Hunger improves mental clarity

For all you living on a calorically restricted diet, it turns out that you may be doing more than extending your lifespan—you may also be improving your mental clarity and wakefulness.

This revelation isn't a huge surprise to me. Several years ago I used to fast on a regular basis. The first couple of days were awful, but I remember feeling uncharacteristically alert and energetic as the fast went on. I could never account for this increase in brain power, but scientists at Washington University in St. Louis may have finally uncovered the mechanism behind this phenomenon.

New research in fruit flies suggests that hunger may provide a way to stay awake without feeling groggy or mentally challenged. It turns out that the need for nourishment pushes aside the need for sleep. While experimenting on fruit flies, the researchers discovered that starvation nearly tripled the amount of time they could survive without sleep.

What they found was that the ability to resist the effects of sleep loss was linked to a protein that helps the fruit fly brain manage its storage and use of lipids, a class of molecules that includes fats such as cholesterol and fat-soluble vitamins such as vitamins A and D.

"The major drugs we have to either put people to sleep or keep them awake are all targeted to a small number of pathways in the brain, all of them having to do with neurotransmission," says Paul Shaw, PhD, assistant professor of neurobiology and anatomy. "Modifying lipid processing with drugs may provide us with a new way of tackling sleep problems that is more effective or has fewer side effects."

Scientists have long known that there is a complex relationship between sleep and dietary metabolism. Inadequate sleep results in obesity and contributes to the development of diabetes and coronary disease. But until now, no one had connected genes linked to lipids with regulation of the need for sleep; the results fit into a growing awareness that organisms use lipids for much more than energy storage.

"It's becoming apparent that fats serve as signaling molecules in a number of contexts. If you identify the appropriate lipids involved in sleep regulation and figure out how to control them, you may be able to decrease suffering associated with loss of sleep or the need to stay awake," says Clay Semenkovich, MD, a Washington University lipid expert not directly involved in the study.

Shaw uses fruit flies as models for sleep's effects in higher organisms. He has proven that flies enter a state comparable to sleep, showing that they have periods of inactivity where greater stimulation is required to rouse them. Like humans, flies deprived of sleep one day will try to make up for it by sleeping more the next day—what's called sleep debt. Sleep-deprived flies also perform poorly on a simple test of learning ability.

Scientists tested the starving, sleepless flies for two markers of sleep debt: an enzyme in saliva and the flies' ability to learn to associate a light with an unpleasant stimulus. Both tests showed that the starving flies were not getting sleepy.

Studies in other labs have shown that starvation or, in the case of human volunteers, fasting leads to less sleep. More recent research has also shown that starvation can change the activity levels of genes that manage storage and use of lipids.

"From an evolutionary perspective, this makes sense," says Matt Thimgan, PhD, a postdoctoral research associate. "If you're starving, you want to make sure you're on the top of your game cognitively, to improve your chances of finding food rather than becoming food for someone else."

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Scientists one step closer to mimicking caloric restriction with anti-aging drugs

A team of University of Michigan scientists have discovered how a gene's action may help explain why restricting diet lengthens life in animals. The results offer promising early evidence that scientists may succeed at finding targets for drugs that someday could allow people to live longer, healthier lives.

Specifically, they found that suppressing a newly discovered gene lengthens the lifespan of roundworms. We've long known that significantly restricting food intake makes animals live longer, but the goal is to find less drastic ways to achieve the same effect in humans someday.

To find possible avenues for future anti-aging drugs, many scientists are focusing on signaling pathways in cells that sense nutrients. The one examined by the Michigan team, the target of rapamycin pathway or TOR pathway, is so named because its activity can be influenced by the drug rapamycin. Recent results from a large federal study being conducted at U-M and elsewhere have shown that in mice, rapamycin is effective at mimicking the anti-aging effects of dietary restriction.

Research in the last 25 years has shown that animals, including mammals, live longer and have lower levels of certain measures of age-related decline when scientists have restricted their food intake. It's highly suspected that the same effect hold trues for humans, hence the caloric restriction life extension movement.

When calories or certain nutrients are restricted, scientists detect less oxidative damage in animal cells and a slower decline in DNA repair, a decline that normally occurs with age. It's thought that limiting oxidative damage and slowing the decline in DNA repair could help postpone or avoid many age-related diseases.

That said, scientists know relatively little about why reducing food intake causes these effects. In the last 10 years, they have made progress in identifying genes and associated proteins that are suppressed when diet is restricted. By learning more about the cell processes involved, they may be able to discover targets for future drugs that could delay aging without the need to restrict food intake.

Drugs tailored to block specific genes or proteins involved in nutrient-sensing pathways would have much more appeal than reducing what one eats. To achieve anti-aging benefits, it's thought that people would have to restrict food intake by 30 to 40 percent, a grim prospect. In addition, drugs might be designed to avoid other disadvantages of this level of dietary restriction, which include reduced fertility.

C. elegans is a tiny roundworm, a nematode whose two-week lifespan is a great advantage for scientists studying aging. The 1-millimeter-long transparent worms have other advantages, too. C. elegans exhibits many age-associated changes observed in higher organisms. "Many genes identified in C. elegans to control the speed of aging turned out to be evolutionarily conserved, meaning that you can find them in other animals, too. And many are very similar to those found in humans," Ao-Lin Allen Hsu says, lead researcher of the Michigan team.

Hsu and his team created different mutant strains of roundworms, some with drr-2 genes silenced and others in which the gene was over-expressed. They wanted to learn whether inactivating drr-2 is essential for TOR to influence longevity, and found that it was. Other newly discovered genes may affect TOR signaling as well. But Hsu's team has found a promising lead for anti-aging drugs of the future: They were able to show that silencing drr-2's action alone was sufficient to make worms live longer than wild-type C. elegans used as controls.

"It is known that reduction of TOR signaling in response to a change in the environment or genetic manipulation triggers a cascade of cellular signals that alter cell growth, metabolism, and protein synthesis, and decrease the pace of aging," says Hsu. "Our recent studies have shown that drr-2 might play a pivotal role in the TOR signaling network to control protein synthesis as well as longevity."