A old article from the NYT has some more info. 10X longer? If the mice were first developed 20-30 years ago they would just be dying now. Something is wrong.
August 17, 2004
In Aging, Being Small May Have Its Advantages
By INGFEI CHEN
In a brick research building at Southern Illinois University, midget rodents are teaching gerontologists that smallness has its advantages in the rat race of survival.
On a recent day here, standing amid metal shelves stacked with plastic bins of mice, Dr. Andrzej Bartke, an endocrinologist, pulled a normal-sized female mouse from Cage 25. In rodent terms, she was a senior citizen -- 2 years old. Her brown fur had lost its sheen and was thinning.
''Her back is coming up,'' said Dr. Bartke, gently tracing a finger along a distorted arch in her spine, sort of a mouse's dowager hump. The female came from a strain that lives two years on average, so her hourglass was running low.
But two cagemates of the same age were Dorian Grays: only about half as large, they still looked like sleek, healthy furballs. ''When the normals start looking like old mice, these guys still look fine,'' Dr. Bartke said.
On average, the midgets -- called Ames dwarfs -- live 50 percent longer, to 3 years old. The difference in survival is ''absolutely huge,'' said Dr. Bartke, director of geriatric research at the university's medical school. ''If you wanted to translate to average life expectancy in the human, this means going from 75 to something like 110.''
Dr. Bartke's laboratory first published a study reporting the extended longevity of the Ames dwarfs in 1996. Other researchers have since documented a similar increase in mice called Snell dwarfs. Labs elsewhere have reported that two additional types of mice, including a genetically engineered strain, are also Methuselahs.
Although the different mouse strains have various hormonal abnormalities, they share a common trait; they are deficient in or cannot respond to growth hormone, the substance that prompts the liver to churn out another hormone called IGF-1, for insulin-like growth factor. That factor, in turn, stimulates cells to divide and tissues to mature. The two hormones are critical for normal development.
With the dwarf mouse studies, a paradox about growth hormone and aging has emerged. In people, growth hormone naturally dwindles with age. Scientists suspect that this decline contributes to weakened muscles, thinner bones, increased flab and higher odds of diabetes and heart disease. That is why some doctors, and countless Web sites, claim that injections of human growth hormone, or H.G.H., can build muscle and counter the effects of aging, even though the Food and Drug Administration approves it only for treating shortness in children and growth hormone deficiency in adults.
But the mouse research has led Dr. Bartke and other gerontologists to a counterintuitive and controversial theory: that having more growth hormone and IGF-1, as Dr. Bartke put it, is ''not optimal for longevity.''
The long-lived Ames and Snell mice carry natural mutations that make them deficient in growth hormone. The mutations cripple the pituitary gland's release of other important hormones, too; lacking thyroid-stimulating hormone and a reproductive hormone called prolactin, the mice tend to be sluggish, chubby and infertile. ''Dwarf mice would never win any athletic or beauty contest,'' said Dr. Richard Miller, a pathology professor at the University of Michigan Medical School, who studies Snell mice.
Other puny rodents designed with isolated growth-hormone defects have fewer troubles. For instance, Dr. John Kopchick, a molecular endocrinologist at the Ohio University College of Osteopathic Medicine in Athens, created mice that produce growth hormone but cannot respond to it. Called Laron dwarfs, they are fertile and live as much as 50 percent longer than normal mice. The oldest mouse on record, which lived nearly five years, was a Laron dwarf.
After the discovery of the Ames dwarfs' impressive longevity, ''a whole lot of stuff started to make sense,'' said Dr. Steven Austad, an evolutionary biologist at the University of Texas Health Science Center in San Antonio.
Dr. Bartke's finding dovetailed with studies of microscopic mutant roundworms that survive two or three times as long as normal. Many skeptics, Dr. Austad included, initially doubted that the worms offered any clues to how mammals age. In 1997, however, Harvard geneticists showed that the hardy worms carried a defect in a network of genes controlled by a protein similar to human insulin and IGF-1. That Ames dwarfs were also long-lived gave credence to the idea that the same genetic pathway might regulate life span in worms and in mammals.
Moreover, the dwarf mouse research fit with the observation that smaller members of a species tend to live longer, Dr. Austad said. Among dogs, for example, Great Danes and Irish wolfhounds typically develop age-related problems and die before they reach 10, while Chihuahuas and miniature poodles commonly last 15 years.
The situation with humans is less clear. Some studies, including one of professional baseball players, have concluded that taller people die younger. But Dr. Austad said those results were shaky because they failed to adjust for complicating factors like as smoking and socioeconomic background; other studies, with better controls, have reached the opposite conclusion. Meanwhile, Dr. Kopchick said, data on human dwarfs are sparse and conflicting.
The dwarf mice also taught scientists another important lesson. In mammals, aging is so complicated that few gerontologists thought it could be profoundly influenced by changing one gene. The Ames and Snell mice studies challenge this view. ''Aging can be slowed down,'' Dr. Miller of Michigan said. Studies from his laboratory and others indicate that compared with ordinary mice, the dwarfs experience delayed development of osteoarthritis, cataracts, memory problems and age-related changes in the immune system. They also display superior defenses against harmful stresses, like exposure to free radicals that can damage cells and DNA.
In a study published last year, Dr. Miller's team grew tail cells from Snell dwarfs in petri dishes. When exposed to lethal stresses like heat shock and peroxide, which generates free radicals, the cells showed higher survival rates than normal.
The dwarf mouse researchers speculate that the key to longevity lies in the insulin or IGF-1 genetic pathways. Unlike growth-spurring IGF-1, insulin plays a mainly metabolic role, ushering sugar into cells from the blood. The midget mice have low blood levels of IGF-1 and insulin, yet are highly sensitive to insulin's effects, Dr. Bartke said. The same is true of rodents placed on a calorie-restricted diet, the only other strategy known to stretch longevity in rats and mice. The scientists speculate that such hormonal changes somehow put animals into a survival mode that bolsters their resistance to stress.
But critics say it is premature to blame insulin, IGF-1 or growth hormone for shortening life span. ''To say that the effects are due to growth hormone is flawed,'' said Dr. William Sonntag, a professor of physiology and pharmacology at the Wake Forest University School of Medicine.
The Snell and Ames dwarfs' lack of thyroid hormone may be what is changing their longevity, Dr. Sonntag said. Similarly, he noted, the Laron dwarfs have slightly depressed thyroid hormone levels as a secondary effect of being unresponsive to growth hormone. ''It ends up being a very complicated model,'' he said.
But Dr. Bartke cites other experiments to support his case. When French scientists designed mice with an impaired ability to respond to IGF-1, the females survived 33 percent longer. And in a Harvard report last year, mice whose fat cells were immune to insulin's effects gained an 18 percent edge in longevity.
In several studies, Dr. Bartke said, disrupting the insulin-like pathway, or its equivalent, increased life span not just in worms and mice but also in fruit flies and yeast, implying that the mechanism has deep roots in evolutionary history.
For now, the implications of the Methuselah mouse studies for clinical uses of growth hormone are unclear.
Some gerontologists worry that hormone treatments might curtail longevity. ''All of the animal data point in one direction,'' Dr. Austad said. ''So it suggests to me at least that we need to be pretty darned cautious about this stuff.'' Giving children H.G.H. shots is of particular concern, he said, because it is theoretically possible that the critical period of growth that determines one's longevity occurs before puberty.
But Dr. Pinchas Cohen, chief of pediatric endocrinology at Mattel Children's Hospital at the University of California, Los Angeles, said the mouse models were so complex and hard to understand that their relevance to growth hormone therapy remained ''entirely speculative.''
IGF-1 has good and bad effects in people, so the picture is complicated, Dr. Cohen said. Adults with a severe deficiency often get heart disease and die young unless treated with growth hormone. But high concentrations of IGF-1 have been linked to cancer. Treatment to restore growth hormone to normal levels in short children carefully weighs the risks and benefits and provides substantial physical and psychosocial benefits, he said.
Likewise, scientists are trying to figure out the pros and cons of H.G.H. replacement in the elderly. Although clinical trials have found that the injections raise energy, trim body fat, and build muscle mass and bone density, those changes have not translated into more strength or greater independence for old people, said Dr. Marc Blackman, chief of the endocrine section at the National Center for Complementary and Alternative Medicine in Bethesda, Md.
The suggestions from the dwarf mouse research that growth hormone may promote aging are ''a sober warning'' that should prompt further inquiry, Dr. Blackman said. But he, too, questioned whether the mouse studies were pertinent for humans. In people, a central puzzle is whether the natural drop in growth hormone harms or helps. As Dr. Blackman said, ''We don't know the true answer to that.''
