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 August online issue of
the Journal of Biological Chemistry.
According to co-author Thomas W. Kensler, professor in
the
Department of Environmental Health Sciences at the
Bloomberg School, 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, 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 said 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 toward
receptors of interest to the pharmaceutical industry. The
receptors include those 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, senior author and the Kitty DeGree Endowed Chair
in Toxicology at the University of Louisiana at Monroe.
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.