DALLAS - New research from the UT Southwestern Medical Center suggests that not only what we eat, but also when we eat it, could play a role in how long we live.

The idea that reducing the amount of calories you eat can extend your lifespan has been around for a while.

But recently, a team led by UT Southwestern neuroscience professors Joseph Takahashi and Carla Green discovered that caloric restriction extended mice’s life spans the most when the mice chowed down in accordance with their circadian clocks: internal timekeeping devices that make sure our cells are primed for food, sleep and activity. Their work was published in the journal Science in May.

“It really cemented this idea that aligning your eating with your circadian rhythms is so important to overall health,” said Green, who is also a Distinguished Scholar of Neuroscience at UT Southwestern.

While the research was performed on mice, future studies could yield clues about how human eating habits factor into our lifespans, as well.

Both Takahashi and Green have studied circadian rhythms for years. Takahashi, who is chair of the department of neuroscience and an investigator in the Howard Hughes Medical Institute at UT Southwestern, identified the first gene known to control circadian clocks in mammals in 1997 with his lab. He and Green, who are married, have worked together on research projects in the past.

Eight years ago, the two of them pored over previous research on caloric restriction in mice, and discovered something surprising. The mice in these experiments were being fed exclusively during the day, even though mice are nocturnal. Further, the mice were only being fed three times a week.

“That’s kind of an unusual feeding protocol, because mice don’t eat every other day,” Takahashi said.

This outdated feeding protocol prevented scientists from coming into work at odd hours to feed their mice, but it wasn’t a good representation of how mice would normally grab their meals.

So Green and Takahashi decided to test how important caloric restriction was to mice’s lifespans when the mice ate according to their normal daily rhythms.

Green and Takahashi set up their experiment with several different groups of mice. They varied what and when the mice could eat, using three different feeding factors.

The first was calorie number. In the researchers’ control group, the mice’s diet wasn’t calorie-restricted. In the remaining five groups, the mice’s calories were restricted by 30 percent.

The second was circadian rhythm alignment: how the mice’s feeding schedule aligned with when they normally ate. Some of the mice ate only at night, like they were used to, and others ate only during the day.

The third was fasting time, or how long the mice weren’t eating. In the day and night groups, some of the mice were given their food spaced out over 12 hours, and fasted for the remaining 12 hours. The other mice were given their day’s meal all at once, and binge-ate it in two hours. A final group of mice was given their food over 24 hours, with no fasting at all.

When it came to actually feeding the mice, though, the researchers hit a roadblock. To manually feed groups of mice during the day and night, they needed to be in the lab at all hours, every day, for the mice’s entire lifespan.

“We quickly realized that this would be an incredibly difficult experiment to do,” Takahashi said.

Green and Takahashi’s labs solved this problem by creating their own feeders. They designed a set of 500 feeders — one for each mouse — to dispense food pellets at a pre-programmed time. The process of creating and testing the feeders took almost two years.

Once the tech was ready, the team measured how long all the mice lived, and took a look at what genes were expressed in each mouse over time.

They found that the mice that ate fewer calories, but over a period of 24 hours — with no circadian rhythm alignment — lived only 10% longer than the control mice.

The calorically-restricted mice that ate at night over a 12-hour period lived 35% longer than the control group.

“It’s the same amount of food, the same calories,” said Victoria Acosta-Rodriguez, a postdoctoral researcher in Takahashi’s lab and an author of the study. “It’s when the mice eat that could have a huge impact on how long they live. For me, this was crazy.”

Roman Kondratov, a professor of biology at Cleveland State University, said the research provided compelling evidence for the role of fasting in extending lifespan.

“In my opinion, they provided the first direct evidence that fasting is an essential component of caloric restriction,” said Kondratov, who was not involved with the UT Southwestern study. “Reduction of … calories has positive effects, but in combination with fasting, it’s even better.”

The mice who lived longest in the study ate from 6 p.m. to 6 a.m., standard time. For humans, that would look like restricting eating to any 12-hour period while we’re awake during the day. Takahashi said there’s evidence it’s better to begin that interval earlier in the day instead of skipping breakfast.

Now the researchers look at a crucial follow-up question: Why? Figuring out exactly which clock-regulating molecules or genes in mice helped them live longer in this study could be the key to applying these findings to humans.