A multidisciplinary research team at the University of Wisconsin-Madison has uncovered new clues about calorie restriction and how it works to delay aging and age-related diseases.

The study, “Caloric Restriction Engages Hepatic RNA Processing Mechanism in Rhesus Monkeys,” was published today in Cell Metabolism with first author, Assistant Scientist Timothy Rhoads, PhD. The study's focal point was a group of monkeys from the Aging and Caloric Restriction Study led by Assistant Professor Ricki Colman, PhD, at the Wisconsin National Primate Research Center, and Associate Professor of Medicine Rozalyn Anderson, PhD.

“We knew that restricting calories helps monkeys to live longer, healthier lives, but we did not understand the basis for this extraordinary finding,” said Anderson, the study's corresponding author. “We are now at the beginning of a very exciting journey to discover how calorie restriction works on the molecular level.”

The research team looked at two groups of Rhesus monkeys over two years. One group of monkeys had a normal diet while the experimental group ate a diet with 30 percent fewer calories. The team focused on liver – the tissue where all the nutrients from the diet are processed and the major player in establishing metabolic health.

The researchers used a range of molecular profiling techniques including next generation sequencing, mass spectrometry and nuclear magnetic resonance, cataloguing over 20,000 molecules in the liver tissue. Data were analyzed using complex statistical approaches including machine learning techniques to find out what calorie restriction does and how that might change aging.

The team showed that calorie restriction caused a massive reprogramming of metabolism in the liver that included pathways for proteins, carbohydrates and lipids. Most surprising was how calorie restriction accomplished these changes – harnessing completely different control mechanisms to create change across metabolism, most notably, RNA processing.

“The study showed a highly integrated reprograming of hepatic metabolism by calorie restriction and that RNA processing was specifically engaged to exert these changes,” said Anderson. “Although for some it will not be a surprise that metabolism is important to how (calorie restriction) works, we are talking about a dietary intervention after all. What is more interesting is the recent work showing profound metabolic effects in a whole host of age-associated diseases that are otherwise unrelated. We think that the metabolic response to (calorie restriction) is at the very heart of its ability to delay aging and the onset of age-related disease.”

This multidisciplinary study involved experts from UW-Madison departments, institutes and centers across campus, including departments of medicine, biochemistry, biomolecular chemistry, biostatistics and medical informatics, the Wisconsin Institutes for Discovery, the Biotechnology Center, the Genome Center of Wisconsin, the Wisconsin National Primate Research Center and the William S. Middleton Memorial Veterans Hospital.