Source: Economist
Date: 20 April 2006

Eat less, live more

How to live longer— maybe

DIETING, according to an old joke, may not actually make you live longer, but it sure feels that way. Nevertheless, evidence has been accumulating since the 1930s that calorie restriction—reducing an animal's energy intake below its energy expenditure—extends lifespan and delays the onset of age-related diseases in rats, dogs, fish and monkeys. Such results have inspired thousands of people to put up with constant hunger in the hope of living longer, healthier lives. They have also led to a search for drugs that mimic the effects of calorie restriction without the pain of going on an actual diet.

Amid the hype, it is easy to forget that no one has until now shown that calorie restriction works in humans. That omission, however, changed this month, with the publication of the initial results of the first systematic investigation into the matter. This study, known as CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), was sponsored by America's National Institutes of Health. It took 48 men and women aged between 25 and 50 and assigned them randomly to either a control group or a calorie-restriction regime. Those in the second group were required to cut their calorie intake for six months to 75% of that needed to maintain their weight.

The CALERIE study is a landmark in the history of the field, because its subjects were either of normal weight or only slightly overweight. Previous projects have used individuals who were clinically obese, thus confusing the unquestionable benefits to health of reducing obesity with the possible advantages of calorie restriction to the otherwise healthy.

At a molecular level, CALERIE suggests these advantages are real. For example, those on restricted diets had lower insulin resistance (high resistance is a risk factor for type 2 diabetes) and lower levels of low-density lipoprotein cholesterol (high levels are a risk factor for heart disease). They showed drops in body temperature and blood-insulin levels—both phenomena that have been seen in long-lived, calorie-restricted animals. They also suffered less oxidative damage to their DNA.

Eric Ravussin, of Louisiana State University in Baton Rouge, who is one of the study's authors, says that such results provide support for the theory that calorie restriction produces a metabolic adaptation over and above that which would be expected from weight loss alone. (He also points out that it will be a long time before such work reveals whether calorie restriction actually extends life.) Nevertheless, such metabolic adaptation could be the reason why calorie restriction is associated with longer lifespans in other animals—and that is certainly the hope of those who, for the past 15 years, have been searching for ways of triggering that metabolic adaptation by means other than semi-starvation.

The search for a drug that will stave off old age is itself as old as the hills—as is the wishful thinking of the suckers who finance such efforts. Those who hope to find it by mimicking the effect of calorie restriction are not, however, complete snake-oil salesmen, for there is known to be a family of enzymes called sirtuins, which act both as sensors of nutrient availability and as regulators of metabolic rate. These might provide the necessary biochemical link between starving and living longer.

An elixir of life?

Boosting the activity of sirtuins in yeast, nematode worms and fruitflies (three rapidly reproducing stalwarts of biological laboratories) does indeed result in longer lifespans. In 2003 a team led by David Sinclair of Harvard Medical School described 19 plant-derived molecules that activate sirtuins in yeast. One of these molecules, resveratrol, is found in red wine—which created excitement among those who think that a wine-rich diet is part of the explanation for the healthy old age apparently enjoyed by many who live in southern Europe.

In February, a group led by Dario Valenzano of the Scuola Normale Superiore in Pisa, Italy, showed that the effect applies in vertebrates, too. Dr Valenzano's experiments with resveratrol increased the maximum lifespan of a small fish, called Nothobranchius furzeri, by 60%. (Nothobranchius furzeri was chosen because it is the shortest-lived vertebrate known, with a normal maximum lifespan of 12 weeks.)

Resveratrol, however, is only a starting point. Sirtris Pharmaceuticals, a firm based in Cambridge, Massachusetts, of which Dr Sinclair is a co-founder, has identified a number of synthetic molecules whose effect on yeast is many times more potent than resveratrol's. Although there is, as yet, no published evidence that sirtuins extend life in mammals, or that resveratrol activates sirtuins in human cells, some of these molecules are already in clinical trials for safety.

Moreover, Dr Sinclair thinks he knows why plant molecules such as resveratrol might affect longevity in animals. Resveratrol is produced when a vine is under stress—for example, due to dehydration or over-exposure to sunshine. According to Dr Sinclair's theory, which he calls xenohormesis, animals rely on such botanical stress signals to give them extra information about their own environments, in the same way that the alarm calls of one species warn others of danger. If bad things are happening to plants, he surmises, that is a reason for pre-emptive animal action. Animal bodies thus react to molecules such as resveratrol by activating their own defence mechanisms. These, in turn, protect their cells from stress-related damage.

Xenohormesis is a variation of a more general theory, hormesis, which interests Suresh Rattan of Aarhus University in Denmark. A good example of hormesis is exercise. In theory, this should damage cells because it increases oxygen uptake, and oxidative stress is bad for things like DNA. Of course, exercise is not actually bad for cells—and the reason is that the body activates defence mechanisms which overcompensate for the stress the exercise creates, producing beneficial effects. So, while chronic stress is always bad for you, a short period of mild stress followed by a period of recovery can be good.

Many of the health benefits of exercise are thought to be due to the synthesis of damage-controlling molecules called heat-shock proteins, and Dr Rattan's group has been experimenting with other ways of triggering these proteins. He has found, for example, that taken in combination with exercise, a spice called curcumin boosts the production of heat-shock proteins several-fold.

According to Dr Rattan, such interventions improve the function of a cell over time, and in doing so, may produce clinical benefits such as protection against neurodegenerative diseases. Resveratrol may also produce benefits, he says, but how it does so is not yet clear. He disagrees with Dr Sinclair over the existence of a regulatory pathway for longevity in which sirtuins play a key role. In his view, ageing is about the accumulation of damage, and is not under tight genetic control. Sirtuins will, he says, probably be but a small part of a more complicated picture.

Dr Rattan also doubts whether calorie restriction will extend maximum human life expectancy. He argues that the concepts of ageing and longevity must be separated. It may, indeed, be possible to reduce or eliminate particular age-related diseases, and that would increase average lifespans in the way that eliminating other diseases has done in the past. But this is not the same as slowing down ageing itself, and thus increasing maximum lifespans. Longevity is a more complex trait than any individual disease, and, in his opinion, it will not be altered so easily.

Cynthia Kenyon, a researcher at the University of California, San Francisco, and a co-founder of Elixir Pharmaceuticals, another company looking into anti-ageing drugs, believes that molecules such as resveratrol are likely to be approved in the next five to ten years, for use as prophylactics against age-related diseases. People then will start taking them, and a huge natural experiment will get under way. If Dr Rattan is wrong, maximum lifespan as well as average lifespan will increase. If he is right, at least people will enjoy a healthier old age.
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