This article is part of a broad series on recent advances in the science and medicine of longevity and aging. The series covers a range of topics, including musculoskeletal health. Expect more articles on bone and muscle regeneration to follow.

Our spinal cord is a highway of information; it is what allows signals to be sent from the brain to the rest of the body, and vice versa. These signals allow us to move and feel, and even the slightest damage can have serious consequences. As with any other road, the spinal cord develops “potholes” over time. Signals become less snappy and, in some areas, nerves are lost entirely. The result? Impaired movement and loss of sensation. Novel research led by the University of Chinese Academy of Sciences, China, suggests that degeneration of the spinal cord with age may be triggered by a protein called CHIT1. The findings, published in Nature, uncover a promising new target for future drug development.

Motor Neurons and the Spinal Cord

The spinal cord is made up of two main compartments: peripheral white matter and central gray matter. The peripheral white matter surrounds the central gray matter, which sits within the very middle of the spinal cord. White matter’s main job is to send nerve impulses between different regions of the body, facilitating the transfer of sensory information. Gray matter, on the other hand, is in charge of interpreting the sensory information and enabling us to act on it — it is critical to the normal functions of daily life.

Motor neurons are a specialized kind of cell that connects the nervous system to muscles, enabling movement. Although they make up only 0.4% of total cells of the spinal cord in mammals, they are the main nerve type involved in muscle activation and contraction. Without motor neurons, we would not be able to move. Nor would we be able to speak or swallow or breath. Anything that requires the use of muscles depends on motor neurons. Unfortunately, motor neurons decline with age, in number as well as function. This can leave older adults with impaired movement and muscle weakness, ultimately leading to a decrease in physical activity and, often, a drop in quality of life.

Although it is known that motor neurons decline with age, the mechanisms underlying the decline remain unknown. This is what the researchers set out to investigate.

Microglia: Highway Patrol of the Central Nervous Sytem

If our spinal cord is a highway, then microglial cells are the highway patrol officers. They are the primary immune cells of our central nervous system and are there to make sure things stay orderly and safe — if they spot any antigens or potential threats, they jump into action. Microglial cells also act as highway maintenance workers, removing old or dead neurons and synapses to prevent a buildup of clutter.

But as we age, microglial function begins to wane. They still detect and dispose of threats, damaged cells, and dead cells, but more such issues go unnoticed than before. Year by year, the number of potholes slowly starts to grow. Unfortunately, our microglial cells are not renewed to keep pace. In fact, they are long-lived cells that are largely formed during the very earliest stages of development, while we’re still just a yolk sac in the womb. Once formed, they have only limited repopulation capacity.

Considering the importance of microglial cells to the health of the central nervous system, it is no surprise that their weathering comes hand in hand with a host of neurodegenerative disorders, including Alzheimer’s disease and amyotrophic lateral sclerosis (ALS).

The researchers suspected that microglial activity and age-related degeneration of the spinal cord were somehow related to each other. But how exactly?

Ready for Retirment? Characterizing Aged Microglial Cells

To gain a better understanding of what the aged spinal cord “looks” like, the researchers turned to single-cell tagged reverse transcription sequencing. This is a laboratory technique that enables researchers to study the gene expression patterns of individual cells. By comparing the same cell type at different points in time —for example, during young age versus old age— sequencing of this type can help paint a picture of the changes that the cell undergoes during its lifespan. It also helps scientists derive a sense of what the quintessential “aged” version of a cell is like; the genes associated with an aged state, along with the proteins and so on.

Through use of single-cell sequencing, the group of researchers noticed that, in non-human primates and spinal cord biopsies from humans, aged microglial cells linked to spinal-cord degeneration all displayed elevated expression of CHIT1, a gene that encodes a chitinase enzyme. Chitinase enzymes are a type of protein that degrade chitin, a substance found in many fungi and insects. As such, they are modulators of our immune response. As with other immune modulators, they tread a thin line: too little activation and the pathogen might survive the immune response, but too much activation and they might begin damaging the body of the host. Indeed, over-expression of chitinase-like proteins has been associated with cystic fibrosis and other inflammatory diseases.

Microglia high in CHIT1 were discovered to crowd around motor neurons. This crowding by CHIT1-positive microglial cells causes the motor neurons to enter into a state called “senescence”. In brief, this is when the cells become old and can no longer self-replicate, compromising their ability to perform their usual functions. Despite a breakdown in replication, senescent cells are still metabolically active. This means that they end up spewing out a bunch of inflammatory molecules that damage nearby cells and tissue. When left unchecked, such inflammation can cause a number of problems. Cell senescence is very closely related to aging, to the point that such inflammation has become known as “inflammaging”.

In a series of follow-up experiments, the researchers confirmed the role of CHIT1-positive microglia in motor-neuron degeneration. The degenerative effect was seen in both the spinal cord of non-human primates and in a sophisticated human motor-neuron cell culture model.

Crucially, treatment with ascorbic acid —more commonly known simply as vitamic C— helped counteract the damaging effects of CHIT1-positive microglial cells on motor neurons; cell senescence was curbed and neurodegeneration attenuated.

Takeaways

This new research helps illuminate the cell-state of microglia associated with aging and, by extension, motor neuron damage. The results are based on both non-human primate models as well as tissue samples from humans, which provide a more accurate account relative to mouse models or simple cell cultures. The findings provide a firm foundation for future research and open the door to novel drug development to help slow, and possibly reverse, the degeneration of the spinal cord seen in older adults.



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