Are Motor Neurons the Cause of the Hard Limit on Lifespan?

Examining the evidence.

The majority of people die of heart disease, stroke, or cancer by the time they are in their 80s. However, if those don’t kill you, and you make it through your 90s, then what is the limiting factor?

It seems to be frailty. People in their 90s and 100s tend to die of ‘old age’, when frailty eventually leads to an inability to get around, slowed movement, slowed breathing, and peaceful passing in their sleep.

But why does frailty eventually cause the hard limit on lifespan?

A recent article from Unaging caught my attention. In it, the author argues that motor neuron breakdown is what sets the cap on human lifespan at around 120 (assuming you don’t die of heart disease or cancer).

In the article, the author explains that longevity interventions like diet and exercise reduce all-cause mortality, but the effect is based on reducing mortality at age 60 or 70. When looking at much older individuals (90s, 100s), then those interventions aren’t important. At that age, frailty - the inability to walk across the room - takes over as the limiting factor, and that may be due to motor neuron loss. Centenarians rarely die of cancer or heart disease; instead, they are more likely to die of ‘old age’.

One metric that is often used in studies on old age is grip strength. Poor grip strength is predictive of increased mortality rate, which I took to mean that I should do some hand exercises to prevent death. Turns out that motor neuron failure is what is decreasing grip strength and predicting death — not the lack of using one of those hand grip exercisers.

Let’s take a look at what studies show on this, and then see if there are any possible solutions.

What are motor neurons?
First, some background science (skip ahead if you know this). Motor neurons are the long nerve cells that carry signals from the central nervous system (brain, spinal cord) to your muscles and glands. They are why you move, breathe, and have a heartbeat.

The two main types of motor neurons are upper and lower motor neurons. They have a large cell body (called the soma) and a long axon that carries the signal. These are some of the longest cells in the body, with some lower motor neurons reaching over 3 feet in length.

• Upper motor neurons (brain) have their cell bodies in the motor cortex of the brain and send long axons down through the brainstem and spinal cord. They don’t directly contact muscles, but instead fire the lower motor neurons.

• Lower motor neurons (brainstem/spine) are in the brainstem and the spinal cord’s ventral horn. Their axons exit the spine and directly innervate skeletal muscle fibers at the neuromuscular junction.

The lower motor neuron, plus the muscle fibers that it controls, is called a motor unit. These range from the neurons and muscles that handle fine movements (fingers, eyes) to the large motor units that control gross movement of the legs.

What causes motor neuron loss?
Motor neurons are vulnerable to degradation in part because they are really large cells that need constant energy. This means that proteins, ATP, and cellular waste end up getting transported long distances. They are also highly excitable with lots of glutamate receptors, making them vulnerable to excitotoxicity, or damage from excessive stimulation. Finally, they have a lot of mitochondria for energy production, but a relatively low calcium-buffering capacity.

Moreover, these big neurons have a very limited capacity for regeneration. There’s some regrowth of peripheral neurons, but it is slow. Nearby neurons can also branch out and cover a lost neuron.

What’s the evidence for motor neuron degeneration as the hard limit on lifespan?

Sarcopenia is the loss of muscle mass that happens in aging. It’s the shrinking, weakness, and shakiness that is the picture, in my mind, of frailty in the elderly. Research now points to the loss of motor neurons as a key component of sarcopenia.

Motor neuron loss happens throughout adulthood, but for a long while, the nearby surviving neurons sprout new branches to cover the muscle. This seems to work up to about 70 or 80 for most people, when a tipping point is reached, and too many motor neurons have been lost.

Motor neuron loss —> sarcopenia:
Researchers now think that the loss of motor neurons is the driving cause, or at least initiation, of sarcopenia. The loss of muscle mass then causes frailty, falls, and even a diminished ability to breathe due to the loss of diaphragm muscle strength.¹²

There’s an interesting study (in mice) that showed that inhibiting autophagy caused neuromuscular dysfunction in old age — and that could directly be measured by the diaphragm function decreasing.³

A large Japanese study in adults over age 65 found that sarcopenia approximately doubled the risk of death in both men and women. The researchers broke out the results, looking at low muscle mass by itself compared to low muscle mass along with slow gait and reduced grip strength. Low muscle mass by itself wasn’t correlated to all-cause mortality. Instead, it is the combination of gait and grip changes, along with muscle weakness, that increases mortality, illustrating the role of motor neurons instead of strength.⁴

ALS, Lou Gehrig’s disease —> motor neuron loss:
ALS is the first thing many people think about when they hear the term “motor neuron”. It’s a motor neuron degeneration disease that causes muscle weakness, paralysis, and eventually respiratory failure.

ALS can be due to genetic mutations in about 10-15% of cases, and looking at the genetic cause (SOD1 mutations) sheds light on the argument for motor neuron loss being the limiting factor for lifespan.

Researchers used a mouse model with the SOD1 gene knocked out to show that sarcopenia is initiated in motor neurons. This leads to neuromuscular junction disruption, which then causes mitochondrial dysfunction and reactive oxygen species (ROS) production in muscles. This creates a feedback loop that further disrupts the neuromuscular junction and leads to muscle fiber loss.⁵

Metabolic connection:
Motor neurons also innervate organs, such as the pancreas. This ties the theory to both the idea of pancreatic digestive enzymes causing autodigestion and also the links to insulin and metabolic changes affecting aging and lifespan.

All together, the evidence is fairly compelling that motor neuron degeneration is a limiting factor for lifespan, if you don’t die of heart disease or cancer first. I don’t know that I am totally convinced that it is the only limiting factor, but it is a plausible theory.

So what can we do to maintain our motor neuron health?

To me, it makes sense to protect and try to restore motor neuron function, whether it increases my lifespan or not. Motor neuron health is undeniably integral to healthy longevity, and preventing the neurodegeneration and breakdown of the axonal sheath may be beneficial for multiple reasons.

First, there’s research going on right now with small-molecule drugs that can protect motor neurons. Keep an eye on research trials for drugs for motor neuron diseases, such as for ALS.

Slowing decline:

There are a number of interventions that slow the degeneration of motor neurons — note that this is just slowing and not preventing or reversing.

Keto: A ketogenic diet in old mice showed significantly increased motor neuron unit number estimates and improved grip strength. Interestingly, the improvement was in motor unit connectivity, not raw muscle strength, which again points to the role of motor neurons being the linchpin here.⁶

Thiamine: Vitamin B1, or thiamine, plays an essential role in mitochondrial ATP production, which is essential for maintaining motor neuron function. Low thiamine may play a role in motor neuron degeneration and motor neuron diseases.⁷⁸ Benfotiamine is the form that is better absorbed and utilized by the body.

Creatine: Motor neuron loss in ALS may be helped with creatine supplementation, at least in animals. Creatine helps to enhance ATP production, and it may also limit excitotoxicity from glutamate.⁹

Vitamin B12: A phase III clinical trial in ALS patients showed that methylcobalamin injections slowed the clinical progression of the disease.¹⁰

Environmental factors: Oxidative stress and excess ROS are thought to play a primary role in motor neuron diseases. A number of environmental factors, including pesticide and heavy metal exposure, may damage motor neurons. Several herbicides, including glyphosate and 2,4-D, are linked to an increased risk of motor neuron diseases. Similarly, the pesticides carbaryl and chlorpyrifos also increase the relative risk.¹¹¹² Thus, avoiding herbicide and pesticide exposure as much as possible is a good idea.

Viruses, including polio and enterovirus-A71, are known to directly trigger degeneration in motor neurons. Avoiding polio is also a good idea.

L-Carnitine: Another protector of mitochondrial energy is L-carnitine, which is a cofactor used in the beta oxidation of long-chain fatty acids. A mouse study using a model of ALS showed that L-carnitine increased survival time.¹³

Final thoughts:

A study of a lady who had reached the ripe age of 117 showed that she didn’t have heart disease, cancer, or dementia — but she had been in a nursing home for a while due to deteriorating mobility. In the end, she passed away peacefully, and it was likely due to respiratory muscle failure. It’s likely that motor neurons to her diaphragm eventually failed, and she simply stopped breathing in her sleep.¹⁴

If researchers can prove that motor neuron degeneration is the hard limit for lifespan, then it seems like this is a solvable problem. While we don’t have the solutions right now, here’s a lot of current research on motor neuron diseases that has me hopeful. In the meantime, improving mitochondrial function and avoiding exposure to environmental neurotoxins may be the best bet. If motor neuron degradation can be solved, then heart disease and cancer become the bottleneck again. This then implies that the longevity roadmap is essentially a sequence of bottlenecks to clear.

What do you think? What does aging look like if we solve heart disease, cancer, and motor neuron degeneration?

1. https://doi.org/10.1152/physrev.00061.2017

2. https://www.sciencedirect.com/science/article/abs/pii/S0531556521002473?via%3Dihub

3. https://journals.physiology.org/doi/full/10.1152/japplphysiol.00365.2023

4. https://doi.org/10.1002/jcsm.12651

5. https://www.sciencedirect.com/science/article/abs/pii/S0891584918311444?via%3Dihub

6. https://doi.org/10.21203/rs.3.rs-3335211/v1

7. https://pmc.ncbi.nlm.nih.gov/articles/PMC10274516/

8. https://pubmed.ncbi.nlm.nih.gov/37333039/

9. https://pmc.ncbi.nlm.nih.gov/articles/PMC2631353/

10. https://jamanetwork.com/journals/jamaneurology/fullarticle/2792228

11. https://oem.bmj.com/content/79/6/412

12. https://pmc.ncbi.nlm.nih.gov/articles/PMC10756230/

13. https://pmc.ncbi.nlm.nih.gov/articles/PMC2631353/

14.