Since 1935, when Clive M. McKay at Cornell University noticed that drastically reducing calorie intake slowed the aging process and doubled the lifespan of laboratory rats, scientists have extended the lives of yeast, worms, flies, spiders, mice, rats, cows, and dogs. In fact, according to researcher Charles Mobbs, Professor of Neurology and Geriatrics at Mount Sinai School of Medicine in New York City, “This is a very robust phenomenon that could apply to most species. It’s worked in all animals in which it has ever been tried.”

The question, of course, is whether it will work in humans. Scientists began taking important steps toward finding an answer in 1987, when they did the first controlled studies of applying dietary calorie restriction (CR) to rhesus and squirrel monkeys—genetically far more similar to humans than are non-primates such as rodents. Results of the studies suggested that CR slowed aging and maintained health and vitality among the monkeys. In general, CR lowered blood insulin level, body temperature, LDL (bad cholesterol) and total cholesterol levels, triglyceride level, and blood pressure. It also reduced arterial stiffness, raised high density lipoprotein level (good cholesterol), and slowed the decline of DHEAS (a sex hormone that rapidly diminishes with aging) in the bloodstream. All of these effects imply that CR can help monkeys to remain healthier longer and could very well do the same thing for people.

Whether CR can actually extend the natural limits of the human lifespan, however, is debatable. “It’s my personal opinion that caloric restriction isn’t actually going to have much of an effect on human lifespan,” says Mobbs. “Over the millennia, there have been many, many people who have been subjected to caloric restriction, probably most or all of their lives. Many had it imposed on them, but there were also religious, monastic people who fasted all the time. Among all of them, there has never been any substantiated report—really, almost no claim at all—that such people live much longer than everyone else. Even the present-day Okinawans, who have exactly the kind of diet we’re talking about, don’t live beyond the maximum known human lifespan.” However, Okinawans, on average, do live longer than any other group on the planet, and they suffer from far less heart disease, cancer, and neurological diseases such as Alzheimer’s and Parkinson’s as they age.

No one is really sure how CR works, but there are some favored theories. One of the most widely accepted states that caloric restriction reduces damage to the body caused by free radicals, which may be the driving culprits behind aging. But stopping this “oxidative” damage (analogous to rusting in metal) may be only part of the benefit CR provides. It also seems to reduce sensitivity to oxidative damage. When test subjects, such as microscopic lab worms called C. elegans, are given a high concentration of some oxidative toxin, then CR greatly enhances their ability to survive it.

Some scientists have a different perspective. Researchers at the University of Wisconsin profiled the aging activity of 6,347 genes in one group of CR mice and in one of non-CR mice. They found that in the non-CR mice, less than 2 percent of their genes changed significantly over time. However, those genes controlled critical biological tasks such as stress responses, protein repair, and energy production. In the CR mice, on the other hand, hardly any genetic change occurred at all. The explanation may be that dietary restriction slows down metabolism, which in turn reduces the number of damaging toxins that appear as byproducts of metabolism.

Researchers at the University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center report that aging causes a dramatic increase in the concentration of two proteins called p16INK4a and ARF, which are well known to suppress tumor cell growth. It’s possible that these proteins, in high volume, may slow or stop the production of normal cells as well, which would prevent the body from replacing damaged tissue with healthy tissue. CR, however, seems to inhibit the production of these proteins and allow normal cell replacement to continue.

Although CR shows great promise as a way to maintain good health into old age, most people would find it too restrictive a regimen to follow for any length of time. Scientists, therefore, are currently looking for medications that mimic the effect of CR on the body at the molecular level. Some of the most promising breakthroughs have come from the laboratory of Leonard Guarente, PhD, at MIT. He and his colleagues searched for genes that would extend the lifespan of yeast, and they found a gene they called SIR2. Sure enough, if the yeast had more of this gene, it lived longer, and if it had less, it died sooner. SIR2 seemed to regulate the expression of other genes. Even more interestingly, they found that the activity of this “master switch” gene was regulated by glucose. If you have high glucose, it’s turned off; if you have low glucose (which can result from CR), it’s turned on. Through later studies, Guarente’s students found a drug that would switch this gene on.

Today, at Mount Sinai, Dr. Mobbs is doing similar work. “But it’s kind of like the downstream part of the search,” he says. “The thing about the SIR2 is that it’s good for you, but nobody knows why. So what we have discovered are maybe the downstream metabolic consequences of low glucose.” Glucose regulates its own metabolism, and it changes gene expression in such a way that if you have low glucose, it produces a very powerful antioxidant metabolic profile. High glucose causes the opposite—a damaging, pro-oxidative metabolic profile. “So again,” Mobbs says, “the key trigger here is glucose, and what we’re looking for is what actually causes those effects of low and high glucose.” That discovery might lead to a drug that would mimic the effect of low glucose without actually having to lower its level in the bloodstream. This could have huge effects on health, practically eliminating the diseases of aging such as cancer, heart failure, Alzheimer’s, and many others.

For now, scientists believe it’s only a matter of time before these wonder drugs are developed and become available.