The Skinny on Life Extension

by: Frank Adam
Date: April 2006

The warm Caribbean air breezed through the sails, gliding the ship along the surface of an aquamarine ocean. The year: 1513. The captain, Juan Ponce de Leon, is sailing about the West Indies in search of a mythical entity: the Fountain of Youth.

Purported to cure illness and sustain eternal youth, the Fountain is a worthy aspiration for any explorer. Ponce de Leon's quest for immortality took him to present-day St. Augustine, Florida, but no mystical spring awaited him there. Through the generations, however, this legend has persisted, though its form has changed. Now, a new breed of explorers is pursuing this goal. But these mavericks are no longer searching for enchanted wells; instead they are experimenting with an amazingly simple practice: calorie restriction.

Treasure-ho!

Six years ago, Warren Taylor made a tremendous, but difficult, change in his life. He endeavored to become a modern Ponce de Leon, hunting down the key to longevity, if not immortality. To achieve his goal, Warren was not compelled to sail around the world; rather, he only needed to stop eating. Not completely of course, but some people think he may as well have: he restricted his daily calorie intake by 40 to 50%.

"I used to exercise a lot, which required me to consume a huge number of calories per day," says Taylor. "So when I started practicing calorie restriction, it was really a tremendous drop for me in the number of calories I ate."

Figure 1. Reducing an animal's daily intake of calories extends their lifespan. For example, rats whose feeding is restricted have been found to live up to 76% longer than rats who can eat all they want. Researchers are now trying to determine wheth… — Figure 1. Reducing an animal's daily intake of calories extends their lifespan. For example, rats whose feeding is restricted have been found to live up to 76% longer than rats who can eat all they want. Researchers are now trying to determine whether the same effect can be found in humans. Graphic by Adam Frank.

But what does it really mean to "restrict calories?" Is it as easy as just eating less?

"Caloric restriction does not mean eating half a hamburger, half a pack of French fries, and drinking half of a sugary beverage," explains Luigi Fontana, a nutrition and aging researcher at the University of Washington. "People [like Taylor] have very good nutrition. They eliminate calories by eating nutrient-dense foods."

In fact, calorie restriction, or CR, is often referred to by the acronym CRON for Calorie Restriction with Optimal Nutrition. A practicing CRON individual eats foods that supply all of the known vitamins, minerals, and other nutrients, such as essential fatty acids, hence the "optimal nutrition." The other aspect, that of "calorie restriction," simply means that overall daily calorie intake is kept at a bare minimum, just enough to facilitate bodily functions.

Peter Voss, like Taylor, is also on the trail to longevity and has been a CR "explorer" and advocate for almost ten years.

"I make a point of studying nutritional labels on food," says Voss. "The trick, then, is to crowd out bad foods with good foods that you enjoy and that are practical. Really, it's not about what 'I shouldn't do or eat' . . . [but about] experiencing and enjoying new and delicious foods."

Mice, and Rats, and Worms, Oh My!

Scientists have known for a long time that reducing an animal's daily intake of calories has the paradoxical effect of extending lifespan. In 1934, experimenters compared the lifespan of rats allowed free access to food known as ad libitum feeding to animals whose daily calorie intake was reduced by varying degrees. What they found is truly astonishing: calorie-restricted rats lived an average of 76% longer than normal: that would be like a human living 140 years!

Since then, this apparent biological anomaly has been observed across a vast range of animal species that include worms, spiders, fish, and mice. It is striking how similar these animals are at the molecular level. Processes that underlie the most basic functions of life how an organism obtains energy from nutrients, for example all follow general formulas that apply across the vast taxonomy of life on Earth. It is very likely, then, that the mechanism of aging at operation in these animal systems is the same one affecting humans. Furthermore, the means by which CR fights this aging process is also likely to be conserved in humans.

Figure 2. Caloric restriction does not mean eating less of the same old junk foods you always ate, but eliminating empty calories in favor of more nutrient-dense foods, like vegetables. Graphic by Adam Frank.

For this reason, scientists are keenly interested in studying CR in animal models that more closely approximate man, such as primates. The problem, however, is the considerably longer lifespan. Experiments in lower animals are relatively quick and easy, given the average lifespan of 3 years for the typical mouse. But animals like the rhesus macaque live about 25 years. Despite this lengthy time span, the National Institutes of Aging (NIA), in 1987, began such a CR study in macaques. For CR researchers this means a long wait until hard results can conclusively show lifespan extension in primates.

However, experiments using the rhesus macaque are not plugging along without any interesting and exciting results. Just because scientists have not yet been able to actually witness lifespan extension since their subjects are still alive does not mean that they can't demonstrate a slowing of the aging process itself.

Biomarkers of Aging

The aging process is enormously complex and involves most, if not all, of the organ systems in the body. Science is tackling the mechanisms underlying this process, but a firm understanding of all the aspects of aging is a goal for the future, not a reality of the present. What researchers do have are several theories and models of what is occurring at the cellular level when a body begins to decline. And with each of these models come several molecular markers that alert scientists to the aging process. Think of it this way: you walk into a house, smell smoke and immediately know something must be burning, even if you do not see the fire. Here the smell of smoke is the marker for the fire, which in the example represents the aging process. So even if scientists can't directly see this "fire" in the body, they can see signs that it is occurring.

These signposts for researchers are known as biomarkers of aging and they allow one to determine the biological rather than chronological age. The distinction here is an interesting and logical one: imagine someone who is 85 and so healthy and vital it's as if she is 55. Researchers might then say that biologically this person is 55, even though she has chronologically lived for 85 years.

Scientists are continually uncovering new biomarkers. Some of these are chemicals made in the body; others are physiological changes that occur. Several established and reliable biomarkers have been studied across many species. One such marker is the level of DHEA, the most abundant hormone in the body, which is made primarily by the adrenal gland and functions as a precursor to other hormones such as testosterone and estrogen. The full host of effects of DHEA in the body is not completely understood but it is implicated in a staggering array of processes such as immune response, cancer resistance, stress, diabetes, high blood pressure, memory, and fatigue to name a few. So what makes DHEA a biomarker for aging? Studies have shown that levels of DHEA gradually and reliably decline with increasing age after reaching a peak in adulthood. Furthermore, long-term studies in the elderly have found that levels of DHEA are inversely related to mortality rate. This means that the higher the level of DHEA a person has, the lower the risk of death.

Figure 3. DHEA: the most abundant hormone in the body. This hormone is implicated in a huge array of body processes, including the immune response, cancer resistence, stress, diabetes, high blood pressure, memory, and fatigue. DHEA levels decline wi… — Figure 3. DHEA: the most abundant hormone in the body. This hormone is implicated in a huge array of body processes, including the immune response, cancer resistence, stress, diabetes, high blood pressure, memory, and fatigue. DHEA levels decline with age, and studies have found that lower levels of DHEA mean higher risk of death.

"DHEA levels are of great interest to us," says George Roth, chief of the NIA's Laboratory of Cellular and Molecular Biology, "not because we believe that DHEA is the fountain of youth, but rather because it gives us a very good marker to measure the rates of aging."

Roth measured DHEA levels in rhesus monkeys from the 1987 study above. He found that monkeys whose calorie intake was restricted by 30% had a much slower age-related decline in DHEA levels, compared to monkeys with free access to food. Thus it would seem that lowering calorie intake does in fact slow the aging process. Similar studies continue in an effort to confirm these results, but simply having a biomarker such as DHEA is invaluable.

"It is important to develop markers such as DHEAS which can be used to determine the effects of various interventions, such as diet and exercise, on aging," says Donald Ingram, a co-author on Roth's study.

Additional chemical biomarkers of aging include molecules that accumulate with age, rather than decline like DHEA. A normal, healthy cell uses oxygen to generate energy, and, in the process, it creates reactive oxygen species (ROS), a dangerous class of compounds known as "free radicals." Some scientists think that free radicals are the main cause of aging through a mechanism known as oxidative stress. In this model, these highly reactive species bounce around inside of cells and tear apart the large, essential molecules such as proteins and DNA. At any single point for any given cell, this may not harm an animal much. However, over time, this damage gradually accumulates and as an organism ages more and more molecules in more and more cells become affected, eventually leading to failure of the organs within the body. So it makes sense for scientists to look at markers of ROS damage as a means to gauge age. One way to do this is to examine the amount of oxidized, or damaged, proteins in the body: higher levels are observed in biologically older animals.

A third group of molecules often associated with aging are pro-inflammatory molecules. Inflammation is a group of processes that occur when tissue is damaged. As animals age, there is a general rise in the levels of inflammatory molecules circulating in the blood. Though no one specific organ is severely damaged, there seems to be a background rise in overall tissue damage.

More Gold for CRers'

In addition to chemical biomarkers, researchers also study declines in physiological events and processes. In this way, the mechanical malfunctioning of the body can also be used as a biomarker of aging. For example, as an animal ages, the heart pumps blood more slowly. To pump the same amount of blood, the heart must now work harder and beat faster.

Luigi Fontana of the University of Washington examined how the heart pumps in both middle-aged CR dieters and middle-aged individuals consuming a typical "Western" diet. The CR dieters, who had practiced CR for an average of six years, ate about 1,600 calories per day about half the calories that the Western dieters ate. Fontana found that the CR dieters' hearts worked more efficiently and appeared to be, biologically, about 15 years younger.

Fontana and his colleagues also examined the levels of inflammatory molecules circulating in the blood of the two groups. Again, CR dieters had lower levels of inflammatory molecules.

"It's very clear from these studies that caloric restriction has a powerful, protective effect against diseases associated with aging," says co-investigator John O. Holloszy. "We don't know how long each individual will end up living, but they certainly have a longer life expectancy than average because they're most likely not going to die from a heart attack, stroke or diabetes. And if, in fact, their hearts are aging more slowly, it's conceivable they'll live for a very long time."

The CR Perspective

For these individuals, CR is not a simple diet that you go on for a few weeks and then come off. It is a change in lifestyle.

"[These are] habits you change permanently, [its] not just a short-term weight-loss program," explains Voss. "CR does not have to be difficult or unpleasant, or as detractors like to say: 'a longer life, not worth living'. Quite the opposite: a sound approach to CRON will increase one's appreciation of food, and generally lead to a better quality of life."

Yes, it can be hard in the beginning: "You have to train your mind and defeat the misconceptions of the eat me, eat me, eat me' advertising so prevalent in our society," says Taylor.

But, with time, you adjust and reach a steady state, comments Voss: "I've changed eating habits slowly, but steadily and have implement changes that I'm happy to maintain indefinitely."

For CR dieters, the pay-off is worth it: "Death comes too soon, too fast," says Taylor. "You really do want to stay youthful, healthy, functional, and productive as long as possible. Look at me, I'm older than my two brothers but both of them are balding and graying. Me, I've got a full head of brown hair. Really, life is like a candle. I'm just burning my candle with a lower, slower flame."

But Voss also sees benefits from CR beyond life extension: "[Soon after beginning CR] I also experienced various other immediate benefits such as a greater appreciation and enjoyment of food, fewer colds, feeling fitter and healthier, and of course lower blood pressure, and better blood lipids."

Fontana concurs with what Voss and Taylor have to say about CR: "If you change the quality of your diet by increasing the servings of nutrient-dense food and reducing -- actually, it would be better to slowly eliminate -- all of the servings of 'empty' calorie foods, you improve your chances of living a healthier and longer life."

A New Fountain?

Taylor and Voss both seem to be reaping benefits of the relatively simple practice of reducing calorie intake. Additionally, science is finding more evidence that CR really does slow aging and extend lifespan. Have these new age explorers truly stumbled across Ponce de Leon's elusive Fountain of Youth? Perhaps. But only time and more research can tell for sure.