Fewer calories lead to longer lives

Scientists have known for years that eating less tends to make animals live longer, but no one is quite sure why. Several School of Medicine researchers who are studying the effects of caloric restriction on humans may help provide an answer to that very question.

The following St. Louis Post-Dispatch article explores the thoughts of various researchers on the subject of calories and longevity. WUSTL researchers John O. Holloszy, Luigi Fontana, Samuel Klein, Shin-ichiro Imai and Kerry Kornfeld contributed to this story.

Unlocking the secrets to longer life

(Republished with permission from the St. Louis Post-Dispatch. This article originally ran in the Science & Medicine section on Saturday, July 17, 2004)

By Tina Hesman

The secret to a longer healthy life could be in a laboratory near you.

Researchers, including some in the St. Louis area, are hot on the trail of a substance that will prolong life and preserve health.

One undisputed fact guides them: Eating less makes animals live longer.

But no one knows why or exactly how food and aging are linked.

Over the years, scientists have chased plenty of theories. But so far, aging has only teased researchers, luring them with a hint here and there, but not letting anyone close enough to expose its secrets.

“There’s no way this is going to be simple,” said Thomas T. Perls, director of the New England Centenarian Project at Boston University.

No serious researcher on aging expects to find a fountain of youth. But scientists do hope to find something that will help people age better.

Studies on very elderly people by Perls and others have revealed some common traits among them and have linked some genes associated with cholesterol to aging.

But observing elderly human beings hasn’t proved useful to learning about the molecular changes that lead to aging and how to stop or slow them, said Leonard P. Guarente, a molecular biologist at the Massachusetts Institute of Technology.

Scientists turned to mice for that. More than 70 years ago, rodents on diets showed researchers that calorie cutting leads to long lives.

The relationship is striking. Cut a mouse’s caloric intake by 30 percent of what it would eat given unlimited access to food, and the mouse lives 30 percent longer. Restrict the diet so the mouse consumes 40 percent fewer calories and the animal lives 40 percent longer, and so on. Of course, there is a limit, Guarente said. If you cut calories too severely or don’t give the mouse proper nutrition, it will die.

Many scientists have repeated the experiment using different organisms. So far, caloric restriction has prolonged the lives of yeast, spiders, worms, fish, mice, rats and dogs. Experiments are under way to see if monkeys and baboons also will live longer on low-cal diets. That’s not a practical solution for most people, Guarente said, and could even be dangerous.

Researchers are betting that by learning how caloric restriction works, they can develop a drug that has been only a dream to many people – one that has all the benefits of caloric restriction without the need to diet. While that could keep people healthy longer, it probably won’t lengthen maximum life span.

Most of the gains in life expectancy have come from eliminating or reducing deadly childhood illnesses, said Dr. Richard Miller of the University of Michigan in Ann Arbor. But even those medical advances have not increased the upper limit of human lifespan, he said.

Studies on humans

Some groups of people, though, do seem to have an advantage in the aging game. A higher percentage of people on the islands of Okinawa and Sardinia live to be 90 or 100 than people in neighboring areas, Miller said.

No one is entirely sure why. Some people have speculated that a combination of genetics and diet (the Okinawans tend to eat a lot of fish, but take in few calories) explains it. But other researchers say the data don’t support that.

“You really can’t use the Okinawans to make the argument that food restriction slows aging in humans,” said Dr. John O. Holloszy, an aging, exercise and nutrition researcher at Washington University. “The oldest old people in Okinawa aren’t any older than the oldest old people anywhere else in the world.”

Holloszy and colleagues Dr. Luigi Fontana and Dr. Samuel Klein, all of Washington University, are studying the effects of caloric restriction on humans.

The researchers compared heart health indicators from people who put themselves on restricted calorie diets with those from people who consumed “a normal American diet.”

The calorie cutters, members of the Caloric Restriction Optimal Nutrition Society – they call themselves CRONies – ate 1,112 calories to 1,958 calories each day for an average of six years. That is about half the 1,976 calories to 3,537 calories the average American consumes each day.

As a group, the CRONies were leaner and had lower blood pressure, triglycerides, “bad cholesterol” and indicators of inflammation than their well-fed counterparts. They also had more “good cholesterol” and were sensitive to insulin, an indicator of low risk for developing diabetes.

Athletes and regular exercisers also have some protection from heart disease and diabetes. But Holloszy has some bad news from studies of running rats – burning calories doesn’t prolong life.

On average, exercising rats were healthier and began dying at older ages than sedentary rats, but the most elderly runners didn’t live any longer than the oldest nonexercisers. Only the group of rats that took in fewer calories to begin with got significant gains in longevity, he said.

Those results don’t surprise Steven N. Austad, a comparative gerontologist at the Barschop Center for Longevity and Aging Studies at the University of Texas Health Science Center in San Antonio.

“Just the fact that (people) can run marathons at 80 doesn’t mean they’ll live to be 100,” Austad said. “The ranks of 100-year-olds are not filled with endurance athletes.”

Aging and cells

Scientists have several theories to explain how caloric restriction produces its benefits.

One says that vandal molecules known as free radicals cause damage to cells. Those injuries produce aging, a sort of “rusting from the inside,” said Hans Peter Zassenhaus, a researcher at St. Louis University.

Tiny power plants inside cells, called mitochondria, make energy, but also generate cell-destroying free radicals. Free radicals are the reason you’ve heard so much about antioxidants – those substances in everything from blueberries to vitamin supplements that fight cell damage.

Not only do mitochondria make free radicals, but they also are major casualties of free radical damage. Injured mitochondria limp along, producing little energy until the cell eventually poops out and dies. At least that was the theory.

Zassenhaus and his colleagues tested the idea. They created mice that racked up damage to mitochondria only in their hearts. The mice developed congestive heart failure at very young ages.

But when the researchers examined the heart cells, they got a surprise. The mitochondria were working well and hadn’t ramped up free radical production, Zassenhaus said.

Instead, the mitochondria sent out a distress signal to tell cells to commit suicide. Some cells succumb to such siren songs, usually dying in droves. But other cells make valiant efforts to stay alive.

“The cell responds. It says, ‘Yes, I hear you, but I’m too young to die,'” Zassenhaus said.

But ignoring the death knell has its own consequences. With their hands over their proverbial ears, cells can block out the suicide call, but they also shut off communication with their neighbors. That’s disastrous for heart cells, which have to coordinate efforts to beat effectively.

The results would seem to indicate that oxidative stress has nothing to do with aging, at least in heart muscles. But free radicals could be the source of the mutations that cause mitochondria to issue death warrants in the first place, Zassenhaus said.

Some scientists say free radicals have gotten a bad rap. New research has shown that free radicals are essential for cells to survive, said Richard Weindruch, director of the Aging Research Group at the Wisconsin Regional Primate Research Center at the University of Wisconsin.

“Their role has broadened from just frying molecules to controlling how cells function and live,” Weindruch said.

Weindruch and his colleagues compared the activity of 11,000 genes in mice on calorie restricted diets with animals fed standard rations.

Their studies found evidence that caloric restriction alters metabolism, Weindruch said. That finding fits well with the free radical hypothesis and another idea about aging based on body size.

Some people have noted that smaller species tend to have shorter lives than larger animals. One explanation for the difference is that small animals dial their metabolisms to top speed in order to keep warm.

“It’s much easier on a per-gram basis to heat an elephant than to heat a mouse,” said Miller of the University of Michigan.

But fast living can produce burnout far sooner than slower metabolisms. Some scientists say that theory, called the rate-of-living hypothesis, jibes with the idea that burning more energy leads to production of free radicals, the buildup of toxic waste products, and increased damage to cells.

Even good theories may have problems, said Austad.

A parakeet is roughly the same size as a house mouse. But a parakeet’s metabolic rate is almost two times higher than a mouse’s. Yet parakeets live five times to 10 times longer than mice do, Austad said.

Numerous other examples have led Austad to conclude that metabolic rate is not linked to the speed of aging, he said.

Counting calories

Miller’s money is on the theory that caloric restriction drops levels of growth hormones that may set the pace of aging. Low levels of Insulin-like Growth Factor 1, a cousin of insulin, produce smaller, tougher little animals, he says.

In Miller’s laboratory, one dwarf mouse named Yoda lived to be 4 years and 12 days old – roughly the mouse equivalent of 137 years, he said.

But an unnamed mouse from the Springfield, Ill., laboratory of Andrzej Bartke holds the life span achievement award for mice. That mouse died just a week shy of his fifth birthday (a truly ancient 150 plus in human terms). He was tiny, weighing just a quarter ounce at death. Mice typically weigh an ounce to an ounce and a half and live about 2 1/2 years.

What Yoda and his Springfield cousin had in common was a deficiency in growth hormones. Defects in insulin signaling, which also controls growth, make worms and fruit flies live longer.

“You would think that good growth and development would be correlated with good health and longevity, but the data don’t support that,” Bartke said.

Neither do some bulked up mice in Bartke’s lab. The mice make extra growth hormone and grow to be the size of small rats, he said.

“They look like supermouse personified when they are young, but then they quickly deteriorate,” Bartke said. They live about half as long as regular mice.

Mice on restricted calorie diets resemble growth-hormone deficient animals, he said. Both are small, produce little insulin, have low body temperature – an indication of slower metabolism – delay puberty, and may have reproduction problems.

But the little animals are tough. Cells taken from the small mice withstood the assault of heat stress, heavy metals, UV radiation, poison, and oxygen stress better than cells from regulation-size mice, Bartke said.

The ability to handle stress seems to be a recipe for long life. Austad, from the University of Texas, compared cells from long-lived animals, such as Eastern gray squirrels (which live an average of 23.5 years) and naked mole rats (28 years) with cells from animals with short lifespans, such as opossums, which rarely live much longer than two years. The cells from the long-lived species also withstand stress better, he said.

Dr. Shin-ichiro Imai, a cell biologist at Washington University, says fat might control aging. Fat produces many hormones that affect metabolism, inflammation and immune function, he said. Other tissues, including the pancreas, liver and a region of the brain called the hypothalamus, also could be aging command centers, Imai said.

One group of scientists, led by Dr. C. Ronald Kahn at the Joslin Diabetes Center in Boston, stopped fat cells in some mice from responding to insulin. The mice were lean even though they ate more than regular mice. And the lack of body fat lengthened their lives by 18 percent. Those results suggest that insulin, fat and aging are intertwined. But skeptics remain.

“Some experiments indicate that having less fat is the key to longevity,” Bartke said. That’s not what his mice show. Dwarf mice “don’t have less fat. They’re not skinny. In fact, they’re often rotund, but they do very well,” he said.

“The question is ‘how?'”

Many researchers agree that certain proteins are likely to be important in regulating aging. A protein nicknamed Sir2, whose real name is Silent Information Regulator 2, extends the life of yeast and worms when over-produced.

Humans have seven different versions of Sir2 (called sirtuins), including one produced in mitochondria.

“I think Sir2 is at least one of the most important key regulators that control the pace of aging,” Imai said. “The question is ‘how?'”

Early experiments in yeast showed that Sir2 ties metabolism to aging, said Guarente of MIT. Guarente’s lab recently uncovered evidence that the mouse equivalent of Sir2, a protein known as SIRT1, causes fat cells to release stored fat into the blood.

Sirtuins probably work as molecular maintenance men, running around cells and tweaking other proteins to keep them working correctly, said David Sinclair, a Harvard University geneticist. In addition to shrinking fat cells, SIRT1 works through other proteins to stop cells from dividing, giving them more time to repair damage caused by free radicals. SIRT1 also teams with other proteins to talk down cells on the brink of suicide.

All this research on molecules and caloric restriction might show how to affect the rate of aging but doesn’t uncover the underlying causes, said Kerry Kornfeld, a geneticist at Washington University.

Kornfeld is trying to determine whether genetic programs control both the development and destruction of an organism. He’s also looking for pharmaceuticals that may reprogram the self-destruct code.

For most researchers, the goal is not merely to prolong life, it’s to lengthen healthy life.

“For people, maximal longevity is not the issue,” Bartke said. “For humans the issue is preventing age-related diseases that will kill you before an age you think is fair.”

Such a therapy could be just around the corner.

Sinclair and others reported Thursday in the journal Nature that two compounds that stimulate Sir2 activity caused worms and fruit flies to live longer without making them infertile – a problem for animals on caloric restriction. The compounds, resveratrol and fisetin, affect the body the way caloric restriction does, but without some of the side effects, Sinclair said.

Resveratrol is a substance made by at least 70 different plants in response to stress, such as weather or getting eaten. Grape skins, mulberries and peanuts all contain the substance. Fisetin is a flavonoid extracted from the wood of Venice sumac. Flavonoids are well-known antioxidants derived from plants.

Sinclair has teamed with a biotech company to produce drugs that could give people another healthy decade of life. The researchers have yet to determine whether the drugs will work for mice, let alone people.

“We’ve never been so close, that’s for sure. But I don’t think the molecules we’re using are good enough to be used as drugs for humans,” Sinclair said. But researchers are already so far ahead of the game that they can take time to get the formula right, he said. “We’re already 50 years ahead of where I thought we’d be,” Sinclair said.

Copyright 2004 St. Louis Post-Dispatch, Inc.