Live, Fast, Die Old 

A growing body of evidence suggests that eating less, way less, could thwart disease and delay old age.

Page 3 of 6

Mortality data supports that contention. America's leading killers at the turn of the last century were influenza, tuberculosis, and pneumonia, but according to a recent status report on aging from the Centers for Disease Control, this century's top killers so far are conditions linked to aging and consumption: heart disease, cancer, and strokes. We've won the battle against many infectious diseases, only to lose the war against milkshakes and ranch dressing.

Lab mice, who live similarly protected, sedentary, and overfed lifestyles, tend to die of like afflictions, particularly cancer and kidney failure. Perhaps the reason calorie-restricted lab mice live so long, Hellerstein theorized, is that eating less somehow slows the onset of these diseases. Using a new technique he developed, Hellerstein and Elaine Hsieh, then his graduate student, were able to show that restricting the food intake of lab mice leads to much slower growth rates for skin, breast, and white blood cells. This translates to a slowdown in tumor growth. "It makes sense," Hellerstein says. "Why would you waste energy and grow and divide cells and turn over cells if you can't even feed yourself?"

Consequently, they realized, calorie restriction may even halt or delay the onset of cancer. After all, Hellerstein notes, cells have to divide for our bodies to fix daily wear and tear, but that can create problems. "It's a dangerous thing to divide," he says. "Every time a cell divides there is chromosomal damage that could happen."

It's even more dangerous for a cell to divide rapidly and often, because if the cell splits before it has fixed existing DNA damage, those genetic mutations get passed on to the daughter cells. And if the cells continue to mutate and divide before the errors are fixed, four or five divisions later the cells become cancerous. Slowing down cell proliferation makes this less likely.

Mark Mattson, a neuroscientist at the National Institute on Aging who also researches calorie restriction, believes eating less may slow cancer by triggering a hormonal reaction. "Levels of insulinlike growth factor and levels of insulin are decreased, which is a good thing," he explains, because the former hormone is known to promote the growth of cancer cells. Mattson points out that calorie restriction also bolsters immune-system agents that course through the body removing DNA-damaged cells, another step in thwarting cancer. And reducing insulin levels has profound implications for another common age-related killer -- diabetes.

Mattson's own research aims to clarify how calorie restriction inhibits degenerative brain disorders such as Alzheimer's and Parkinson's diseases, which are becoming more common as people live longer. One theory, he says, is that the stress of fasting is analogous to physical exercise. "When you're exercising vigorously, it's a stress on your cells, your heart muscles, but they respond in an adaptive way," he says. "We have pretty good evidence that when the nerve cells are exposed to a mild stress it activates genetic programs that help them resist more stress."

Helping stave off age-related diseases is one thing, but could calorie restriction somehow put the brakes on aging itself? Bruce Ames, a senior scientist at Children's Hospital Oakland Research Institute, longtime Cal professor, and leader in aging research, promulgates the widely accepted idea that mitochondria are key to how fast our bodies wear out. These subcellular power plants are where we consume oxygen and convert food metabolites into molecular fuel our bodies can use. But like cell division, Ames notes that this process, which strips electrons from molecules, is also dangerous. Some of the electrons invariably go astray, resulting in highly reactive oxidants called free radicals that damage the surrounding DNA. This happens more frequently as cells age. "As you get older, you're making more and more oxidants in your mitochondria -- it's like an old car engine that's leaking out more black smoke and is more inefficient," Ames says. That means more DNA damage, which leads to breakdowns that cause disease and what we call aging.

Calorie restrictors approach this problem with some simple math: Less eating means fewer nutrients to burn, which means fewer free radicals and slower aging. Ames himself believes some of the mitochondrial damage can be mitigated with multivitamins and a well-balanced diet. In 1999, he founded Juvenon, an Orinda company that sells a dietary supplement of the same name -- a combination of acetyl-L-carnitine and alpha-lipoic acid designed to maintain mitochondrial health.

But scientists also wonder whether food deprivation kicks in an even more fundamental self-preservation reaction: activating genes that extend lifespan. Dr. Su-Ju Lin, an assistant professor of microbiology at UC Davis, has seen remarkable results in yeast. She found that food deprivation caused changes in genes called Sir2 and Hst2 that increased the cells' metabolic efficiency and allowed them to live three times longer than normal. (Although single-celled organisms, yeast are genetically closer to humans than they are to bacteria.)

Likewise Cynthia Kenyon, a biochemist at UC San Francisco and another pioneer in longevity research, has produced genetically mutant roundworms that live up to six times the standard lifespan. Her experiments targeted a gene called daf-2 that seems to regulate a host of longevity-related processes -- including turning on genes that help the organism resist free-radical damage and act as blueprints for "chaperone" proteins that fix damaged cells. Daf-2 also controls a growth-signaling system in worms that works much like a human system involving hormones insulin and insulinlike growth factor, which Kenyon believes play a crucial role in aging. Calorie restriction researchers embrace Kenyon's work because it, too, links longevity to slower cell growth and reduced free-radical damage.

Lest you wonder what yeast and worm genes have to do with people, Lin and Kenyon explain that most species, including humans, have genes very similar to the ones they are investigating. Scientists use simpler organisms like yeast, roundworms, and fruit flies because their genes are easy to manipulate. In fact, Kenyon believes there's a master aging-control apparatus embedded in the genes of every species. "My idea is that in all animals it would be the same, but it would be set to run differently in different animals," she says. "Mice have, say, a two-year lifespan and bats a fifty-year lifespan, and they are both about the same size. That tells you that obviously genes influence aging enormously."

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