Exercise and caloric restriction rejuvenate synapses in lab mice

The research, conducted in the labs of Joshua Sanes and Jeff Lichtman and described this week in the journal Proceedings of the National Academy of Sciences, begins to explain prior findings that exercise and restricted-calorie diets help to stave off the mental and physical degeneration of aging.

"Caloric restriction and exercise have numerous, dramatic effects on our mental acuity and motor ability," says Sanes, a professor of molecular and cellular biology and director of the Center for Brain Science at Harvard. "This research gives us a hint that the way these extremely powerful lifestyle factors act is by attenuating or reversing the decline in our synapses."

Sanes says their research, conducted with mice genetically engineered so their nerve cells glow in fluorescent colors, shows some of the debilitation of aging is caused by deterioration of connections that nerves make with the muscles they control, structures called neuromuscular junctions. These microscopic links are remarkably similar to the synapses that connect neurons to form information-processing circuits in the brain.

In a healthy neuromuscular synapse, nerve endings and their receptors on muscle fibers are almost a perfect match, like two hands placed together, finger to finger, palm to palm. This lineup ensures maximum efficiency in transmitting the nerve's signal from the brain to the muscle, which is what makes it contract during movement.

As people age, however, the neuromuscular synapses can deteriorate in several ways. Nerves can shrink, failing to cover the muscle's receptors completely. The resulting interference with transmission of nerve impulses to the muscles can result in wasting and eventually even death of muscle fibers. This muscle wasting, called sarcopenia, is a common and significant clinical problem in the elderly.

The new work showed that mice on a restricted-calorie diet largely avoid that age-related deterioration of their neuromuscular junctions, while those on a one-month exercise regimen when already elderly partially reverse the damage.

"With calorie restriction, we saw reversal of all aspects of the synapse disassembly. With exercise, we saw a reversal of most, but not all," Sanes says.

Because of the study's structure -- mice were on calorie-restricted diets for their whole lives, while those that exercised did so for just a month late in life -- Sanes cautions against drawing conclusions about the effectiveness of exercise versus calorie restriction. He notes that longer periods of exercise might have more profound effects, a possibility he and Lichtman are now testing.

Though much of Sanes and Lichtman's work focuses on brain synapses, both have investigated neuromuscular synapses for many years. Neuromuscular junctions are large enough to be viewed by light microscopy, and can be a jumping-off point for brain study, highlighting areas of inquiry and potential techniques.

"These findings in neuromuscular synapses make us curious to know whether similar effects might occur in brain synapses," Sanes says.

While the changes to the synapses through caloric restriction and exercise were clear in the images the researchers obtained, Sanes cautioned that their work was structural, not functional, and they have not yet tested how well the synapses worked.

The research, largely conducted by postdoctoral researchers Gregorio Valdez, Juan Tapia, and Hyuno Kang, was funded by the National Institute on Aging, National Institute of Neurological Disorders and Stroke, and Ellison Medical Foundation.