November 24, 2010
Learning How Muscle Keeps Aging at Bay
The loss of muscle mass and waning strength that humans experience as they grow older are classic hallmarks of aging in all animals. A study in fruit flies now shows that turning back the clock on aging muscles not only keeps the insects stronger longer, it also delays aging in the whole animal and extends life span.
“If you keep the muscles young, you slow the aging process,” says Norbert Perrimon, the Howard Hughes Medical Institute investigator who led the new work. “We’ve found that the state of muscle tissue is very important for the overall physiology and regulation of aging of the entire body.”
“We’ve found that the state of muscle tissue is very important for the overall physiology and regulation of aging of the entire body.”
In the field of aging research, Perrimon says, the idea that muscles play a central role is not new. However, he says the study, published November 24, 2010, in the journal Cell, provides the best evidence yet for the phenomenon.
In the experiments, Perrimon’s postdoctoral fellow, Fabio Demontis, examined muscle tissue for the actions of a well-known anti-aging gene, FOXO. Over the past decade, scientific interest in FOXO has skyrocketed as many studies have shown that increasing the gene’s activity can extend the life span of flies and mice. FOXO accomplishes this by revving up a cell’s ability to cope with damaged proteins, a marker of aging in many tissues. In the brain, adipose tissue, and other areas of the body, damaged proteins tend to accumulate into clumps during aging. In fact, many neurodegenerative diseases, including Alzheimer’s disease and amyotrophic lateral sclerosis (ALS), are characterized by these clumps of tangled proteins.
In fruit flies, Demontis discovered similar aggregates within old muscle cells. “Not much is known about muscle aging,” says Demontis. “But in flies, we saw protein accumulations in the muscle, and these strongly resembled the protein aggregates seen in aging brain tissue.”
When Demontis bred flies with defective FOXO, the protein aggregates accumulated more quickly. Conversely, when he revved up FOXO production in the flies’ muscle cells, the protein clumps stayed away, the flies grew weaker later, and their aging was delayed.
Other researchers have reported that FOXO acts as a transcription factor, or a master genetic switch, turning hundreds of other genes on and off. FOXO itself is activated in response to a variety of stressors, and in turn it switches on genes that help cells dispose of damaged proteins and prevent their accumulation. “The bottom line is that, normally, a muscle cell is able to degrade these damaged proteins, but this ability is decreased in aging,” says Demontis. “FOXO maintains the ability of the cell to dispose of bad proteins, which in turn keeps the cell young.”
But in the pair’s experiments, revving up the FOXO protein in muscle cells did more than keep those cells strong and healthy. Protein clumps also appeared at a slower rate than normal in the retina and fat cells of the fly, even though those tissues did not receive extra FOXO. The flies with extra FOXO in their muscles appeared younger longer, climbing and flying at a youthful pace well into old age. The flies also lived longer than usual.
Because the entire organism aged slower in response to increased FOXO in the muscles, Perrimon and Demontis propose that muscle acts as a signaling organ, telling other tissues in the body to slow their aging process. “Our studies support the notion that muscle is an endocrine organ, like the pancreas, and that muscle is not just important for movement, but that it sends signals that have an impact on the whole organism,” Demontis says.
Perrimon says that he expects many organs, not just muscle, to contribute to the overall speed of aging in animals. Previous studies in flies, for instance, show that increasing FOXO activity in the fat body, a primitive insect organ similar to the liver, also increases life span. But because muscle tissue represents a major part of the fly body mass, keeping muscles young can have a “striking impact” on aging, Perrimon says.
His laboratory is now actively seeking the “stay young” signals that youthful muscle cells send to other tissues. Perrimon thinks that insulin will probably be involved. In fact, Perrimon and Demontis say that the cellular impact of increased FOXO is similar to a decrease of nutrient intake, a well-studied route to extending life span. In the current study, flies with increased FOXO in their muscles ate less, and in turn they release less insulin, which is well known to accelerate aging. “FOXO basically acts as a brake on metabolism,” says Perrimon.
And, of course, Perrimon hopes that understanding the fundamentals of the cellular signals involved in aging will inspire the development of new drugs to slow the process in humans. “Aging is so multi-factorial, and there are so many processes involved, that it’s going to be hard to find the magic cure for it,” he says. However, he’s now shown that keeping muscles sprightly offers at least a partial solution.