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Circadian research shows promise of a natural molecule in healthy aging

Jake Chen, PhD; Eugenia Mileykovskaya, PhD; Sally Yoo, PhD; William Dowhan, PhD; Kazunari Nohara, PhD; and Venkata Mallampalli pose inside Chen’s Lab. Nohara and Mallampalli served as the first and second author of the paper.
Jake Chen, PhD; Eugenia Mileykovskaya, PhD; Sally Yoo, PhD; William Dowhan, PhD; Kazunari Nohara, PhD; and Venkata Mallampalli pose inside Chen’s Lab. (Photo by Dwight Andrews/UTHealth)

A collaborative team of investigators in the Department of Biochemistry and Molecular Biology at McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), led by associate professor Zheng (Jake) Chen, PhD, and assistant professor Seung-Hee (Sally) Yoo, PhD, used a naturally found molecule to fortify mitochondrial respiration in skeletal muscle in order to promote healthy aging against metabolic challenges. The team’s research is featured in Nature Communications.

“As we age, circadian rhythms become dampened or weaker,” Chen said. “So now the question is, if there’s a causal relationship between weaker circadian rhythms and age related decline, can we actually manipulate, or enhance, circadian rhythms in aged humans to achieve the goal of having a healthier aging process.”

The team’s approach was to take a small pharmacological agent, in this case Nobiletin, a flavonoid found in citrus peels, which has previously shown as capable of enhancing circadian rhythms, to determine whether that agent was able to improve the aging process in experimental mice.

“Nobiletin is actually already in our diet, but not to the amount that it’s going to be significant,” Chen said. In order to find a potent role for Nobiletin, the team treated naturally aged mice with the compound by inserting it into two different types of diets, normal and high fat.

Their study found that for aged mice in regular diets, Nobiletin improved aging conditions. When the aged mice were subjected to the high-fat diet, a metabolic challenge occurred, and more pronounced effects on healthy aging were observed. Chen said the research showed robust improvement in several parameters including energy, metabolism, sleep, circadian behavior, and several other parameters relating to skeletal muscle functions.

The next step was to focus on the skeletal muscle, the largest metabolic organ in our body, and study the physiological and molecular effects of Nobiletin on muscles. The team noticed that the circadian gene expression was enhanced, specifically in the mitochondria, prompting the use of a pair of independent global surveys, one of the entire gene sequence in skeletal muscle and another on mitochondrial respiration improvement, to zero in on mitochondrial respiration in skeletal muscle.

“Mitochondria’s main function is to produce energy like ATP,” Chen said. “We found that in many of the different assays, the ATP level was enhanced. However, the one problem with ATP production by mitochondria is that it generates deleterious byproducts.”

However, with the Nobiletin study, Chen and the team found that while ATP production was up, the byproduct level was down, which is not typically the case.

“This is why we say Nobiletin fortifies mitochondrial respiration, with credit to Sally for coming up with word to beautifully capture the essence of our finding.” Chen said. “It doesn’t just optimize. It doesn’t just enhance or increase. It fortifies. The reason is that one of the main mechanisms that we uncovered is that Nobiletin promotes mitochondria respiratory supercomplex formation. We are fortunate to have a leading expert, Bill Dowhan, PhD, and his team, including Eugenia Mileykovskaya, PhD, to help figure this out.”

The respiratory chain has several protein complexes, but they are not randomly located, so they tend to form super complexes. The formation of super complexes facilitates electrons shot between different complexes to increase ATP production, and it tightens up the structure to prevent leakage of radicals, which directly leads to reactive oxygen species formation.

The team also observed that these specific effects are dependent and specific to a certain time of the day, meaning the effects rely on circadian time.

“We now have this small molecule (Nobiletin) that can enhance circadian rhythm oscillation,” Chen said. “What that means is that you can make circadian rhythm machinery more robust and do things at the right time. The effect in aging is that it’s going to increase aging circadian rhythm and that will promote healthier aging.”

Armed with two recent federal grant awards in part attributable to this research, the team aims to deepen the mechanistic investigation to discover how exactly circadian rhythm drives metabolic processes in different tissues.

“Here we’re focusing on skeletal muscle, but circadian rhythm is everywhere,” Chen said. “Going beyond metabolism, we’re going to move to cognition, memory, or neural degeneration. That is another key area of research that’s coming up, and that’s also being supported. This is a natural product that is proven safe in both human and mice, so I think there’s a pretty good potential to take the next step and go beyond mice.”

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