by Michio Kaku
But what about the greatest gene enhancement of all, extending the human life span?
REVERSING AGING
Throughout history, kings and warlords had the power to command entire empires, but there was one thing that was forever beyond their control: aging. Hence, the search for immortality has been one of the oldest quests in human history.
In the Bible, God banishes Adam and Even from the Garden of Eden for disobeying his orders concerning the apple of knowledge. God’s fear was that Adam and Eve might use this knowledge to unlock the secret of immortality and become gods themselves. In Genesis 3:22, the Bible reads, “Behold, the man is become as one of us, to know good and evil: and now, lest he put forth his hand, and take also of the tree of life, and eat, and live for ever.”
Besides the Bible, one of the oldest and greatest tales in human civilization, dating back to the twenty-seventh century BC, is The Epic of Gilgamesh, about the great warrior of Mesopotamia. When his lifelong, loyal companion suddenly died, Gilgamesh decided to embark upon a journey to find the secret of immortality. He heard rumors that a wise man and his wife had been granted the gift of immortality by the gods, and were, in fact, the only ones in their land to have survived the Great Flood. After an epic quest, Gilgamesh finally found the secret of immortality, only to see a serpent snatch it away at the last minute.
Because The Epic of Gilgamesh is one of the oldest pieces of literature, historians believe that this search for immortality was the inspiration for the Greek writer Homer to write the Odyssey, and also for Noah’s flood mentioned in the Bible.
Many early kings—like Emperor Qin, who unified China around 200 BC—sent huge fleets of ships to find the Fountain of Youth, but all failed. (According to mythology, Emperor Qin gave instructions to his fleet not to come back if they failed to find the Fountain of Youth. Unable to find the fountain, but too afraid to return, they founded Japan instead.)
For decades, most scientists believed that life span was fixed and immutable, beyond the reach of science. Within the last few years, this view has crumbled under the onslaught of a stunning series of experimental results that have revolutionized the field. Gerontology, once a sleepy, backwater area of science, has now become one of the hottest fields, attracting hundreds of millions of dollars in research funds and even raising the possibility of commercial development.
The secrets of the aging process are now being unraveled, and genetics will play a vital role in this process. Looking at the animal kingdom, we see a vast variety of life spans. For example, our DNA differs from that of our nearest genetic relative, the chimpanzee, by only 1.5 percent, yet we live 50 percent longer. By analyzing the handful of genes separating us from the chimpanzees, we may be able to determine why we live so much longer than our genetic relative.
This, in turn, has given us a “unified theory of aging” that brings the various strands of research into a single, coherent tapestry. Scientists now know what aging is. It is the accumulation of errors at the genetic and cellular level. These errors can build up in various ways. For example, metabolism creates free radicals and oxidation, which damage the delicate molecular machinery of our cells, causing them to age; errors can build up in the form of “junk” molecular debris accumulating inside and outside the cells.
The buildup of these genetic errors is a by-product of the second law of thermodynamics: total entropy (that is, chaos) always increases. This is why rusting, rotting, decaying, etc., are universal features of life. The second law is inescapable. Everything, from the flowers in the field to our bodies and even the universe itself, is doomed to wither and die.
But there is a small but important loophole in the second law that states total entropy always increases. This means that you can actually reduce entropy in one place and reverse aging, as long as you increase entropy somewhere else. So it’s possible to get younger, at the expense of wreaking havoc elsewhere. (This was alluded to in Oscar Wilde’s famous novel The Picture of Dorian Gray. Mr. Gray was mysteriously eternally young. But his secret was the painting of himself that aged horribly. So the total amount of aging still increased.) The principle of entropy can also be seen by looking behind a refrigerator. Inside the refrigerator, entropy decreases as the temperature drops. But to lower the entropy, you have to have a motor, which increases the heat generated behind the refrigerator, increasing the entropy outside the machine. That is why refrigerators are always hot in the back.
As Nobel laureate Richard Feynman once said, “There is nothing in biology yet found that indicates the inevitability of death. This suggests to me that it is not at all inevitable and that it is only a matter of time before biologists discover what it is that is causing us the trouble and that this terrible universal disease or temporariness of the human’s body will be cured.”
The second law can also be seen by the action of the female sex hormone estrogen, which keeps women young and vibrant until they hit menopause, when aging accelerates and the death rate increases. Estrogen is like putting high-octane fuel into a sports car. The car performs beautifully but at the price of causing more wear and tear on the engine. For women, this cellular wear and tear might be manifested in breast cancer. In fact, injections of estrogen are known to accelerate the growth of breast cancer. So the price women pay for youth and vigor before menopause is possibly an increase in total entropy, in this case, breast cancer. (There have been scores of theories proposed to explain the recent rise in breast cancer rates, which are still quite controversial. One theory says that this is in part related to the total number of menstrual cycles a woman has. Throughout ancient history, after puberty women were more or less constantly pregnant until they hit menopause, and then they died soon afterward. This meant they had few menstrual cycles, low levels of estrogen, and hence, possibly, a relatively low level of breast cancer. Today, young girls reach puberty earlier, have many menstrual cycles, bear an average of only 1.5 children, live past menopause, and hence have considerably more exposure to estrogen, leading to a possible rise in the occurrence of breast cancer.)
Recently, a series of tantalizing clues has been discovered about genes and aging. First, researchers have shown that it is possible to breed generations of animals that live longer than normal. In particular, yeast cells, nematode worms, and fruit flies can be bred in the laboratory to live longer than normal. The scientific world was stunned when Michael Rose of the University of California at Irvine announced that he was able to increase the life span of fruit flies by 70 percent by selective breeding. His “superflies,” or Methuselah flies, were found to have higher quantities of the antioxidant superoxide dismutase (SOD), which can slow down the damage caused by free radicals. In 1991, Thomas Johnson of the University of Colorado at Boulder isolated a gene, which he dubbed age-1, that seems to be responsible for aging in nematodes and increases their life spans by 110 percent. “If something like age-1 exists in humans, we might really be able to do something spectacular,” he noted.
Scientists have now isolated a number of genes (age-1, age-2, daf-2) that control and regulate the aging process in lower organisms, but these genes have counterparts in humans as well. In fact, one scientist remarked that changing the life span of yeast cells was almost like flicking on a light switch. When one activated a certain gene, the cells lived longer. When you deactivated it, they lived shorter lives.
Breeding yeast cells to live longer is simple compared to the onerous task of breeding humans, who live so long that testing is almost impossible. But isolating the genes responsible for aging could accelerate in the future, especially when all of us have our genomes on a CD-ROM. By then, scientists will have a tremendous database of billions of genes that can be analyzed by computers. Scientists will be able to scan millions of genomes of two groups of people, the young and the old. By comparing the two sets, one can then identify where aging takes place at the genetic level. A preliminary scan of these genes has already isolated about sixty genes on which aging seems to be concentrated.
Furthermore, these computer studies may be able to locate precisely where aging primarily takes place. In a car, we know that aging takes place mainly in the engine, where gasoline is oxidized and burned. Likewise, genetic analysis shows that aging is concentrated in the “engine” of the cell, the mitochondria, or the cell’s power plant. This has allowed scientists to narrow the search for “age genes” and look for ways to accelerate the gene repair inside the mitochondria to reverse the effects of aging.
By 2050, it might be possible to slow down the aging process via a variety of therapies, for example, stem cells, the human body shop, and gene therapy to fix aging genes. We could live to be 150 or older. By 2100, it might be possible to reverse the effects of aging by accelerating cell repair mechanisms to live well beyond that.
CALORIC RESTRICTION
This theory may also explain the strange fact that caloric restriction (that is, lowering the calories we eat by 30 percent or more) increases the life span by 30 percent. Every organism studied so far—from yeast cells, spiders, and insects to rabbits, dogs, and now monkeys—exhibits this strange phenomenon. Animals given this restricted diet have fewer tumors, less heart disease, a lower incidence of diabetes, and fewer diseases related to aging. In fact, caloric restriction is the only known mechanism guaranteed to increase the life span that has been tested repeatedly, over almost the entire animal kingdom, and it works every time. Until recently, the only major species that still eluded researchers of caloric restriction were the primates, of which humans are a member, because they live so long.
Scientists were especially anxious to see the results of caloric restriction on rhesus monkeys. Finally, in 2009, the long-awaited results came in. The University of Wisconsin study showed that, after twenty years of caloric restriction, monkeys on the restricted diet suffered less disease across the board: less diabetes, cancer, heart disease. In general, these monkeys were in better health than their cousins who were fed a normal diet.
There is a theory that might explain this: Nature gives animals two “choices” concerning how they use their energy. During times of plenty, energy is used to reproduce. During times of famine, the body shuts down reproduction, conserves energy, and tries to ride out the famine. In the animal kingdom, the state of near starvation is a common one, and hence animals frequently make the “choice” of shutting down reproduction, slowing metabolism, living longer, and hoping for better days in the future.
The Holy Grail of aging research is to somehow preserve the benefits of caloric restriction without the downside (starving yourself). The natural tendency of humans apparently is to gain weight, not lose it. In fact, living on a calorically restricted diet is no fun; you are fed a diet that would make a hermit gag. Also, animals fed a particularly severe, restricted diet become lethargic, sluggish, and lose all interest in sex. What motivates scientists is the search for a gene that controls this mechanism, whereby we can reap the benefits of caloric restriction without the downside.
An important clue to this was found in 1991 by MIT researcher Leonard P. Guarente and others, who were looking for a gene that might lengthen the life span of yeast cells. Guarente, David Sinclair of Harvard, and coworkers discovered the gene SIR2, which is involved in bringing on the effects of caloric restriction. This gene is responsible for detecting the energy reserves of a cell. When the energy reserves are low, as during a famine, the gene is activated. This is precisely what you might expect in a gene that controls the effects of caloric restriction. They also found that the SIR2 gene has a counterpart in mice and in people, called the SIRT genes, which produce proteins called sirtuins. They then looked for chemicals that activate the sirtuins, and found the chemical resveratrol.
This was intriguing, because scientists also believe that resveratrol may be responsible for the benefits of red wine and may explain the “French paradox.” French cooking is famous for its rich sauces, which are high in fats and oils, yet the French seem to have a normal life span. Perhaps this mystery can be explained because the French consume so much red wine, which contains resveratrol.
Scientists have found that sirtuin activators can protect mice from an impressive variety of diseases, including lung and colon cancer, melanoma, lymphoma, type 2 diabetes, cardiovascular disease, and Alzheimer’s disease, according to Sinclair. If even a fraction of these diseases can be treated in humans via sirtuins, it would revolutionize all medicine.
Recently, a theory has been proposed to explain all the remarkable properties of resveratrol. According to Sinclair, the main purpose of sirtuin is to prevent certain genes from being activated. A single cell’s chromosomes, for example, if fully stretched, would extend six feet, making an astronomically long molecule. At any time, only a portion of the genes along this six feet of chromosomes are necessary; all the rest must be inactive. The cell gags most of the genes when they are not needed by wrapping the chromosome tightly with chromatin, which is maintained by sirtuin.
Sometimes, however, there are catastrophic disruptions of these delicate chromosomes, like a total break in one of the strands. Then the sirtuins spring into action, helping to repair the broken chromosome. But when the sirtuins temporarily leave their posts to come to the rescue, they must abandon their primary job of silencing the genes. Hence, genes get activated, causing genetic chaos. This breakdown, Sinclair proposes, is one of the chief mechanisms for aging.
If this is true, then perhaps sirtuins can not only halt the advance of aging but also reverse it. DNA damage to our cells is difficult to repair and reverse. But Sinclair believes that much of our aging is caused by sirtuins that have been diverted from their primary task, allowing cells to degenerate. The diversion of these sirtuins can be easily reversed, he claims.
FOUNTAIN OF YOUTH?
One unwanted by-product of this discovery, however, has been the media circus that it sparked. Suddenly, 60 Minutes and The Oprah Winfrey Show featured resveratrol, creating a stampede on the Internet, with fly-by-night companies springing up overnight, promising the elixir of life. It seems as if every snake oil salesman and charlatan wanted to jump on the resveratrol bandwagon.
(I had a chance to interview Guarente, the man who started this media stampede, in his laboratory. He was cautious in his statements, realizing the media impact that his results may have and the misconceptions that may develop. In particular, he was incensed that so many Internet sites are now advertising resveratrol as some sort of fountain of youth. It was appalling, he noted, that people were trying to cash in on the sudden fame that resveratrol has gotten, although most of the results are still tentative. However, he wouldn’t rule out the possibility that one day, if the fountain of youth is ever found, assuming it even exists, then SIR2 may play a part. His colleague Sinclair, in fact, admits that he takes large quantities of resveratrol every day.)
Interest in aging research is so intense within the scientific community that Harvard Medical School sponsored a conference in 2009 that drew some of the major researchers in the field. In the audience were many who were personally undergoing caloric restriction. Looking gaunt and frail, they were putting their scientific philosophy to the test by restricting their diets. There were also members of the 120 Club, who intend to live to the age of 120. In particular, interest was focused on Sirtris Pharmaceuticals, cofounded by David Sinclair and Christoph Westphal, which is now putting some of their re
sveratrol substitutes through clinical trials. Westphal says flatly, “In five or six or seven years, there will be drugs that prolong longevity.”
Chemicals that did not even exist a few years ago are the subject of intense interest as they go through trials. SRT501 is being tested against multiple myeloma and colon cancer. SRT2104 is being tested against type 2 diabetes. Not only sirtuins but also a host of other genes, proteins, and chemicals (including IGF-1, TOR, and rapamycin) are being closely analyzed by various groups.
Only time will tell if these clinical trials will be successful. The history of medicine is riddled with tales of deception, chicanery, and fraud when it comes to the aging process. But science, not superstition, is based on reproducible, testable, and falsifiable data. As the National Institute on Aging sets up programs to test various substances for their effects on aging, then we will see if these intriguing studies on animals carry over to humans.
DO WE HAVE TO DIE?
William Haseltine, a biotech pioneer, once told me, “The nature of life is not mortality. It’s immortality. DNA is an immortal molecule. That molecule first appeared perhaps 3.5 billion years ago. That selfsame molecule, through duplication, is around today …. It’s true that we run down, but we’ve talked about projecting way into the future the ability to alter that. First to extend our lives two-or threefold. And perhaps, if we understand the brain well enough, to extend both our body and our brain indefinitely. And I don’t think that will be an unnatural process.”
