrial ROS production was increased optimally, it was enough to extend the cells’ lifespan on its own.

Shadel surmises that a small amount of ROS molecules prepares a cell to get rid of damaging ROS in the future—similar to the way a vaccine works. It’s when a cell is bombarded with high numbers of ROS molecules at once that they cause damage. “The cell remembers these reactive oxygen species and mounts a response against them better next time,” he says.

And lifespan isn’t the only way that low levels of ROS may be helpful, according to another recent study led by Sabrina Diano, Ph.D., associate professor of obstetrics, gynecology, and reproductive sciences and neurobiology.

While researching neurons in the brain that regulate eating, Diano and senior author Tamas L. Horvath, D.V.M., Ph.D., the Jean and David W. Wallace Professor of Biomedical Research, discovered that ROS molecules play a vital role in controlling hunger. “When these neurons were active, and the mice would stop eating, the ROS levels were higher,” says Diano. “It was just an incidental observation, but we decided to look at it more closely.”

ROS molecules are produced when the body metabolizes food, so it makes sense that they might be involved in feeding, but Diano, Horvath, and colleagues discovered that they play a vital role. When there are no ROS molecules around a particular set of neurons in the brain, the group found, these neurons send a hunger signal to the rest of the body. But when these neurons are exposed to ROS, they send a satiety signal that tells the body it’s time to stop eating. 
“When you eat a large meal, it’s actually very important to get a surge of reactive oxygen species,” says Horvath. “That’s the signal to stop eating.”

In their most recent work, published in the August issue of Nature Medicine, the Diano and Horvath team show how this pathway goes awry in animals that overeat. These animals’ bodies, the researchers found, start to generate cellular organelles called peroxisomes that eliminate ROS from cells, so the ROS molecules no longer build up enough to signal satiety. “The body adapts and you can no longer feel satiety anymore,” Horvath says.

But fortunately this effect is reversible. When the scientists blocked peroxisome function in mice on a high-fat, high-carbohydrate, “junk food” diet and simultaneously increased the amount of ROS in the neurons, “the neurons became active again, and the animals stopped eating,” says Diano.

The new research suggests that perhaps we shouldn’t rush to rid our bodies of free radicals. Sometimes they’re necessary, and Shadel says the next step is to devise new ways to keep free radicals in balance without losing their benefits. “Yes, there are many diseases caused by reactive oxygen species, and in those circumstances, antioxidants are beneficial,” he says. “But now we’re seeing other cases where they can be detrimental. There’s a sweet spot to hit where you’re eliminating stress but not normal signaling.”