Severely reducing calorie intake causes rhesus monkeys (among many other species) to live longer and prevents aging-related diseases, but how this occurs has long been a mystery.

A team of researchers co-led by Rozalyn Anderson, PhD (pictured at upper right), associate professor, Geriatrics and Gerontology, reported a research breakthrough: the process involves reprogramming of liver (hepatic) metabolism through alterations in RNA processing.

“We knew that restricting calories helps monkeys to live longer, healthier lives, but we did not understand the basis for this extraordinary finding,” said Dr. 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.”

Researchers investigated two groups of Rhesus monkeys over two years: one group with a normal diet, and an experimental group fed a diet with a 30-percent reduction in calories. Liver samples from each group were analyzed with molecular profiling techniques including next generation sequencing, mass spectrometry and nuclear magnetic resonance.

The team showed that calorie restriction caused a massive reprogramming of metabolism in the liver governed by RNA processing. The alterations included changes in pathways for proteins, carbohydrates and lipids.

"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," said Dr. Anderson.

Timothy Rhoads, PhD (pictured at lower right), assistant scientist, was first author of the study. Co-leading the effort was Ricki Colman, PhD (not pictured), assistant professor, Department of Cell and Regenerative Biology and Wisconsin National Primate Center.

The 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.

Editor's note: A version of this story was originally published on March 6, 2018 by the UW School of Medicine and Public Health.

Resources:

• Rhoads TW, Burhans MS, Chen VB, Hutchins PD, Rush MJP, Clark JP, Stark JL, McIlwain SJ, Eghbalnia HR, Pavelec DM, Ong IM, Denu JM, Markley JL, Coon JJ, Colman RJ, Anderson RM. 2018. Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys. Cell Metab. 2018 Mar 6;27(3):677-688.e5.
• "Researchers one step closer to learning how caloric restriction extends lifespan in animals," UW School of Medicine and Public Health, March 6, 2018

Photo caption (top): Dr. Rozalyn Anderson in her research laboratory. Photo credit: Clint Thayer/Department of Medicine