Antiaging protein helps set daily rhythms

WASHINGTON — A protein famous for slowing aging and increasing life span also acts as a metronome, helping coordinate metabolism and the body’s daily rhythms.

SIRT1, one of a group of proteins called sirtuins, plays roles in many cellular processes, including aging. Researchers hope that activating the protein with drugs such as resveratrol can extend life span and improve health for people, as it does in animal studies.

Now, researchers at MIT have evidence that SIRT1 may not only help determine long-term health and longevity, but it also has a hand in setting the body’s daily or “circadian” clock. The finding, reported May 31 at the Metabolism, Diet and Disease meeting, could be important for understanding how metabolism and life span are linked.

Studies of cells in laboratory dishes had suggested that SIRT1 might work with certain gears of the circadian clock in liver cells. But until now no one has shown that the protein could influence the body’s master clock in the brain, says Raul Mostoslavsky, a molecular biologist at Harvard Medical School. 

In the new study, scientists led by Leonard Guarente of MIT monitored the natural activity patterns of mice. Normally, mice’s circadian clocks run just shy of a 24-hour day, at about 23.5 hours. Mice that lack SIRT1 in their brains have a longer internal day, closer to 24 hours, Guarente said. And mice that made twice as much SIRT1 as normal in their brains had a shorter-than-usual day. Mice making five times as much SIRT1 as normal had even shorter natural days.

Amounts of SIRT1 in the brain may help the master clock, which is centered in a group of cells known as the suprachiasmatic nucleus, adjust to seasonal changes in daylight, Guarente said. Previously, some of his colleagues had noticed that mice’s circadian clocks tend to move toward 24-hour days as the mice age. The researchers wanted to know if that lengthening day had anything to do with declining SIRT1 levels in the brain’s master clock.

To find out, the team jet-lagged mice by abruptly shifting light and dark conditions in the lab by four hours. Young mice usually take only about two days to reset their circadian clocks to the new “time zone,” but old mice needed as long as eight days to adjust. In the new tests, young mice lacking SIRT1 in their brains needed about four days to adapt, indicating that SIRT1 is at least partially responsible for the ability to adjust. And old mice that make more SIRT1 than usual in their brains seemed to get over jet lag faster. The researchers also showed that levels of SIRT1 in the brain clock are tied to levels of other important clock proteins.

In a separate experiment, the team found that mice that have their circadian clocks set closest to 24-hour days live longer than mice with faster or slower-running clocks. Constantly resetting circadian clocks may cause stress that leads to aging, Guarente said.