Scientists Identify Compounds That Mimic Calorie Restriction

Investigators from an international consortium of research institutes, including the Johns Hopkins Bloomberg School of Public Health, have identified compounds that mimic the effects of a low calorie diet without changing the amount of essential nutrients. The researchers believe it may be possible to design drugs that imitate many of the beneficial effects of calorie restriction resulting in the prevention of diseases, such as diabetes, heart disease and cancer, which are more common in people who are overweight. Their findings are published in the current online issue of the Journal of Biological Chemistry.

Co-author Thomas W. Kensler, PhD, a professor of Environmental Health Sciences at the Johns Hopkins Bloomberg School of Public Health, explained that calorie restriction has intrigued scientists for decades because it increases the life span of almost every species studied. In mammals, calorie restriction suppresses many diseases associated with the obesity epidemic. However, the mechanisms by which calorie restriction suppresses these diseases are not known.

Lead author, J. Christopher Corton, PhD, with ToxicoGenomics in Chapel Hill, N.C., examined the genetic changes that occur during calorie restriction in mice that were fed a diet for one month containing about 35 percent fewer calories than a normal diet. He explained that these genetic changes, which are referred to as a transcript profile, can be used like a bar-code to distinguish a unique profile from other genetic changes that occur in the body. The researchers compared the profile of calorie restriction with the profiles produced by compounds known to have some properties similar to calorie restriction, including the ability to suppress factors that lead to a number of diseases.

The compounds that shared the greatest similarities in the bar codes included those that have activity towards receptors of interest to the pharmaceutical industry. The receptors include those that are targeted by drugs used to treat high cholesterol and triglyceride levels. One of the receptors, called PPARalpha, is a target for drugs that are currently used to treat high cholesterol and triglyceride levels in people at risk for heart disease.

The investigators also compared responses in normal mice to mice that lack a functional PPARalpha to determine if PPARalpha was directly involved in any of the responses that are induced by calorie restriction. They found that the PPARalpha-mutant mice lack many of the characteristics of calorie restriction, including changes in genes that may play important roles in heart disease and cancer. Calorie restriction is also known to protect animals from chemical exposure, and the investigators found that the protection afforded by calorie restriction in normal mice was lost in PPARalpha-mutant mice.

“PPARalpha may be one of a handful of receptors that play important roles in mediating the beneficial effects of calorie restriction. Our findings could be used to take a rational approach to designing drugs that mimic beneficial aspects of calorie restriction,” said Harihara M. Mehendale, PhD, senior author and professor and Kitty DeGree Endowed Chair in Toxicology at the University of Louisiana at Monroe.

“Mimetics of Calorie Restriction Include Agonists of Lipid-activated Nuclear Receptors” was written by J. Christopher Corton, Udayan Apte, Steven P. Anderson, Pallavi Limaye, Lawrence Yoon, John Latendresse, Corrie Dunn, Jeffrey I. Everitt, Kenneth A. Voss, Cynthia Swanson, Carie Kimbrough, Jean S. Wong, Sarjeet S. Gill, Roshantha A. S. Chandraratna, Mi-Kyoung Kwak, Thomas W. Kensler, Thomas M. Stulnig, Knut R. Steffensen, Jan-Ake Gustafsson and Harihara M. Mehendale.

The study was supported by grants from the National Institute of Environmental Health Sciences, Louisiana Board of Regents Support fund, Marie Curie Fellowship of the European Community program Human Potential, Swedish Science Council and KaroBio.