Body’s 24-hour clock turns gears of metabolism, aging

All animals, including humans, have an internal 24-hour clock or circadian rhythm that creates a daily oscillation of body temperature, brain activity, hormone production and metabolism.

Studying mice, researchers at the School of Medicine and Northwestern University found how the biological circadian clock mechanism communicates with processes that govern aging and metab-olism.

Shin-Ichiro Imai


Reported in Science, their findings can potentially explain why the waning of the circadian rhythm with age could contribute to age-related disorders such as insulin resistance and type 2 diabetes.

“Our study establishes a detailed scheme linking metabolism and aging to the circadian rhythm,” said one of the lead authors, Shin-ichiro Imai, M.D., Ph.D., associate professor of medicine and of developmental biology. “This opens the door to new avenues for treating age-related disorders and ways to restore a healthy daily circadian rhythm. It also could yield new interventions to alleviate metabolic disorders such as obesity and diabetes.”

Imai previously demonstrated that a gene called SIRT1 was at the center of a network that regulates aging. A form of the gene is found in every organism on earth, and seven forms of the gene exist in humans.

SIRT1 influences glucose breakdown and production, cholesterol metabolism, fat burning, and insulin sensitivity. Increasing the activity of proteins related to SIRT1 extends the life span of yeast, worms and flies. SIRT1 is activated when calories are restricted below normal, which has been shown to extend the life spans of some laboratory animals until food becomes more readily available.

Imai’s collaborator in the study, Joseph Bass, M.D., Ph.D., assistant professor of medicine and neurobiology at Northwestern, earlier demonstrated that interfering with the circadian clock of mice led to metabolic complications, including obesity and type 2 diabetes.

Now their joint research, led by Kathryn Moynihan Ramsey, Ph.D., at Northwestern, and Jun Yoshino, M.D., Ph.D., a postdoctoral research associate, and Cynthia S. Brace, senior research technician, both at WUSTL, has linked the circadian clock to SIRT1 through a key metabolite that serves as the energy currency of the body. As a result, they have defined a biochemical mechanism by which the body’s metabolic and nutritional status can directly drive the oscillation of the body’s daily clock and influence aging and longevity.

In mice, the researchers found a daily oscillation of the metabolite NAD (nicotinamide adenine dinucleotide), an important compound that is the body’s way of exchanging energy and moving it where it’s needed. Previously, scientists believed the amount of NAD in cells stayed fairly constant.

The researchers found that this NAD rhythm was linked to the daily rise and fall of the activity of “clock” genes, those that serve as the gears that run the body’s internal clock. They discovered that the clock genes directly interact with a biochemical process that produces NAD.

NAD is required for SIRT1 to function, suggesting that SIRT1 activity increased and decreased along with NAD oscillation in the mice. Since SIRT1 is known to inhibit the clock genes, the cycle of its activity feeds back into the clock mechanism.

Studying the mice under controlled conditions of light and dark, the researchers established the details of the NAD-SIRT1-clock gene loop and showed that it functions in liver and fat cells.

“We showed that this feedback cycle is driven by NAD,” Imai said. “Because NAD levels reflect nutrion and energy levels, NAD’s link to the circadian and aging mechanisms makes them sensitive to the nutrional status of the organism.”