The connections between your nerves and muscle deteriorate with age--a phenomenon that may help explain the serious loss of muscle that often strikes old people. New evidence suggests that caloric restriction--a nutritionally complete but low-calorie diet--could help prevent these changes. According to a study published this week, a very-low-calorie diet, and to a lesser extent exercise, can prevent or slow some aspects of muscle decline in aging mice.
Slow decline: In young mice (top), the part of a motor neuron that releases chemical signals (green) and the receptors on the muscle that receive those signals (red) align to create a structure known as the neuromuscular junction. The overlap between these two components is shown as yellow. As the animals age (bottom), the structure begins to deteriorate.
The researchers hope that the findings will point toward new ways to stem loss of muscle mass, one of the most common problems of aging and a major cause of injury. They also say it could help them understand how similar factors affect neural connections in the brain. "Much of the research on aging in the nervous system has been done in the context of neurodegenerative diseases, such as Alzheimer's," says Joshua Sanes, a neuroscientist at Harvard Medical School and one of the senior authors of the study. "Remarkably little is known about the basic phenomenon of aging in the nervous system."
The researchers studied the structure of the neuromuscular junction--the connection between the motor neurons and muscle--in mice that had been genetically engineered to make these neurons glow. Because these junctions are relatively large and tend to have a regular structure, it is easy to see when things go wrong. When the mice were about two years old, roughly the equivalent of a 70- to 80-year-old person, the junctions had clearly deteriorated. "The majority of muscle fibers had abnormal junctions," says Jeff Lichtman, a neuroscientist at Harvard University and a senior author of the study. The connections were generally smaller, and the nerves and corresponding receptors on the muscle, which are normally aligned, were askew. "They looked old and decrepit, kind of like a person looks old," says Lichtman.
The findings, hinted at in previous research, could shed light on a major health issue in aging: sarcopenia, or loss of muscle mass. "That is one of the most robust age-related impairments observed across many species, but it's not really clear what causes it," says Charles Mobbs, a neuroscientist at Mt. Sinai School of Medicine, in New York, who was not involved in the research. "This study provides evidence that an important mechanism involves neuromuscular junctions and the role of motor neurons."
To look for factors to stem this decline, the researchers examined animals that had been on a restricted diet most of their lives. This type of diet has previously been shown to extend lifespan in a number of species and to reduce some signs of aging, such as diabetes and heart disease, in some animals. "With caloric restriction, we saw a striking absence of abnormalities," says Lichtman. "These animals' synapses looked quite young."
The findings are among the first to show that caloric restriction has a robust effect on the nervous system, which has been a matter of debate. "This paper demonstrates the protective effect of dietary restriction on muscle and the neurons that regulate muscle function," says Mobbs. "It's one of the most convincing papers I have seen demonstrating a protective effect of dietary restriction in neural function."
Those who are disinclined to diet for their whole lives still have hope, however. Mice that exercised for a month in old age also had healthier neuromuscular junctions, though the findings weren't as significant as those for caloric restriction. "Just a month of exercise actually seemed to reverse the course of the downward spiral," says Lichtman.
"If there were ever two scientists who did not want to hear this result, it's us," says Lichtman, of himself and Sanes. "We don't love to exercise, and I find it real torture to starve myself." Because few people want to or are able to maintain a severely restricted diet, scientists and drug developers are searching for molecules that can mimic these health-boosting effects.
Others say the study gives reason for optimism. "The effects are remarkable, given the short time span and late onset time of exercise," says Leonard Guarente, a biologist at MIT who was not involved in the research. "It suggests it's never too late."
It's not yet clear how well the findings will translate to humans. Exercise has been shown to have health benefits for older people, but "many studies demonstrate that exercise cannot restore muscle to the same functionality that a young exercised muscle would have," says Mobbs.
The researchers are now searching for the molecular basis for the decline of neuromuscular junctions, as well as for the benefits of caloric restriction and exercise. "Is there some key molecule that goes away so the synapse falls apart?" says Sanes. "Is it the nerve's fault and muscle is fine, or vice versa? We won't be able to find out [how caloric restriction helps] until we know the normal mechanisms of age-related decline."
It's also unclear whether the two treatments work via the same mechanism or different ones. "I believe that caloric restriction is fundamentally affecting the processes of aging, whereas exercise training doesn't really do that," says Russell Hepple, a scientist at the University of Calgary, in Canada. "An exercise-trained muscle is definitely happier than a sedentary one, but it's not going to affect the processes of aging like caloric restriction does."
Researchers hope ultimately to apply the same approach to study nerve connections in the brain, which is more difficult because these nerves are much smaller and more densely packed. Previous research suggests that the number of connections declines with age, and that caloric restriction can help stem memory loss in older mice.
By Emily Singer
From Technology Review
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