Many people are interested (and invested) in finding ways to extend lifespan. Studies done in animal models support the hypothesis that caloric restriction can extend lifespan, however, the mechanism remains poorly understood. Caloric restriction involves chronic cycles of two-hour-feeding and 22-hour-fasting, raising the question of whether calories, fasting, or time of day are causing the effect.

Now, new research suggests that circadian rhythms may play a part in the effect that caloric restriction has on longevity. Eating only during their most active time of day substantially extended the lifespan of mice on a reduced-calorie diet. The results provide evidence that circadian interventions, such as timed feeding, enhance the lifespan benefits of caloric restriction.

This work is published in Science, in the article, “Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice.

The findings, obtained from hundreds of mice over four years, found that a reduced-calorie diet alone extended the animals’ lives by 10%. But feeding mice the diet only at nighttime, when mice are most active, extended life by 35%. That combination—a reduced-calorie diet plus a nighttime eating schedule—tacked on an extra nine months to the animals’ typical two-year median lifespan. For people, an analogous plan would restrict eating to daytime hours.

Joseph Takahashi, PhD [Brandon Wade/AP Images for HHMI]
The research helps disentangle the controversy around diet plans that emphasize eating only at certain times of day, said Joseph Takahashi, PhD, a professor of neuroscience at the University of Texas Southwestern Medical Center and an HHMI investigator. Such plans may not speed weight loss in humans, but they could prompt health benefits that add up to a longer lifespan.

Takahashi’s team’s findings highlight the crucial role of metabolism in aging. Scientists are just beginning to understand how calorie restriction slows aging at the cellular and genetic levels. As an animal ages, genes linked to inflammation tend to become more active, while genes that help regulate metabolism become less active. Takahashi’s new study found that caloric restriction, especially when timed to the mice’s active period at night, helped offset these genetic changes as mice aged.

Recent years have seen the rise of many popular diet plans that focus on intermittent fasting, such as fasting on alternate days or eating only during a period of six to eight hours per day. To unravel the effects of calories, fasting, and daily, or circadian, rhythms on longevity, Takahashi’s team undertook the extensive four-year experiment. The team housed hundreds of mice with automated feeders to control when and how much each mouse ate for its entire lifespan. They compared behavioral, metabolic, and molecular outcomes in the mice throughout their lifespans.

Mice housed alone with access to a running wheel were fed defined amounts of food at specific times of day. Some of the mice could eat as much as they wanted, while others had their calories restricted by 30–40%. Those on calorie-restricted diets ate on different schedules. This was done across five different calorie-restricted groups of mice that differed only in the daily pattern—not amount—of food consumed, as well as in a control group in which eating was unrestricted.

Mice fed the low-calorie diet at night, over either a two-hour or 12-hour period, lived the longest, the team discovered.

The authors further showed that calorie restriction at night ameliorated age-related changes, including increases in gene expression associated with inflammation. Thus, the authors said, maximal benefits of caloric restriction can be achieved by a fasting interval of more than 12 hours in which the time-restricted feeding occurs in an organism’s natural active phase.

The results suggest that time-restricted eating has positive effects on the body, even if it doesn’t promote weight loss. Takahashi points out that his study likewise found no differences in body weight among mice on different eating schedules—“however, we found profound differences in lifespan,” he said.

Takahashi hopes that learning how calorie restriction affects the body’s internal clocks as we age will help scientists find new ways to extend the healthy lifespan of humans. That could come through calorie-restricted diets, or through drugs that mimic those diets’ effects.

In the meantime, Takahashi is taking a lesson from his mice—he restricts his own eating to a 12-hour period. But, he said, “If we find a drug that can boost your clock, we can then test that in the laboratory and see if that extends lifespan.”

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