Unlocking the secret to longevity

Most people would like to slow the ticking of nature’s time clock and tack some healthy, active years onto their lives. But the search for longevity has proven to be elusive.

Medical researchers have endeavored through various means to tap the brakes on the aging process, stem the onset of age-associated diseases, and extend the normal lifespan. These efforts have been laborious and costly. And the results have fallen short of their mark.

Until now.

In recent years, biogerontologists at U-M’s Paul F. Glenn Center for Aging Research have made significant strides toward unlocking the secret of longevity. Their work offers a glimmer of hope.

“People assume aging is immutable and that it is a fool’s errand to look for drugs that slow the aging process ─ but they are wrong,” says Richard Miller, director of the Glenn Center and professor of pathology at the medical school. “We have documented four different drugs that work in mice to decelerate aging and postpone the diseases and disabilities which make aging troublesome.”

Miller reports that in laboratory testing, the anti-aging drugs have been shown to lengthen the average healthy lifespan of mice by 15-25 percent.

These initial findings are very promising, says Miller, who has been studying the biology of aging since 1982. He joined the U-M faculty in 1990.

“People would like to be able to swallow an anti-aging pill that would help them stay healthy and live 10 to 20 years longer,” he says. “The only way to do that is by conducting research with mice, which are very similar to humans. Drugs that work in mice will often ─ though not always ─ work in people.”

Anti-aging drugs on the horizon

Studies regarding three of the four drugs with the largest anti-aging effects have been published in journals such as Nature and Aging Cell. Two of these are existing drugs that have been prescribed to people for various uses. The third is an experimental chemical, Miller says.

Rapamycin, a drug administered short-term to human patients to block the growth of certain kinds of cancer, has been highly effective in extending the healthy lifespan of both male and female mice by more than 20 percent.

Whether rapamycin is safe to give to healthy people for extended periods to promote longer life is unknown. However, there is a distinct possibility the drug may help to fend off age-related illnesses and physiological declines.

One published study reports elderly people who received rapamycin for a short period showed a better vaccine response to a flu shot. Other studies are being conducted with healthy dogs as well as healthy human volunteers to determine whether taking the drug for months or even years can stave off diabetes, cancer, heart attacks, and other age-related diseases and extend the span of healthy living.

Acarbose, a drug commonly used in other countries to control diabetes in human patients, also has shown promising anti-aging effects. In normal or diabetic individuals, it slows down the conversion of starches to sugars and blunts the rapid rise of blood-sugar levels after a meal.

“When we gave acarbose to our mice, the effect in males was quite striking,” Miller says. “The male mice had a 22 percent increase in healthy lifespan. There was a smaller, consistent, but significant effect in females who got a 5 percent to 10 percent lifespan extension.”

A third drug, 17-α-estradiol, which is a chemical variant of the more familiar form of estrogen, 17-β-estradiol, has been shown to lengthen the lifespan of male mice by 15-18 percent. However, it has had no similar effect on female mice.

Another drug on the horizon is metformin. While it does not seem to extend lifespan in mice, metformin has been proven safe in humans for the treatment of diabetes.

“There is a bit of evidence that indicates metformin might have an anti-aging effect in people,” Miller says. “Some scientists have proposed studying the effects of metformin on healthy adults in their late 50s and early 60s to see whether it protects them from developing age-linked diseases over their next 10 to 20 years.”

Clues to controlling aging

Drugs are not the only answer, however. Miller notes there are other ways of extending the lifespan of mice.

“It’s been known for 70 years or more that if you give mice less food than they would like to eat, they get very slim and live a long time,” he explains.

These so-called calorie-restriction diets can extend the average 2.5-year lifespan of mice by one year (40 percent). Translated into human terms, this anti-aging intervention would produce 112-year-old people with the same set of abilities and disabilities seen in today’s 80-year-olds. However, such diets are not feasible for people, because almost no one can voluntarily reduce calorie intake so drastically by willpower alone.

“Still, this is a good model for looking at cell biology and the endocrinology of aging and disease,” Miller says.

Another approach to promoting longevity in mice is through genetic mutation.

“We have several single-gene mutants in mice that extend their lifespan by up to 40 percent,” says Miller. “We can use these genetically altered mice to get clues about how to control the whole aging process and what drugs can be used to achieve the same anti-aging effects as the genetic mutations.”

Taking the next steps

“The work we’re doing with mice has set the foundation for many promising new avenues in basic aging research and the first steps toward translation to human health,” says Miller. “We’ve shown it is possible to slow aging with diets, mutations, and drugs in an animal that is very similar to people. If our work leads to methods for accomplishing the same thing in humans, it would keep people healthy, happy, and productive for many more years. And that would be exciting for everybody.”

Miller identifies a number of benefits that would result from earmarking more government resources for the study of aging. Currently, the U-M’s biogerontology program receives its funding from two main sources: the Glenn Foundation for Medical Research and the National Institute on Aging.

“An anti-aging approach postpones a lot of diseases at once,” Miller says. “If you stop just one disease, such as cancer or Alzheimer’s, it has surprisingly little effect on how long a person stays healthy. But if you are able to slow down many diseases altogether as well as other age-related declines such as skin wrinkles, hair loss, cataracts, and cardiovascular changes, it’s much more valuable.”

A second consideration, Miller says, is that enormous amounts of money already have been invested into research on specific diseases. Yet, these efforts have produced little, if any, impact on whether people actually contract the diseases and die from them.

“Researchers still have no ability to prevent, slow, or treat many of these diseases once they start,” Miller says. “Looking at one disease at a time is not only inefficient, but it’s also apparently much harder than slowing the overall aging process. And we can already do that in mice.”

Barriers to adoption

The transition of anti-aging drug interventions from mice to mankind will not be easy, Miller concedes. Health politics and drug policy are just two of the many barriers.

Building support for aging research will require teaching people about the success, and promise, of basic and translational aging research and encouraging these “newly enlightened experts” to move into positions where they can influence national policy, higher education, research trajectories, and grant funding, Miller says.

“Only after this type of research becomes the hot thing for people to study will the smartest researchers be attracted to the field and money become available,” he says. In addition, changes will be needed in the Food and Drug Administration’s rules governing the introduction of new drugs in order to make anti-aging drugs more easily available to people.

“My guess is that within the next 10 years, we will know whether these drugs slow aging in dogs,” Miller predicts. “If they do, many people will want to take them. These individuals will either abide by the FDA’s current rules or put political pressure on the agency to permit them to try the drugs under safe conditions and see if they work.”

In the meantime, nature’s time clock will keep on ticking.
 
 
(Top image courtesy of Richard Miller.)