Calorie Restriction: The Fountain of Youth

Stories abound about the Spanish explorer Juan Ponce de Leon, who back in the 15th century searched in vain for the Fountain of Youth in what is now Florida (with some historians stating that he was actually looking for a solution to his own sexual impotence). In recent times, the magician David Copperfield has stated that he owns the Fountain of Youth, which is located on his Bahamas property. Copperfield claims that his Fountain of Youth actually brings animals that are close to death back to life. Stories about fountains, trees, and fruit with properties of everlasting youth have been in existence since the Babylonians composed the Epic of Gilgamesh. In modern times, scientists have purported that there is another source of youth and prolonged life: calorie restriction.

Calorie restriction involves limiting one’s calorie intake in order to delay or even reverse the process of aging (including the halting or reversal of aging-related diseases). Therefore, if a 150 pound woman regularly eats 2,000 calories a day, calorie restriction for her would entail decreasing the amount ingested to perhaps 1,500 calories a day, or even fewer calories. However, all the nutritional requirements for this woman would still need to be satisfied, meaning that her new “diet” would include eating foods high in vitamins and minerals. Meanwhile, “junk food” ingestion would have to cease almost completely, since it would add only empty calories. In the case of calorie restriction, malnutrition is always a looming threat, so foods that pack the most “bang for the buck” have to be consistently selected.

Most individuals who choose to undergo voluntary calorie restriction eventually show significant weight loss. Other issues may also appear, such as feelings of being constantly cold, loss of sensation in fingers and toes, and trouble with sitting or lying on hard surfaces. Most of these problems arise because a person who is undergoing calorie restriction has very low body fat, which is critical to maintaining a steady body temperature as well as fat pads on the buttocks, thighs, and stomach.

Calorie restriction has been studied for over 75 years, and the knowledge that it extends lifespan and improves overall health has been known for a while. Back in 1934, Mary Crowell and Clive McCay described how laboratory rats, having been fed a calorie reduced diet over several years, actually outlived the rats that were not calorie reduced. Roy Walford, who conducted most of his work at the University of California in Los Angeles, used mice in his research to achieve the same effect. In Walford’s case, mice had their dietary intake of calories reduced by almost 50%. Such calorie restricted mice also lived twice as long as mice kept on a regular diet. Furthermore, Walford’s calorie restricted mice also had increased energy, a lower incidence of hormonal deficits (e.g., insulin, thyroid hormone), and a better overall performance score on problem-solving and memory tests.

The research performed thus far on rats and mice looked encouraging for rodents, but nothing had as of yet been attempted with higher mammals (including humans). Then, an opportunity for such research arose quite by accident. Walford, along with the crew of the Biosphere 2, ran out of an adequate food supply during the time they were nestled inside of the giant biodome. Rather than terminate the experiment, the Biosphere 2 crew decided to survive on a lower calorie diet (which at times consisted primarily of bananas). While Walford and his crew did end up losing a significant portion of their body weight, other changes were recorded as well: lower blood pressure, improved insulin sensitivity, and reduced total cholesterol and LDL numbers were just some of the changes seen.

Richard Weindruch, who at the time was a student of Walford’s, had already been working on the effects of caloric restriction with his mentor. Weindruch became intrigued by the molecular consequences of this lifestyle. He started his research by also looking at mice fed either calorie restricted or regular diets. What he found was the following: the mice that were fed 50% fewer calories not only exhibited an extended lifespan (32 to 45 months on average), but an extended maximal lifespan (40 to 53 months) as well. This was rather amazing in light of the fact that most improvements in health care and technology over the past century have certainly allowed humans to live up to their full lifespan potential, but not to live beyond that allotted lifespan. In other words, the mouse data was hinting that a human being could live an average of 112 years of age and a maximal average of up to 132 years of age.

As previously evidenced, not only did calorie restricted mice live longer, they also experienced better overall health. The incidence of tumors in calorie-restricted mice was 38%, while in free feeding mice it was 78%. Calorie restricted mice also had better immune systems, higher liver enzyme production, and superior memory and learning ability.

Unfortunately, mice data, no matter how encouraging, are not always relevant to human physiology and lifespan. Therefore, Weindruch wanted to determine if his mouse findings would correlate to what might be seen in higher order mammals, such as primates. Once Weindruch moved to the University of Wisconsin in Madison, he set up groups of primates that lived on either a calorie restricted diet plan or ate as much food they wished. The results of such studies were astonishing: the rhesus monkeys that underwent 11 years of calorie restriction had lower triglyceride and insulin levels compared with their free-feeding counterparts. The restricted monkeys were also leaner, had higher energy levels, and had faster and better neuronal activity. Because rhesus monkeys can live anywhere from 27 to 40 years of age, a lifetime extension measure could not be taken at the time. However, in 2009, Science published a report from Weindruch and his colleagues which stated that, in the 19 years since the study had started (back in 1990), some of the rhesus monkeys had begun dying from old age or diseases associated with old age. The calorie restricted group had thus far experienced only a 13% death rate for the group as a whole. Meanwhile, the no-calorie restricted group had already experienced a 37% death rate.

As encouraging as all this research was, the question remained: what is it about calorie restriction that delays aging, as well as the onset of aging-related diseases? What is the underlying mechanism in calorie restriction that allows animals to live longer and healthier lives?

Several theories have been proposed regarding this phenomenon. One such theory, called the “wear and tear” theory, proposes that aging is the result of damage accumulated over time to the body’s tissues and organs. As a result of these accumulated physiological insults, the body ages and eventually fails (dies). First proposed by August Weismann in 1882, the “wear and tear” theory is supported by such evidence as increased genetic mutations over time (resulting in cancer), as well as protein-protein crosslinking and tangles in aging diseases such as Alzheimer’s.

Additional evidence arises from the shortening of telomeres, which are the genetic end pieces of chromosomes. Telomeres act much like the protective plastic caps located on the ends of shoelaces. As a cell continually divides, these protective ends shorten. Once telomeres are too short to protect the chromosome, it is thought that the cell starts undergoing impaired cell division, which leads to its demise.

Unfortunately, it has been difficult to prove that calorie restriction slows down wear and tear on the body. The calorie restricted rhesus monkeys that were under Weindruch’s care did not appear to be any less energetic than their normally fed counterparts. When their metabolic profiles were analyzed, monkeys undergoing calorie restriction were found to produce as much, if not even a little bit more, energy than the normally fed monkeys. Apparently, calorie restriction does not appear to slow metabolic rate or energy level.

What about the telomeres? When researchers analyzed telomere lengths in both humans and mice, they found that mice actually have much longer telomeres than humans. However, mice live an average of 7 years, a lifespan that is certainly shorter than that of humans. Such data argue that lifespan and telomere length may not be related.

Caenorhabditis elegans N2 strainThere are also various hypotheses that propose that aging is the result of specific genes. The first direct evidence for the gene hypothesis came from Cynthia Kenyon’s work on the C. elegans worm. When C. elegans carried a mutation in its daf-2 gene, it lived almost 500% longer than its non-mutated counterparts, taking it from its normal lifespan of 2-3 weeks to almost 2 months. In humans, the equivalent of daf-2 is the insulin growth factor-like (IGF) gene. Both daf-2 and IGF control energy production in their respective organisms. Likewise, both genes have been found to be affected by calorie intake.

Another candidate aging gene affected by calorie restriction is SIRT1. This gene, first found in a family of yeast genes termed SIR1, extended yeast lifespan dramatically when it was overexpressed by researchers Matt Kaeberlein and Mitch McVey. Conversely, when the gene was mutated (and thus rendered nonfunctional), yeast lifespan was shortened.

For a long time, the exact function of SIRT1 was unknown. Recently, the gene has been shown to code for a series of proteins involved in energy production and usage. When SIRT1 mutated mice were exposed to calorie restriction, not only did their metabolic rate and activity level not increase (as is typical for normal mice undergoing caloric restriction), but calorie restriction also did nothing to extend their lifespans. Thus, total lifespan appears to be controlled by a subset, or subsets, of genes that are activated during calorie restriction.

Interestingly, the antioxidant resveratrol, which is thought to be the key factor in red wine that results in better overall health and life extension, is an activator of SIRT1. When SIRT1 is active, one of the factors it regulates is the Heat Shock Factor 1 (HSF1). HSF1 itself regulates proteins, called chaperones, that protect other proteins from becoming misfolded. Because misfolded proteins are a big problem in aging diseases such as Alzheimer’s, Huntington’s, Parkinson’s, and adult-onset diabetes, resveratrol has garnered significant scientific and commercial interest. This is especially relevant in light of the fact that SIRT1 protein levels decrease with age.

Superoxide dismutase (SOD) is a protein also under heavy scrutiny, since it has been found to protect DNA from oxidation and other stresses. SOD is a free radical scavenger, neutralizing the damaging effects of oxidizers such as hydrogen peroxide. Michael Rose, who is based at the University of California in Irvine, mated many generations of the fruit fly Drosophila melanogaster and selected only long-lived strains for further mating and analysis. In time, Rose had obtained a “superfly” that, in addition to being long-lived, could also withstand various physiological insults such as UV radiation. These long-lived flies were found to have exceedingly high levels of SOD.

The "fountain" now made into a well.

SOD is also present in humans and other mammals, and its protective effect against radiation and other cellular insults is well known. Interestingly, during research studies on calorie restricted rats, a relationship was shown between calorie intake and protection from free radical damage. This suggests that the total number of calories consumed may affect SOD levels. Thus, SOD brings the wear and tear theory full circle to calorie restriction.

In summary, there are many reasons why calorie restriction has such a profound effect on longevity. By initiating changes in gene expression, the body that undergoes calorie restriction becomes adept at handling the stress of reduced calorie intake. Interestingly, total energy output of the body does not decrease. Likewise, it does not appear that calorie restriction leads the body into a state of “suspended animation”, where its resources stay intact longer because they are not being used up as quickly. Rather, the organism seems to enter a protected state, where damage does not occur as easily or as quickly due to the ramped-up defenses of the calorie-restricted state.

Such a physiological response also suggests that the maximal lifespan of an organism may not be set in stone as previously thought. Lifespan may in fact be a very plastic state, and capable of being shifted. The fact that this shift can occur via calorie restriction suggests something else: the long-sought fountain of youth may lie directly within us.

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Halina Zakowicz

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