Mitochondrial DNA damage starts as soon as an egg is fertlised. Try having an open mind you might learn something.
If mitochondrial DNA damage “starts as soon as the egg is fertilized,” then how do you explain that humans grow stronger and faster up to around age 25? If mitochondria were the root cause, performance and function should decline from birth.
Instead, all markers of strength, speed, and resilience rise until peak adulthood, and only then do we see decline, coinciding with the onset of motor unit loss. That timing alone shows mitochondria are not the ceiling. They adapt and regenerate continuously. Motor neurons, once lost, cannot.
Try having an open mind you might learn something.
If what you’re saying were true, then elite endurance athletes should maintain all their motor units. Marathon runners and cyclists have the best mitochondrial profiles of any humans alive…massive mitochondrial density, turnover, and efficiency.
Yet these same athletes are the first to lose their fast motor units. By midlife, many endurance athletes have already sacrificed most of their Type 2X fibers and the corresponding motor units. If mitochondria were the decisive factor, they should be protected, but the evidence shows the opposite.
This is exactly why motor unit loss cannot be reduced to mitochondrial decline. Mitochondria adapt and regenerate. Motor neurons are terminally differentiated and post-mitotic. Once they’re gone, they’re gone. That is why motor units, not mitochondria, define the true ceiling of aging.
In the end if we are not going to agree then there is no sense simply repeating the points on which we disagree.
My basic point is that motor neurons have mitochondria in them and how well they function as almost all cells depends upon how well the mitochondria in them function.
We both agree that it is currently essentially impossible to replace failed motor neurons. The question is to identify why they fail and what can be done to delay this.
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You may just learn something. Read carefully, please!
So by your argument, mitochondria “control the fate” of motor units. If that’s the case, then food also controls motor units because if I don’t eat, I die. Oxygen controls motor units too, because if I stop breathing, they fail. Blood flow controls them as well.
Do you see the flaw? Mitochondria are a support system, not the driver. They provide energy, but they don’t tell motor units when to fire, how to fire, or how to adapt. Motor units are controlled neurogenically by the motor neuron, the descending drive, and the neuromuscular junction.
Mitochondria don’t issue commands. They don’t create firing rates. They don’t generate motor engrams. They just keep the lights on.
You may just learn something. Read carefully, please!
Mitochondria control gene expression through post translational modifications. They control what versions of proteins cells produce. They don’t only produce ATP.
John. Thank you for this conversation. I appreciate what you are saying.
However, you’ve made my point for me. Yes, mitochondria influence gene expression, but motor units are not genetically controlled, they are neurogenically controlled.
Genes provide the raw materials, mitochondria support energy and signaling within the cell, but it is the nervous system, descending drive, firing rates, common drive, and the neuromuscular junction that actually controls how a motor unit functions.
That is why two people with the same genes can end up with completely different motor unit profiles based on training and experience. Even identical twins do not have the same motor units, because motor units are created and shaped by lifetime movement experience.
So let us be clear. Mitochondria support, but they do not command. Motor unit fate is set by the nervous system.
I just checked the study you linked. Nowhere in it does it say mitochondria command or control motor units. It says mitochondrial dysfunction contributes to vulnerability in motor neuron disease, but the precise cause remains elusive. That is very different from command.
And what are you talking about with proteins? That is cell biology, not motor unit control. Motor neurons are not just “cellular structures.” They are post-mitotic and neurogenically controlled. Their firing, recruitment, and survival are not commanded by mitochondria.
So, where in this study does it say what you just claimed? Because it doesn’t. You are making a leap the paper never made.
The nervous system generates and coordinates the signals that recruit and fire motor units, while mitochondria serve a downstream role in supporting the cellular energy needs and maintenance of these motor units once they have been activated.
This neural activation is considered upstream because it precedes mitochondrial engagement; mitochondria only become involved after motor neurons signal the muscle fibers to contract. It is called common sense!!!
Mitochondria react to the metabolic demand triggered by neural commands, supporting prolonged contractile activity, maintaining neuromuscular junctions, and protecting against fatigue and degeneration. Their energy output and antioxidant protection are vital, but only after the nervous system has delivered its signals.
“By regulating mitochondrial transport, neurons control the local availability of mitochondrial mass in response to changes in synaptic activity.”
I can give you 100 more studies if you like. You have to come better than this!!! I am done with this conversation!
I have given a link to a research paper that demonstrated a link between mitochondrial dysfunction and motor neuron failure. I won’t respond beyond this point. The mitochondria control what proteins a cell produces without the proteins it cannot build or maintain cellular structures. This process changes throughout the life of an organism and the process of change starts at the fertilisation of the egg.
Mitochondria do “command” and they command through PTMs mainly 1 and 2 carbon PTMs.
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As someone “liked” this topic I had another glance and noticed that Tony had responded by editing his post to which I responded.
I would wish to emphasise the point that we should aim to learn from disagreements rather than aim to “win” discussions. That is why abuse should not be part of arguments. Abuse is used by human beings in conversations as a tool to shout down the person being argued with. The truth should not be shouted down.
I thought it would be useful to add a post to explain what I have learnt from this discussion.
I have learnt from this topic because it encouraged me to look at the question of motor units. I think I was vaguely aware of this previously, but I revisited the question of what happens to motor neurons for people who don’t have MND/ALS and in fact as people get older it can be said that part of sarcopenia is a form of ALS which hits selective motor neurons rather than all of them at one time. As I see this is part of evidence that ALS is a form of accelerated aging of motor neurons. It also highlights the need for motor neuron signalling of muscle cells as well as the creation of new satellite cells.
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Do you want a cure or do you want to be right that there will never, ever be a cure. Maybe we can’t replace lost motor units, maybe we can. But better methods of preserving the ones we currently have is feasible.
I agree with that for the most part, but that’s not something that is unique to motor units. There are a lot of other things that will stop you from getting to 120 if they are not adressed.
I disagree. Sure there may be nothing available that puts a huge dent in the rate of motor unit loss, however, people definitely differ in their rate of motor unit decline and it’s not all genetics. That means there are some things that can influence it. What these things are and how much of an effect they have is another question. I wouldn’t be surprised if calorie restriction had a positive effect on it, although I haven’t looked into that.
I don’t know who you’re talking about. Not many people here think there are some “magic pills” that have a huge effect on lifespan.
That’s not true. You’re calling people here naive and ignorant. That’s quite cocky, specially since you yourself show signs of ignorance.
I don’t think he is under the illusion that he will conquer aging simply with his diet and biomarker tracking but that doesn’t mean he isn’t going anywhere. He will have some positive effects on his longevity, which will increase the chances of him being alive when better age-reversal technologies arrive. That’s what most of us are trying to do.
That’s a weird thing to say. Who moves like an old man at 50?
I didn’t read it in full but glanced through some of it quickly and see big problems with your reasoning. Here is a quote from your preprint:
"If telomere shortening, mitochondrial decline, proteostasis imbalance, and the rest of the hallmarks were truly the root cause of aging, these processes would initiate the earliest observable signs of functional decline. but they do not. None of these hallmarks appear reliably in healthy individuals in their twenties. there is no telomere crisis at age 25 (López-Otin et al., 2023). There is no mitochondrial collapse in a 30-year-old elite athlete. Yet even in such individuals, fast motor unit loss has already begun (Panday et al., 2019).
This mismatch in chronology challenges the sufficiency of the Hallmarks model as a root-cause framework."
This is poor logic. Just because you don’t see functional decline in some things already in early adulthood, doesn’t mean those things aren’t declining already and don’t cause aging. There are plenty of things that start getting damaged at an early age yet don’t show up as functional decline until much later. Plenty of damages are already apparent in a healthy 25 year old, the damages just have not reached a level high enough to cause noticeable problems. Note that the body is made to have reserve capacity. The kidneys are a good example. Kidney function declines gradually with aging but generally causes problems only at old ages when it has declined a lot. You can be fine with just one kidney when you’re young and healthy, that’s an eaxmple of the excess reserve the body has. Just because you don’t see noticeable problems in early adulthood doesn’t mean that the kidneys haven’t aged significantly yet.
As far as there being no telomere crisis at age 25. Yes that’s true but the telomers are still closer to a crisis at 25 than they were at age 10 as an example. Again, just because you haven’t reached crisis doesn’t mean there isn’t damage done already that contributes to aging. The same is true with mitochondria. Sure there is no mitochondrial “collapse” in a 30 year old elite athlete, but their mitochondria will in some ways be less healthy than those of a much younger adult. You talk about fast motor unit loss having already begun at age 30, as if that’s something unique about motor units. It’s not, and that’s the main error in your theory.
I appreciate that you’re bringing more attention to motor unit loss as a factor in aging, because it certainly makes sense as an important factor to consider and it gets hardly any attention at all. Your error is in assuming that motor unit loss is somehow much more important and much more of a root cause of aging than a whole lot of other things that go bad with aging. People are always arguing about what is the main cause of aging forgetting that everything is interconnected, if only indirectly, and there is a soup of things that go wrong that feed into each other and cause aging.
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Eventually we’ll reach a critical mass of research papers, discovered pathways and case reports of some freak of nature that some experimental therapy will work. Like Huntington’s disease for example.
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Why does ALS take away body movement? The hidden burden that seals the fate of motor neurons
Intrinsically accelerated cellular degradation is amplified by TDP-43 loss in ALS-vulnerable motor neurons in a zebrafish model
My view is slightly different to that in the article. Motor Neurons as with Dopaminergic neurons have a high energy usage which is provided particularly via OxPhos. Cones and Rods in the eye have a high energy usage, but it comes more so via glycolysis.
The reason for the high energy usage is they need to produce lots of proteins to manage the axonal arbour (arbor for americans). This means, however, that a large amount of ROS is generated. Hence a high level of mitophagy is needed and a high level of melatonin (extra of which is normally provided via the CSF from the pineal gland).
If the dynamic equilibrium of the mtDNA falls off its perch then you get accelerated aging of motor neurons. I think this is what causes the symptoms of ALS/MND and PD and possibly it links to other neurodegenerative diseases.
Lots of things have the abililty to disrupt the mtDNA equilibrium. One is a disruption in CSF flow. I think that is why physically active people are more prone to ALS (Sports people, soldiers, farmers).
It is, of course, also sensitive to change in genes linked to the maintenance of mitochondria.
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