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Endurance Testing

The latest wave of scientific discovery could significantly alter the average human life span.

Scientists have made a stunning discovery over the last decade: Aging can be manipulated in the lab. Experiments on small animals, including worms called C. elegans and mice, have shown that, by tinkering with certain genes, scientists can prolong or shorten life spans. With more research, one day, these findings may be applicable to humans, thus answering two of the biggest mysteries in science: Why do we age? Is it possible to prolong human life?

“Before, there was a sense that growing old is like an old car that’s breaking down or rusting,” says Gary Ruvkun, Ph.D., a professor of genetics at Harvard Medical School. “It wasn’t the idea that there was a program and a plan to the process. Now we know that, by making one mutation in the gene, you can affect longevity.”

As the global population ages, the public’s interest in the subject has driven an interest in research that could point the way to prolonging life—and the quality of life.

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“Scientists are now standing up and saying we have a chance to do something about chronic disease,” says Gordon Lithgow, Ph.D., principal investigator and director of the Buck Institute for Research on Aging’s Interdisciplinary Research Consortium in Geroscience. “We have a chance to make late life a lot better for a vast number of people by going after the aging process itself.”

But, as estimates for human life span rocket upward—some scientists expect it to reach anywhere between 120 to 150 years for future generations—a debate has emerged. Can science also improve the quality of life during those extra years?

“There are ways to change life span,” says Ruvkun. “They just may not be consequence free.” In his view, for example, to nab an extra 10 or 20 years, humans might have to go into a state of hibernation and dramatically slow down the pace of living.

“There’s no point in extending life span if you are not increasing health, as well,” says Lithgow. “That’s the problem at the moment. Our life span in human society is getting ahead of our health span. The period of disease and morbidity is growing longer and that’s absolute disaster.” It could even result, says Lithgow, in a global economic and social crisis as the world struggles to support an aging population.

“The demographics over the past century worldwide have gone from a life expectancy of mid-40s to north of 70,” says Ronald DePinho, M.D., professor of medicine at the Harvard Medical School and director of the Belfer Institute for Applied Cancer Science at the Dana-Farber Cancer Institute. “By the year 2025, it is expected that we are going to have 1.2 billion individuals over the age of 60 years old, which is the age where you start to see this dramatic increase in incidents of age-related diseases.”

He continues, “This is an enormous societal and economic issue that we will be facing over the next century. It should motivate us to understand the molecular underpinnings of the aging process.”

Lithgow agrees. “Twentieth-century medicine is a great success, but it will all come crushing down if we can’t fi nd ways to prevent Alzheimer’s and Parkinson’s disease and adult cancer. What we didn’t know until about five years ago is that aging and disease are intrinsically linked.”

If scientists can increase life span while improving healthy living, the possibilities for the beauty industry are immense. In a sense, 70 could become the new middle age, bringing new meaning to a lifelong beauty customer. On the next page, three leading scientists in the field detail their latest research on aging to give us a glimpse of what might be possible in the future.

Ronald DePinho, M.D., professor of medicine at the Harvard Medical School and director of the Belfer Institute for Applied Cancer Science at the Dana-Farber Cancer Institute

There is a point of return for aged tissue—a startling and promising finding by the DePinho laboratory. Ronald DePinho, M.D., and his team found that mouse DNA can be manipulated to help the animals live longer.

“The most fundamental thing we learned is that aged tissue, even tissue in an advanced state of degeneration, retain a remarkable capability to renew themselves if you remove the underlying cause of the damage, which, in this case, is excessive DNA damage,” says DePinho. “Accumulated DNA damage is a very important cause of aging in general—in humans and in virtually all animal systems.”

In the mouse study, DePinho and his team regulated an enzyme called telomerase, which is responsible for repairing DNA damage at the tips of the chromosomes, or telomeres. “As we age, we accumulate damage at those chromosomal ends. That damage reaches a threshold and then impacts part of the aging process,” he explains. With that in mind, DePinho and his team genetically engineered mice—in other words, manipulated their DNA—with a telomerase gene that they could “toggle on and off artificially.”

In the off state, the mice aged prematurely. “By the time they were in their middle years, they looked like somebody in their eight or ninth decade of life. They had smaller brains like Alzheimer’s patients, impaired cognition, gray hair and dermatitis, organ atrophy and they were also infertile. They were at a state of severe degeneration when they were chronologically more like 40-year-olds.” Then the scientist turned the gene back on, removing the underlying cause of aging: damage to the telomeres. “We witnessed a dramatic reversal in the signs and symptoms of aging: Their brains increased back to normal size, their skin was now rejuvenated, they became more active and energetic and their fertility returned,” says DePinho. “It’s pretty dramatic.”

The findings can be extrapolated, to some extent, to humans. “It turns out this particular mechanism of aging—the accumulating damage at telomeres which protect genes from wear and tear—is relevant to human aging, but it’s [only] one instigator,” says DePinho. “But, this particular mechanism is very important in maintaining our health as we get over 60 years old. Beyond the age of 60, epidemiologic studies in humans have shown that those with the most amount of damage, or telomere erosion, are at increased risk for the development of Alzheimer’s, cardiovascular disease, cancer and diabetes.”

These diseases cost the U.S. health care system about $1 trillion a year. “That’s a huge burden,” says DePinho. “Perhaps if we could eliminate this one cause of aging we would increase the years of healthy living in individuals over the age of 60.… The wise and most experienced of our population would continue to be able to contribute to our society.”

He adds, “The study does highlight one aspect of the aging process that we could, down the road, manipulate, but one needs to do a lot more science to understand when we need to turn this gene back on, how long we should turn it on for and are there any side effects? The gene also turns on cancer cells, so it is possible if you carried occult cancer in your body you could actually provoke the progression of cancer.”

DePinho says that, while his study focused on telomeres, other things can go awry in cells as they age, including mitochondria—as you may recall from high school science class, the powerhouse of our cells—which can decline in their function as people age, and free radicals, or “hyperactive oxygen molecules,” that cause an onslaught of damage to DNA and proteins. “It’s these collective factors that are co-conspiring to diminish the health of our cells as we advance in age,” says DePinho.

Finding ways to quell those activities could add improved healthy living. Life span, he contends, is a separate issue. At the moment, he says humans are pegged at a life span of about 120 if “everything were perfect.” He says, “One assumes if one were to remove all the underlying causes of aging that you could signifi cantly increase life span.” If that were possible, he estimates you could increase the life span of humans beyond 120.

David E. Harrison, Ph.D., The Jackson Laboratory

Could rapamycin—a drug typically used on patients receiving organ transplants— be used one day to prolong life?

David E. Harrison, Ph.D., of The Jackson Laboratory in Bar Harbor, Maine, found that, when genetically heterogeneous mice were fed rapamycin late in life, the mice would live on average 10 percent longer. The mice were relatively old— about 600 days old, equivalent to 60 years old in humans—when fed the rapamycin, he says, which inhibits a biochemical pathway important in aging. The test was replicated in three labs and the results were the same.

Although the discovery was made in the fall of 2009, thus far, there has not been “a whole lot of excitement about this with humans,” says Harrison. One reason is that rapamycin shouldn’t be taken by healthy adults since it may decrease one’s ability to fight infection. “It’s a tricky demographic to study because someone who is taking rapamycin, now used for kidney graft recipients, isn’t in good health anyway,” he says.

A paper independent of his study, he continues, showed that rapamycin made the older mice more able to respond to the flu vaccine, “which was kind of cool and unexpected. If response to vaccination is better when taking rapamycin, it could decrease the chances of getting illness after immunization.”

Harrison says the rapamycin may also “postpone a wide variety of cancers” as the mice age. Harrison says he would even be willing to take the rapamycin himself, even though he is in good health, as long “as regular testing showed that it wasn’t doing me any harm.” The mice in the study also exhibited several other reactions to the rapamycin, such as their improved ability to keep up their red blood cells. However, the beginning of type 2 diabetes didn’t appear to wane, something common with aging.

Gordon Lithgow, Ph.D., principal investigator and director of the Buck Institute for Research on Aging’s Interdisciplinary Research Consortium in Geroscience

Aging is not inevitable. That decree emerged from a study done a decade ago by Buck Institute scientists Gordon Lithgow, Ph.D., and Simon Melov, Ph.D., that reported the first successful use of drugs to extend life span in an animal model, which, in this case, was the worm C. elegans.

“We had a hunch that, if you could make animals resistant to stress, then they would be long lived,” says Lithgow. “There are a lot of similarities between what goes on when an animal or human is stressed and what goes on during aging. Our work has been focused on that all along. We keep coming back to the idea that, if you can make an animal resist stress and give it all these inherent methods to do that—and ramp those up a bit—then you can actually slow down the aging process.”

The research has been applied to other living things, as well, including fruit flies and rodents. “We are just beginning to think about how this would apply to the human condition,” says Lithgow. When it comes to human stressors, diet is one of the biggest issues. “The rise in diabetes is occurring with increased calories. That’s a huge metabolic stress and it plays out in different ways in aging, as well.

“The last 10 years have told us that it’s very easy to manipulate aging in simple animals, like C. elegans. And it seems like it might be fairly easy to manipulate aging in mice, as well,” he continues. “People are now hunting down genes that have been found in worms and flies and trying to find them in humans. These genes seem to be affecting life span, and there’s a lot of confi dence that it’s really meaningful for human life.”

Lithgow cites a study co-led by his colleague Melov that found exercise—or, in this case, resistance training—rejuvenates muscle tissue in healthy senior citizens. The study involved before-and-after analyses of gene expression profiles in tissue samples taken from 25 older men and women who underwent six months of resistance training twice a week, compared with similar analyses of tissue samples taken from younger men and women. Results showed that, in the older adults, there was a decline in mitochondrial function (the “powerhouse” of the cells) with age. After rigorous exercise, however, the older tissue began to resemble the younger tissue.

Lithgow is currently working on a soon-to-be released study that features the discovery of a compound that controls aging in nematode worms. “The very fact that a drug can apparently slow down the aging process can really get people going,” he says. In his view, now is the time for the scientific community to make one big push, “because this is the opportunity to turn around the future of the biomedical health care system.”

Lithgow acknowledges that estimating life span is not his area of expertise, but reminds that the longest recorded human life is 122 years, a record held by Jeanne Calment of France. Soon, more people could shatter her record. “Diet, moderate exercise, nutrition and pharmaceuticals could bring everyone up to the realm of an expected life span of 120 to 130 years. Of course, some people are going to do better,” says Lithgow. What could more candles on the birthday cake mean for the beauty industry? It’s not a question the scientist has spent a lot of time thinking about, he quips, but he allows that a longer life means consumers’ buying power will also increase over the years. “People might be coming to the beauty [counter] later in life, but they are still going to be using the products and they might be using them for longer if life span increases.”

Research on Aging: 5 Key Advances

The Big But:
Scientists are able to expand lifespan in laboratory animals, however, the intrinsic link between aging and disease has also become more clear.
On/Off Switch: By regulating an enzyme called telomerase, scientists were able to shorten or prolong the life of mice.
Promising Drugs: Rapamycin, used in humans receiving organ transplants, has been shown to increase the life span of aged mice by 10 percent.
Relax!: Less stress = a longer life.
Future Developments: Gordon Lithgow, Ph.D., will soon release a study featuring the discovery of a new compound that controls aging in worms.