The dream of delaying death has captivated humans throughout history, and over the past 150 years, improved sanitation and infectious-disease control have led to healthier and longer lives for many people. Now the golden age of genetics may bring us even closer to delaying the ultimate nemesis. Take, for example, a biotech company based in Cambridge, Massachusetts, with the apt name of Elixir Pharmaceuticals. Scientists there say they are working on a pill that is expected to have an extraordinary side effect—slowing down aging and extending life span. Elixir CEO William Heiden says, “We are about two years away from putting this compound into humans for testing.”
The pill is being developed as a treatment for such metabolic disorders as obesity and diabetes, conditions that wreak havoc on the body and shorten life span. What goes wrong in these disorders involves insulin, the hormone that helps the body absorb and store sugar. Insulin levels rise and fall depending on the body’s energy needs and how much blood sugar is available for storage. Humans have evolved to store energy when food surpluses are available and to minimize the loss of fat when food is scarce. But in times of plenty, when people can easily eat too much all too often, the system is stressed by insulin overproduction. Constant overeating can cause the feedback signals regulating energy storage to go awry. With rising insulin levels come not only obesity but also the increased risk of diabetes, heart disease, and other physiological changes that age organs and reduce life span.
The obvious key to living longer is to eat less, and significantly cutting calories has been shown to lengthen life span substantially in model organisms such as worms and mice. The studies suggest that it may also be an ancient survival strategy: Eating less when food is scarce slows down an organism’s metabolism, and that alone prolongs life. Elixir’s approach is to provoke the same effect by delivering a drug that targets hormones, enzymes, and other proteins involved in metabolism.
The pill works in mice by blocking the action of an enzyme called ghrelin that regulates appetite. If it can be shown to work in humans, it could decrease obesity, lengthening life. Healthy people might take the pill, says Heiden, because by reducing food intake they could mimic evolutionary pressures that slow aging. However, Heiden declines to say how much longer his test mice are living compared with normal mice.
Elixir’s goal of extending life through molecular intervention is founded upon the paradigm-shattering work of biologist Cynthia Kenyon at the University of California at San Francisco. Kenyon works with a millimeter-long worm called Caenorhabditis elegans. In 1993 she proved that turning down the expression of a single gene, daf-2, through genetic engineering doubled the worm’s life span. Further tweaks to regulatory genes in the worm’s metabolic pathways have upped its life span sixfold. Kenyon believes that tapping into the same mechanisms in humans could lengthen lives. However, Kenyon’s work with worms has involved genetic alteration, an unlikely program for human longevity. Nonetheless, Kenyon believes drugs can be developed to target metabolic pathways common to worms, mice, and humans.
Elixir is not alone in the hunt for an antiaging compound, nor is regulating metabolism the only smart life-prolonging strategy. The risk of cancer and heart problems increases as the body gets older. So at least a dozen companies are working on strategies to fight disease through a better understanding of aging itself. Some aim to reverse the age-related decline in the functioning of mitochondria—the multitude of tiny power-producing structures within cells. Others are trying to reduce overzealous immune responses that take their toll through inflammation-related ailments like heart disease, arthritis, Alzheimer’s disease, and cancers.
Heiden says that drugs already on the market may act to increase life span—including metformin, the most common medication to treat type 2 diabetes. Metformin, which acts on the AMP kinase enzyme, lowers blood sugar and improves insulin sensitivity, thus altering insulin production. Heiden says he has heard of healthy physicians who are taking metformin to increase their life span.
Thomas Perls, associate professor of medicine and geriatrics at Boston University Medical Center, is the founder and director of the New England Centenarian Study, which began in 1994 and has included more than 1,500 people who lived to be at least 100. He is also one of the founders of the biotech firm Elixir Pharmaceuticals.
What got you studying people who’ve lived to the age of 100 and beyond?
P: In 1995 I came across two patients who were 101 and 102. I had expected them to be sick, with numerous age-related diseases. But they were among the healthiest of my patients. I was interested in why they didn’t have Alzheimer’s and what was behind their success in aging.
What have you found?
P: People associate longevity with a certain level of wealth and education, but this is not the case with this group. The average education is eight years. For most people to get beyond the average life span of about 78, the variation has to do with lifestyle, with being healthy. For those who live an extra 10 to 15 years, there are different factors, mostly genetic. There have been a few genes discovered with centenarians, mostly in the area of vascular disease, which is what you would expect, since vascular disease—clogging of the arteries that leads to heart attacks—is the leading killer of the elderly. Long life runs in families. The kids of centenarians have a 20 percent reduced mortality rate.
Do the centenarians you’ve studied have a distinctive genetic profile?
P: They do, but there are fewer differences with the regular population than I had thought. Now I think it’s like the lottery. You have a list of factors that give you an advantage, a predisposition against heart disease and certain cancers. Some of them smoke and drink and live unhealthy lifestyles. Some do everything but throw an atomic bomb at themselves, and they still live past 100.
Would you like to see a pill that lengthens life?
P: Getting people to stop smoking and to live healthy would have a greater impact than a pill. Seventh-Day Adventists, who don’t smoke or drink and are vegetarians, live an average of 10 years longer.
Could humans live to be 150 or 300?
P: At 300, you’re getting into antiaging quackery. Working with a 900-cell organism [C. elegans ] is a far cry from working with humans.
What about mice?
P: They are still a far cry from humans, and you haven’t had huge increases in the life span of mice. As a physician who works with these centenarians, I can tell you that they are far more complex than mice.