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Age-related changes in the peripheral nerves can drastically reduce the quality of life. Würzburg scientists have now identified what triggers such changes.
The average life expectancy is at an all-time high and rising. This is associated with an increase in age-related diseases of the nervous system such as Alzheimer's and other forms of dementia. However, such pathological degenerations do not only affect the brain. The peripheral nervous system, which is responsible e.g. for muscle and skin innervation, also has an increased risk of degenerating as we age.
Progressive muscle weakness
This has severe consequences for those affected: They often suffer from paresthesia and excruciating pain in the extremities. Progressive muscle loss is particularly important as it considerably limits mobility and often leads to dangerous falls which frequently mark the end of a person's independence.
Although the consequences of age-related peripheral nerve degeneration have a massive impact on the quality of life in old age as well as for the economy, its causes have not yet been investigated systematically. This has now changed: A new project conducted by researchers from the Neurological Department of the Würzburg University Hospital looked into an important aspect of age-related nerve degeneration that might be a target for therapy. Professor Rudolf Martini, who heads the Section of Developmental Neurobiology at the Neurological Department, was in charge of the project. The Journal for Neuroscience has now published the results of their research.
Macrophages under the microscope
"Working with our colleagues from the University of Aachen, we first systematically surveyed the changes taking place in the peripheral nerves of people aged between 65 and 79," Rudolf Martini describes his team's approach. During this, the researchers encountered an increased number of macrophages in the samples. Macrophages are cells of our body's immune system that engulf, digest and dispose microbes, foreign substances, cellular debris, aging cells etc. They set inflammatory responses in motion, help heal wounds and cleanse the tissue. Unfortunately, however, they also cause damage in some diseases.
To find out whether this also applies to age-related nerve degeneration, the scientists performed an experiment on mice. "For this purpose, we looked more closely at the nerves of 24-month-old mice which is an advanced age for mice," Rudolf Martini explains. It turned out that the age-related changes in the mice's peripheral nerves are very similar to those in humans. As in their human counterparts, the number of macrophages was increased in the mice. Also, the older animals had less strength than their younger siblings and their motor endplates, the synapses connecting nerves and muscle fibres, were also less intact.
Successful therapy in the animal experiment
In a next step, Martini and his team examined whether macrophages are actually responsible for triggering these changes. To this end, they added a special substance to the mice's food at the age of 18 months which causes the macrophages to die off. "After six months of treatment, we found age-related degeneration in the treated mice to be much less pronounced," Martini describes the outcome. Accordingly, the animals had more muscular strength and their motor endplates were in better shape compared to the untreated control mice.
Martini and his colleagues are convinced, "Our study not only shows a causal relationship between inflammatory responses in aging nerves and degenerative aging processes, but also that this condition can be treated." In their opinion, a targeted, highly specific treatment of age-related, macrophage-induced inflammation can improve the structure and function of nerves, and along with that, increase mobility and quality of life.
Important for infections and diabetes
However, the interpretation of these findings also allows drawing more far-reaching conclusions: Because infections or chronic age-related diseases such as diabetes often involve inflammatory responses as well, they present an additional risk for aging nerves. Therefore, the researchers hope that their findings will contribute to trigger research and development of substances that target macrophages in particular.
Martini and his team are planning to perform further experiments to find out how age-related inflammatory responses in nerves are caused. They want to figure out which cells in the nerves are responsible for the increased macrophage count and whether there are other options to treat the degenerative change besides drugs, for example targeted physical therapy training programmes as are used in other inflammatory diseases. In addition to the important insights into the causes of peripheral neuropathy in age, this study again shows that accurately planned animal experiments are indispensable to develop therapies to treat previously incurable human diseases.
Macrophage depletion ameliorates peripheral neuropathy in aging mice. Xidi Yuan, Dennis Klein, Susanne Kerscher, Brian L. West, Joachim Weis, Istvan Katona and Rudolf Martini. Journal of Neuroscience 30 April 2018, 3030-17; DOI: https://doi.org/10.1523/JNEUROSCI.3030-17.2018
Contact
Prof. Dr. Rudolf Martini, University Hospital Würzburg, Neurological Department, Section of Developmental Neurobiology, e-mail: rudolf.martini@mail.uni-wuerzburg.de
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