Circadian rhythm disruption may accelerate aging, drive cardiometabolic disease

Sleep-wake circadian rhythm is an important mechanism to maintain biological timekeeping, and disruptions from light exposure, dietary challenges and timing of food intake can have cardiometabolic consequences, according to a speaker.

The circadian clock is the “internal biological pacemaker” that governs 24-hour rhythms in sleep/wake cycles, food intake, and endocrine and metabolic pathways that are needed to maintain normal physiology and organismal homeostasis, Selma Masri, PhD, assistant professor in the department of biological chemistry at the Center for Epigenetics and Metabolism at the University of California, Irvine, said during a plenary lecture for the virtual American Society for Bone and Mineral Research Annual Meeting. Altered behavior such as shift work or exposure to light at night, dietary challenges such as high-fat and high-sugar diets, and timing of food intake can disrupt circadian function, she said. The consequences of that disruption can affect every part of the body — changes in mood and sleep regulation, risks for metabolic syndrome and cancer, and even altered health span and accelerated aging.

“We have hardwired into our genetic information the molecular machinery that dictates biological rhythms,” Masri told Healio in an interview before the lecture. “This means you have genes that express proteins that can keep and maintain biological time. This machinery exists in every cell in the body."

Clock disruptions and health risks

Light is one of the major cue that “activates” the circadian clock to the brain, and this maintains synchrony with all other clocks in the body, Masri said. The concept of multiple clocks in the body was first explored by multiple researchers, including Paolo Sassone-Corsi, PhD, a mentor to Masri best known for his work in dissecting transcriptional and epigenetic mechanisms that regulate circadian function. Sassone-Corsi died unexpectedly in July.

“Paolo's lab and many other groups contributed to the fundamental observation that clocks do not just exist in the brain,” Masri said. “The central clock in the brain is activated by light, and this central clock then regulates secretion of several hormones and other factors that dictate biological timekeeping to all tissues in the body. There are clocks in every single tissue, whether it’s the muscle, the heart, the gut liver, kidney.”

Epidemiologic data suggest that disruptions to the circadian clock, such as night shift work, are associated with increased risks for cardiometabolic conditions, such as metabolic syndrome and type 2 diabetes, as well as hormone-driven cancers, poor sleep and mood dysregulation.

Light exposure at night in general can also be detrimental, Masri said.

“We have a dramatic increase in electric light exposure, and that means that after the sun goes down, we still have light exposure from indoor lighting, computers and devices,” Masri said. “All of that is a mechanism to disrupt the clock.”

Masri’s laboratory is also studying how disruption of the circadian clock in the intestine accelerates colorectal cancer by deregulating key signaling pathways that control cell growth and metabolism, she said.

Gut microbiome, drug metabolism

The overall composition of the gut microbiome also has a circadian rhythmic quality, Masri said.

“The composition of the gut microbiome is linked to the clock, but eating a high-fat diet and timing of meals impacts gut microbiome health, so there is a double whammy there,” Masri said. “Behavioral rhythms impact the composition and health of the gut microbiome.”

Additionally, research from the field of chronotherapy — typically involving the timing of drug administration — suggests there may be an ideal window when drugs could have the most efficacy, based on clock rhythms.

“We should be considering how drugs are metabolized,” Masri said. “Also, what are the targets of those drugs? If they target a specific metabolic enzyme, and that enzyme is active during a specific circadian period, we should be giving those drugs at the time of day where they have the most efficacy.”

Prevention key

A focus on reducing disruptions to circadian rhythms as a preventive approach to reducing risks for cancer and metabolic diseases, Masri said. This can include asking simple questions about sleep health, light exposure, diet quality and timing of meals.

Masri said the molecular factors that control these circadian processes are under active investigation.

“Specifically, in models of colorectal cancer that are being studied in our laboratory, the impact of nutrition, timing of food intake, and the role of the gut microbiome are being dissected in terms of their impact on the circadian clock and metabolism in the intestine,” Masri said.