August 13, 2004
Genetic Screen Identifies Compounds That Might Slow Aging

Calorie Restriction (CR) diets that reduce calories about 35% below normal have been shown to increase average life expectancy across a large assortment of animal species (though the longevity enhancing effect of CR has not yet been confirmed in humans). The life extending effect of CR has been the subject of a great deal of research attention as researchers have sought to find compounds that will throw the body into a metabolic state that is like the CR state. The hope is that a drug could provide the same life extending effects but without the need to feel perpetually hungry and to look gaunt.

Some researchers have been comparing the pattern of gene expression found in mice on CR diets with the patterns of gene expression found in mice given a variety of drugs. Some already used drugs may induce a metabolic state that will extend life expectancy by the same mechanism that CR diets extend life expectancy.

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 lack of PPARalpha prevented some of the changes in metabolism normally seen on a CR diet.

Lead author, J. Christopher Corton, PhD, with ToxicoGenomics in Chapel Hill, NC, 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 toward 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

It may turn out to be the case that some existing drugs that target PPARalpha are already benefitting their users by inducing a metabolic state that is similar to the state induced by calorie restriction.

The press release above does not indicate which cholesterol lowering drugs the researchers were using. However, my suspicion is that they were using statin drugs since statin drugs are known to activate PPARalpha. Well, Lipitor and Crestor users might be benefitting from CR-like effects on their bodies.

Share |      Randall Parker, 2004 August 13 04:14 AM  Aging Studies

RB said at August 13, 2004 10:46 AM:

PPAR alpha and gamma are known to be involved in diabetes, heart failure, inflammatory conditions such a RA, some types of cancer esp. uterine, and lipogenesis/body fat. K-111 is a very promising PPAR alpha activator in research. Given the potential for enormous profit in this drug class, more are on the way.

Keep an eye on the drug pipeline for newer PPAR alpha activators. Fenofibrate and gemfibrizole are older drugs used to treat high triglycerides, which are PPAR alpha activators. The potential side effects limit the use of these drugs for people with normal triglycerides. But fenofibrate has been used experimentally to treat rheumatoid arthritis successfully.

Joe said at August 13, 2004 8:59 PM:

Just a quick comment on the "without the need to feel perpetually hungry and to look gaunt" line. Neither are certain side effects of caloric restriction in humans. I've been doing CR for about six years, and found the hunger pretty much petered out to the same as when I was eating large amounts of calories after about three weeks. In some, or at least my own case, the weight loss can be counteracted with a little extra work. A combination of a little extra exercise, creatine, and a protein supplement actually left me with more mass than before I was on CR.

The RSG said at August 23, 2004 6:16 AM:

I normally find myself eating purely out of routine and not because I feel hungry. I wonder what would happen if I just ate once a day or something...

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