Keeping a check on how many calories we consume helps to keep us looking trim from the outside. New research by collaborating scientists in the U.S. and Spain suggests that restricting calorie intake can also help to keep us more youthful on the inside by preventing age-related changes in how the natural rhythmical biological clocks within our cells work to control essential functions.

The two sets of studies in mice, by the team of Paolo Sassone-Corsi, Ph.D., at the University of California, Irvine (UCI), and by a research group headed by Salvador Aznar Benitah, Ph.D., at the Barcelona Institute of Science and Technology, have found that a low-calorie diet prevents age-related changes in the normal daily rhythmic oscillations in liver cell metabolism and adult stem cell functioning. They report their work in separate papers in the journal Cell that are entitled, “Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging” and “Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Stress.”

It’s already known that the process of aging and circadian rhythms are linked, while restricting calorie intake in fruit flies extends the insects’ lifespan. Work by the UCI and Barcelona Institute of Science and Technology researchers has now demonstrated that calorie restriction (CR) can influence the interplay between circadian rhythms and aging processes in cells.

The liver operates at the interface between nutrition and energy distribution in the body, and metabolism is controlled within cells under circadian control, explains the UCI team, led by Dr. Sassone-Corsi, director of the Center for Epigenetics & Metabolism. To investigate the effects of aging on circadian control of metabolism at the cellular level, the team first looked at the effects of aging on rhythmic function and circadian gene expression in the liver cells of both young mice (aged 6 months) and older mice (aged 18 months) that were an unrestricted diet. They found that although both young and old mice demonstrated a circadian-controlled metabolic system, the mechanisms that control gene expression according to the cells’ usage of energy was altered in the old mice. In effect, their liver cells processed energy less efficiently.

However, when these older mice were fed a diet with 30% fewer calories for six months, the biological clock was reset, and circadian functions were restored to those of younger mice. “…caloric restriction works by rejuvenating the biological clock in a most powerful way,” Sassone-Corsi said in a statement. “In this context, a good clock meant good aging.”

For the companion study, the Barcelona Institute of Science and Technology team worked with professor Sassone-Corsi’s team and with colleagues at the Catalan Institution for Research and Advanced Studies, the Universitat Pompeu Fabra, and the Spanish National Center for Cardiovascular Research to compare circadian rhythm functionality in skin stem cells in both young and old mice. Again, stem cells in older mice did retain a circadian rhythm, but exhibited significant reprogramming away from the expression of genes involved in homeostasis to those involved with tissue-specific stresses, such as DNA damage. The stem cells were effectively rewired to match tissue-specific age-related traits.This age-related rewiring of circadian functionality was again prevented by long-term CR in older mice.

“The low-calorie diet greatly contributes to preventing the effects of physiological aging,” commented Benitah. “Keeping the rhythm of stem cells 'young' is important because in the end these cells serve to renew and preserve very pronounced day–night cycles in tissue. Eating less appears to prevent tissue aging and, therefore, prevent stem cells from reprogramming their circadian activities.”

Future studies will be needed to identify which components are responsible for the aging-related rewiring of the daily fluctuating functions of stem cells and to find out whether they could be targeted therapeutically to maintain the proper timing of stem cell function during aging in humans, the Spanish team suggests in their published paper.

“These studies also present something like a molecular holy grail, revealing the cellular pathway through which aging is controlled,” Sassone-Corsi added. “The findings provide a clear introduction on how to go about controlling these elements of aging in a pharmacological perspective.”

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