A new mechanism of aging discovered
Posted October 26, 2006on:
We all age, it’s a fact of life, like death and taxes, and there’s nothing we can do about it. But, how is it possible that of two middle-aged mice, one is already grey, balding and frail? Some mice that age three times faster than normal are revealing to scientists why we grow old.
Researchers have discovered that genetic mutations in the powerhouses of our cells — mitochondria — appear to trigger cells to die and speed up the aging process. Inducing these kinds of mitochondrial mutations leads to premature aging in mice, which live only about half as long as normal mice.
Geneticist Tom Prolla and his group at the University of Wisconsin-Madison created the fast-aging mice by altering just two of the thousands of letters, or bases, of the mouse DNA code. That changed a gene, called polymerase gamma, in the energy-producing mitochondria.
“This gene basically functions as a spellchecker during the copying of mitochondrial DNA,” he explains. “So we altered two bases in the gene and made it defective, so that it… can no longer function as a spell-checker. So as a result of that the mitochondrial DNA accumulates mutations.”
At first the mice looked normal, but around eight or nine months of age the researchers began to notice differences. “We started seeing a lot of aging symptoms in them, such as hair loss, greying, loss of bone mass, loss of muscle mass, problems in the spinal curvature,” Prolla says. “The equivalent age for a human would be 30 years old when they show a lot of these aging symptoms, so they really age very fast.”
Because our mitochondria also control the natural process of cell death within the body, mistakes by the spell-checking gene cause cells to commit suicide. “As mitochondrial mutations accumulate — and we know they accumulate with age in a number of species including humans — we start observing… increased levels of cell death and as a result of that we see the aging characteristics,” explains Prolla.
He says this type of cell death would be most critical in stem cells, which cannot easily be replaced, “Once they’re lost the tissues which they supply will no longer be able to regenerate. “But he says, that doesn’t mean normal aging, in either mice or humans, is caused by faulty spell-checkers. “Even when the spellchecker is working, sometimes you get mutations,” he explains.
What it does mean is that cell death is likely a major factor in aging. “People have linked free radical production to aging, people have linked decreased immune function with aging and other factors. But this is the first time that we’ve linked the mechanism of cell death to aging,” says Prolla.
“Mice live to be [up to] about three years old and humans can live to be a hundred years old, so obviously there must be mechanisms by which one can control mitochondrial mutations, and inhibit cell death so that we observe this great variability in life spans in nature,” Prolla explains. “There’s probably a set of genes which function to prolong life and to inhibit the effects of mitochondrial mutations. So if we can discover what those genes are, we could probably have an impact in hum aging eventually.”
The researchers say their next step will be to try and halt or delay the rapid aging of these mice. They have put a group of the rapidly-aging mice on a calorie-restricted diet, and they are now waiting to see whether caloric restriction will retard their aging process.
Calorie restriction is the only proven way to extend lifespan in animals. “So if you eat less you will live longer, ” says Prolla. “It’s not known how caloric restriction retards aging, but what has been observed is that there is less mitochondrial mutations in animals in caloric restriction and also less programmed cell death in some tissues. So we think that that may be one of the major mechanisms of how caloric restriction retards aging.”
Prolla says calorie restriction is not so easy to implement in people. “Few people would want to restrict their calories more than ten percent,” he says. “Most people would not want to restrict them at all! So if we can understand the genes involved in the actions of caloric restriction we could probably develop drugs or nutritional therapies that might function like caloric restriction.”