In a study on mice, a team of scientists have found how the biological circadian clock mechanism in animals corresponds with processes that control aging and metabolism.
The findings by researchers at Washington University School of Medicine in St. Louis and Northwestern University can explain why the weakening of the circadian rhythm with age could contribute to age-related disorders, such as insulin resistance and type 2 diabetes.
Advertisement"Our study establishes a detailed scheme linking metabolism and aging to the circadian rhythm. This opens the door to new avenues for treating age-related disorders and ways to restore a healthy daily circadian rhythm. It could also yield new interventions to alleviate metabolic disorders such as obesity and diabetes," said one of the lead authors, Dr. Shin-ichiro Imai.
In an earlier study, Imai demonstrated that a gene called SIRT1 was at the centre of a network that regulates aging.
SIRT1 coordinates metabolic reactions throughout the body and manages the body's response to nutrition. The gene is activated when calories are restricted below normal, which has been shown to extend the life spans of some laboratory animals.
"Under nutritional scarcity, SIRT1 may delay aging and extend life span to assure survival until food becomes more readily available," explained Imai.
The researcher had earlier shown that interfering with the circadian clock of mice led to metabolic complications, including obesity and type 2 diabetes.
The new research has linked the circadian clock to SIRT1 through a key metabolite that serves as the energy currency of the body.
Thus, the researchers 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 as well as influence aging and longevity.
The new finding points potentially to innovative ways to correct metabolic disorders and improve health as people age.
In the study on laboratory 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.
"Seeing this striking abnormality in the NAD levels was like discovering the cause of a disease in a patient after running a blood test," said one of the co-authors of the study.
The researchers found that the NAD rhythm was linked to the daily rise and fall of the activity of "clock" genes, the genes that serve as the gears that run the body's internal clock.
Also, 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.
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. Because NAD levels reflect nutrition and energy levels, NAD's link to the circadian and aging mechanisms makes them sensitive to the nutritional status of the organism," said Imai.
The study has been published in the online edition of the journal Science.
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