Just one of Dr. Richard A. Miller’s photos told the story of his anti-aging research: A well-groomed laboratory mouse played with a piece of chalk while its listless littermate lay in a disheveled heap nearby.
The perky mouse had received a methionine-restricted diet beginning when it was 1 year old. The bedraggled sibling had been fed a normal diet and was reaching the end of a normal lifespan. Miller showed the photo as he described how he and other researchers have extended the life of rodents by as much as 40 percent, using a variety of approaches including diet and drugs.
Miller may be best known for a study in which he and his colleagues found that mice receiving rapamycin—a drug used to keep the body from rejecting organ and bone marrow transplants—lived 20 percent longer than mice that did not receive the drug. To Miller’s surprise, the mice achieved this longevity even though they received the drug starting when they were 20 months old, the equivalent of 60 human years.
“It used to be unthinkable that aging could be slowed,” said Miller, a professor of pathology and director of the Nathan Shock Center on Aging at the University of Michigan. Dr. Felipe Sierra, director of NIA’s Division of Aging Biology and founder of the geroscience interest group introduced Miller’s talk, “Anti-Aging Medicines: The Beginning of the End of the Beginning.”
Disease Risk Increases with Age
Understanding the biology of aging may be the most efficient way to understand and delay a variety of diseases, including two leading killers—cancer and heart disease. Age is the primary risk factor for these and most other adult diseases, Miller said.
To have a real impact on the healthy human life-span, you need to tackle the aging process itself, rather than working on one disease at a time, Miller said. Eliminating cancer and heart disease would extend the life expectancy of the average 50-year-old woman by a mere 6 years; slowing the aging process could, in principle, produce much greater gains.
If the results reached with mice in the rapamycin experiment could be achieved with people, average human life could reach 110–120 years, and those additional years would be healthier, Miller said. Postmortem examinations of the longer-lived mice show they have fewer diseases such as cancer and kidney disease and their organs are much healthier than normal mice. (He cautions, however, that rapamycin may have serious side effects that make it much too risky for long-term human use.)
Restricted Diet Extends Rodent Lifespan
“The smart way to do medical research is to focus on aging and its links to the diseases that afflict us as we grow older,” Miller said following the meeting.
Photos: Ernie Branson
A rodent’s life can be extended 30-40 percent by reducing the amount it eats. Like the mice that received rapamycin, calorie-restricted rats aged at a slower rate. After 6 months, they were running 3 miles per night on their exercise wheels, a performance that continued most of their lives. The rats that were on an unrestricted diet became couch potatoes. Another study showed that restricting the calories of mice during the first 3 weeks of life and then restoring regular feeding improved longevity by 15-20 percent.
However, calorie-restricted mice have very little stored energy in the form of fat and this limits their ability to respond to environmental challenges including infections and wounds. They can quickly regain these abilities when they are restored to a regular diet, Miller said.
As part of the NIA-sponsored Interventions Testing Program, Miller collaborates with other laboratories, choosing new drugs that hold promise for extending life. Among the drugs they have studied are aspirin, acarbose (which inhibits sugar uptake from the gastrointestinal tract) and 17-alpha-estradiol, a form of estrogen. The researchers have also begun studying how some of these drugs work in combination.
Sex Differences Observed
This research has shown there are sex differences in rodents’ response to various drugs. Rapamycin extended the lives of both male and female mice. But other drugs such as aspirin, nordihydroguaiaretic acid (NDGA), acarbose and 17-alpha-estradiol have been effective with male mice, but not female. The females cleared the aspirin and NDGA more quickly from their systems, apparently losing the benefit seen in the male mice.
Miller speculated that 17-alpha-estradiol had no effect on females because they already have estrogen in their systems. “We can guess that what we’re doing is producing in males the good stuff that the females already have as their natural birthright.”
Miller’s team has been investigating the underlying mechanisms of the aging process. One intriguing finding has been that the same sets of genes in the liver were activated among long-lived mice, regardless of the intervention used to extend their lives.
“The fact that you can slow the aging rate and in so doing postpone a vast range of age-sensitive diseases suggests to me that the smart way to do medical research is to focus on aging and its links to the diseases that afflict us as we grow older,” Miller said following the meeting.