Natural metabolite might reset aging biological clocks

As we age, our biological clocks tend to wind down. A Weizmann Institute research team has now revealed an intriguing new link between a group of metabolites whose levels drop as our cells age and the functioning of our circadian clocks – mechanisms encoded in our genes that keep time to cycles of day and night. Their results, which appeared in Cell Metabolism, suggest that the substance, which is found in many foods, could possibly help keep our internal timekeepers up to speed.

Dr. Gad Asher’s lab in the Weizmann Institute’s Biological Chemistry Department investigates circadian clocks, trying to understand how these natural timekeepers help regulate, and are affected by, everything from nutrition to metabolism. In the present study, he and his research student Ziv Zwighaft were following clues that certain metabolites called polyamines could be tied to the functioning of circadian clocks. We get polyamines from food, but our cells manufacture them as well. These substances are known to regulate a number of essential processes in the cell, including growth and proliferation. And the levels of polyamines have been found to naturally drop as we age.

Working with mice and cultured cells, they found that, indeed, enzymes that are needed to manufacture polyamines undergo cycles that are tied to both feeding and circadian rhythms of day and night. In mice engineered to lack a functional circadian clock, these fluctuations did not occur.

As the researchers continued to investigate, they discovered a sort of feedback loop, so that polyamine production is not only regulated by circadian clocks, these substances also regulate the ticking of those clocks, in turn. In cell cultures, adding high levels of polyamines more or less obliterated the circadian rhythm while maintaining low levels slowed the clock by around two hours. “The polyamines are actually an embedded part of the circadian clockwork,” says Asher.

The scientists then asked how this plays out in younger and older mice, with naturally higher or lower polyamine levels. It is known that the circadian clocks of elderly mice and run slower; concomitantly, their polyamine levels decline. The team found they could slow down the clocks in the young mice by administering a drug to inhibit polyamine synthesis. In contrast, adding a polyamine to the older mice’s drinking water made their clocks run faster than others of their age group and actually restored their function, similar to that of the young mice.

Asher and his team intend to continue investigating the function of polyamines in circadian systems. “This discovery demonstrates the tight intertwining between circadian clocks and metabolism,” says Zwighaft. “Our findings today rely on experiments with mice, but we think they might hold true in humans. If so, they will have broad clinical implications,” Asher says. “The ability to repair the clock simply, through nutritional intervention with polyamine supplementation, is exciting and obviously of great clinical potential.”

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