Old wiring in a house doesn't announce itself right away: the bulbs still glow, but the light has dimmed, and switches sometimes respond with a delay. Neuromuscular junctions age in much the same way. These are the contacts through which a nerve tells a muscle fiber to contract. Over the years, these contacts wear down, and the muscle receives its commands less and less reliably, even if the muscle itself is still strong. The problem is that peering inside a living junction is no simple task: you need a piece of muscle under a microscope, which is painful and not feasible for every study.
Scientists found a simpler way to eavesdrop on what happens in a deteriorating contact. When a neuromuscular junction remodels, fragments of the protein agrin, which holds that contact together, spill into the blood. One such fragment is called the C-terminal agrin fragment, or CAF for short. If the contact breaks down, more fragments appear in the blood. The study involved 136 men aged 20 to 92, and each had their blood CAF levels measured, along with tests of leg strength, walking speed, and other measures.
The results formed a clear picture. The older the man, the higher his blood CAF level. Those who exercised regularly, meaning at least 150 minutes of activity per week or 10 000 steps a day, had lower CAF levels, especially after age 70. And most importantly, high CAF went hand in hand with worse test results. Such men pressed less forcefully with their legs, rose from a chair more slowly, and covered less distance in 6 minutes.
The link to the actual state of the contacts was confirmed under the microscope as well. Some participants had a tiny sample of thigh muscle taken to see how many fibers had lost their nerve. These "orphaned" fibers are tagged with the protein NCAM. It turned out that the higher the blood CAF level, the more such fibers were present in the muscle. This means a blood test truly reflects what is happening in the neuromuscular junctions themselves.
Not all mechanisms of muscle aging fit into this story. The scientists examined how the brain activates a muscle, how fast a signal travels along a nerve, and how excitable the spinal cord is. Almost none of this was associated with CAF levels. It appears that the agrin fragment speaks specifically to the fate of the nerve-muscle contact, not to the entire nervous system. That is valuable: previously it was unclear whether a blood marker reflects age-related synapse degradation and whether it is linked to functional impairments in healthy people.
Today, a CAF test could become a simple screening measure: a high level of fragments in an older man's blood would tell a doctor that neuromuscular contacts are wearing out, even if the patient isn't complaining yet. This could help start training or other interventions in time. And to return to the old wiring: if you notice the light dimming early enough, you can replace the contacts before the whole circuit goes dark.
CAF levels in physically active 70-year-old men were comparable to those in inactive 50-year-old men, vividly demonstrating the "rejuvenating" effect of movement on neuromuscular synapses.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.