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Boosting Circadian Genes May Help Prevent or Treat Diseases of Aging

Update Date: Jun 20, 2013 02:30 PM EDT

The circadian clock, which corresponds closely with the 24-hour cycle of light and darkness and governs our sleeping and waking patterns, also controls other body functions like metabolism and temperature regulation. Previous experiments on animals found that health problems like obesity and metabolic disorders like diabetes can arise when this internal rhythm gets thrown off.  Observational studies on humans who work night shifts have also found an increased susceptibility to diabetes.

Now, a new study reveals that a gene called SIRT1, previously shown to protect against diseases of aging, plays a key role in controlling these circadian rhythms. Scientists from the Massachusetts Institute of Technology found that circadian function decays with aging in normal mice.  However, boosting SIRT1 levels in the brain could prevent this decay.  In contrast, loss of SIRT1 function impairs circadian control in young mice, mimicking what happens in normal aging.

The study found that the SIRT1 protein itself declines with aging in normal mice, leading researchers to suggest that SIRT1-enhancing drugs could have widespread health benefits for people.

"If we could keep SIRT1 as active as possible as we get older, then we'd be able to retard aging in the central clock in the brain, and health benefits would radiate from that," senior author Leonard Guarente, the Novartis Professor of Biology at MIT, said in a news release.

"What's now emerging is the idea that maintaining the circadian cycle is quite important in health maintenance, and if it gets broken, there's a penalty to be paid in health and perhaps in aging," Guarente added.

In 2012, researchers linked robust circadian periods with longer lifespan in mice. Guarente and his team wanted to understand how SIRT1, which has been shown to prolong lifespan in many animals, promotes longevity.

To understand SIRT1's role in circadian control, researchers created genetically engineered mice that produce different amounts of SIRT1 in the brain.  One group of mice had normal SIRT1 levels, another had no SIRT1 and two groups had extra SIRT1, wither twice or 10 times more than normal.

They found that mice lacking SIRT1 had slightly longer circadian cycles (23.9 hours) than normal mice (23.6 hours), and mice with a 10-fold increase in SIRT1 had shorter cycles (23.1 hours).

Researchers confirmed previous findings and showed that younger mice with normal SIRT1 levels readjust their circadian cycles more easily than older mice when the 12-hour light/dark cycle is interrupted. However, the study also found that mice with extra SIRT1 do not suffer the same decline in circadian control as they age.

An increasing umber of studies suggest that being able to respond to large or small disruptions of the light/dark cycle is important to maintaining healthy metabolic function, researchers explain.

"Essentially we experience a mini jet lag every day because the light cycle is constantly changing. The critical thing for us is to be able to adapt smoothly to these jolts," Guarente says. "Many studies in mice say that while young mice do this perfectly well, it's the old mice that have the problem. So that could well be true in humans."

If the findings can be replicated in humans, researchers believe enhancing circadian function, either by delivering SIRT1 activators in the brain or developing drugs that enhance another part of the circadian control system, could treat or prevent diseases associated with aging.

The findings are published in the journal Cell.

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