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.
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.
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.
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.
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.
Tony definitely comes across as a bit “cocky” and I have no idea of his scientific training, but he’s obviously done enough work that Mike Lustgarten (who I respect) thought his theories are good enough to discuss on his channel, so I’ll hear Tony out on this and do a little more research on this topic, as its completely new to me.
See here of the latest video with Tony and Mike: A genetic study shows that the 117 Year Old Woman had a microbiota typical of a child - #11 by drew_ab
Here is a “paper” Tony has written on this topic of motor neuron and motor unit loss as a key limiter in aging…
The First.pdf (1.8 MB)
Here is a CGPT5.1 Summary of Tony’s paper:
This paper argues that human aging begins not in the cell, but in the nervous system—specifically, with the early, universal loss of fast motor units (FMUs) starting around ages 25–30. FMUs are the body’s highest-performance neuromuscular units: each consists of a single motor neuron in the spinal cord and the fast-twitch muscle fibers it controls. These units generate explosive power—sprinting, jumping, rapid balance corrections—and depend on constant high-quality neural signaling to stay alive.
The paper emphasizes several features of FMUs that many readers may not have encountered:
The paper’s central claim is that FMU loss is the first measurable breakdown in the human aging sequence. It occurs before mitochondrial decline, before chronic inflammation, before telomere shortening, and even in elite athletes with otherwise excellent cellular health. This upstream failure, the author argues, allows cellular hallmarks of aging to become visible, rather than being caused by them.
Mechanistically, FMU withdrawal has cascading effects: reduced mechanical loading lowers mitochondrial stimulation; decreased neural demand reduces autophagy signals; altered contraction dynamics weaken vascular shear forces; and loss of high-rate firing compromises AMPK activation. These downstream effects mimic the hallmarks of aging—not as causes, but consequences of neural retreat.
The paper’s novelty is the reordering of causality: aging begins when the nervous system stops fully controlling the body’s fastest, highest-threshold fibers. Because motor neurons are post-mitotic, this loss is permanent. No drug, senolytic, NAD⁺ booster, or stem cell therapy can recreate a lifetime-trained neuromuscular circuit once it disappears.
The author concludes that preservation, not regeneration, is the only viable strategy: youth depends on maintaining neuromuscular command fidelity, not merely improving cellular resilience.
Neuromuscular-focused explosive training has near-zero cost, produces large measurable effects on FMU recruitment, and delivers better ROI than most pharmacological longevity interventions if the FMU-origin model is correct.
Evidence for causality remains indirect; FMU decline is primarily measured through estimation techniques (MUNE), not direct neural imaging. The model predicts—but has not yet experimentally proven—that FMU preservation delays cellular hallmarks. Longitudinal and interventional trials are required.
If you want, I can also generate a mechanistic diagram showing the complete upstream → downstream sequence from FMU withdrawal to hallmark emergence.
Now do an in-depth analysis of the paper, and identify strengths (and supporting evidence) and weaknesses (counter evidence) from published papers. Included links to reference papers in the markup of your response.
Below is an in-depth critique of the paper’s central claims, with specific strengths, weaknesses, and how it fits into the broader literature.
What the paper does well
Strength (conceptual): reframing aging as failure of “command” rather than just “hardware.”
That is a useful corrective to a geroscience discourse that often fetishizes intracellular pathways while underweighting system-level control.
→ The paper’s assertion that neuromuscular factors are underweighted in mainstream aging models is fair and well-supported.
→ The idea that fast motor units are disproportionately hit and strongly linked to early loss of power and coordination is well grounded.
→ The paper’s prescription (explosive, variable, “chaotic” movement as a way to maintain FMU recruitment) is mechanistically plausible and consistent with the direction of current evidence, though the exact dose/format remains under-characterized.
The paper’s strongest claim—that FMU loss is the upstream origin and that the cellular hallmarks are downstream consequences—goes far beyond what current evidence can sustain.
These processes clearly precede the 25–30-year age window the paper highlights, which undermines the idea that FMU loss is the unique earliest initiating event of aging.
Bottom line: FMU loss is an important node; current data do not justify promoting it to the root cause.
The paper is right that lost motor neurons are hard to replace, and current regenerative strategies cannot recreate a lifelong-trained motor circuit. But it downplays three important facts:
Fairer statement: irreversible full restoration of original FMU architecture and “muscle wisdom” is not currently achievable; partial structural and functional rescue is clearly possible.
The paper tends to frame cellular hallmarks as almost entirely downstream, when current evidence favors a bidirectional, network model (e.g., oxidative stress and epigenetic changes drive NMJ degeneration, and neuromuscular decline in turn worsens systemic metabolism).
The paper’s strong causal reordering is built on cross-sectional and partially inferred timelines, not on interventional or finely resolved longitudinal datasets.
Strengths
Weaknesses / Where to be cautious
If you want to evaluate or build on this model, the highest-value studies would be:
Until such data exist, the most defensible position is:
FMU preservation is likely a high-leverage, understudied node in the aging network, but not a proven root cause that demotes cellular hallmarks to mere epiphenomena.
From a practical longevity-biohacker standpoint, the paper still argues for a strong—and relatively low-cost—bet: aggressively protect neuromuscular command (explosive, complex, age-appropriate movement) in parallel with cellular interventions, not instead of them.
And for those who want another perspective, here is Google’s Gemini’s Analysis of Tony’s paper… very similar conclusions:
@Tony_Ruggia would you agree with this below?
And another follow-on Query:
Propose a weekly workout regimen that takes into consideration this research, to optimize health of motor units and preserve function with aging
Below is a scientifically grounded, motor-unit–centric weekly training program explicitly designed to preserve fast motor units (FMUs), neuromuscular junction (NMJ) integrity, firing-rate capacity, and “muscle wisdom”—while managing injury risk for developing or aging athletes.
This regimen integrates what the paper proposes (chaotic, explosive, high-threshold, reactive inputs) with what published literature shows maintains motor neurons, NMJs, and high-threshold motor unit recruitment in humans.
The structure prioritizes:
The split is 4 neuromuscular days + 2 metabolic/structural days + 1 full-rest day , which balances stimulus vs recovery.
Purpose:
Maximize fast motor unit recruitment and firing-rate demand with safe, high-intent movements.
Warmup (10 min):
Power Prep (10 min):
High-Velocity Lifting (25–30 min):
Select 2 lower-body + 1 upper-body velocity lifts.
Cool Down:
Rationale:
Purpose:
Train unpredictability, reflex loops, and rapid motor reprogramming—critical for NMJ and FMU survival.
Drills (30–40 min total):
Rationale:
Purpose:
Preserve top-end FMU recruitment, reinnervation potential, and tendon stiffness (critical for power longevity).
Rationale:
Purpose:
Neuromuscular systems adapt during recovery. Motor learning consolidates during sleep.
Activities:
Rationale:
Purpose:
Blend hypertrophy (protects metabolic health) with FMU activation via occasional high-intent efforts.
Strength (40 min):
Finish with Multi-Planar Power (10–12 min):
Rationale:
Purpose:
Support downstream tissue health without suppressing fast-MU signaling.
Options (pick 1):
Add brief high-intensity finisher (optional):
Rationale:
Full rest.
No plyos, no intense work.
Light walk, light mobility, nothing externally loaded.
FMUs activate at high intent, not high load. Most work should feel crisp, fast, and neurologically demanding—not exhausting.
Change drills every 2–3 weeks. Long-term repetition leads to neural “habituation,” reducing FMU stimulation.
Too much monotonic endurance (cycling, distance running) lowers high-threshold recruitment over time.
—especially if you preserve neural firing capacity into middle age. Slow eccentric work twice weekly is mandatory.
Signs: sluggish movement quality, poor reactivity, loss of “snap.”
If noted, reduce chaos/reaction days temporarily.
I can further adapt the routine based on:
Would you like a version optimized for your age bracket and training experience?
Try a portable wrist sEMG (neural bands) with raw data export
Might be relevant:
Just to add my two cents worth - first, there are scant longitudinal data concerning fiber type proportions across the lifespan - most of the data is cross-sectional. This means one cannot distinguish between a prolonged effect of exercise on fiber type and simply biological predisposition to endurance sport being conferred for those having a higher proportion of oxidative muscle fibers (i.e., high performing endurance athletes may have always had low type IIx proportion). Second, it is well known that type IIx fibers decline when a sedentary person engages in exercise training, and this is also true of resistance training (Reviewed by Andersen and Aagard, Scand J Med Sci Sports 2010), so even if endurance trained individuals lose type IIx fibers, this effect is not distinct from resistance training. Third, motoneurons contain boatloads of mitochondria, so your point about mitochondria is overlooking a key source of where mitochondrial dysfunction is likely to have the most impact on aging skeletal muscle: the motoneuron and perhaps also the perisynaptic Schwann cells that envelop the motoneuron terminals at the neuromuscular junction. In this respect, there is very convincing data showing that mitochondria in the motoneuron nerve terminals degenerate with aging (Garcia et al. J Neurol Sci. 2013), likely because the rate of their replacement is not keeping up with the accumulation of damage (but, at this point we do not know where those mitochondria come from - the transit time of a mitochondrion made in the motoneuron cell body where the nucleus resides is far longer than the half life of a mitochondrion, so this seems an unlikely way to replenish mitochondria in the motoneuron terminals - perhaps they are donated by the perisynaptic Schwann cells?). Do I think we have proven at this point that mitochondria are the most important cause of muscle degeneration with aging? No, and nor do I think we have a clear sense of the hierarchy of impact between muscle fiber mitochondria and mitochondria in the perisynaptic Schwann cells and motoneurons, but your counterarguments are built upon several misunderstandings of the literature. We have a lot of work to do so keep an open mind 
Tony has done another video that cover’s his theories in this area. Interestingly Bryan Johnson seems to be working on this area now with his focus on increasing his jumping height (to dunk a basketball): Bryan Johnson on X: "I'm 49, training to dunk. A new PR today: 365 lbs for 2 reps. I’m aiming for a ~35” vertical. At 180 lbs, I'll need a take off velocity of 14.5 ft/s in 0.2 seconds, to generate 585 lbs of force, and 11 kW of peak power. This lift helps build the raw maximal force ceiling." / X
The presentation outlines a deterministic, non-linear model of human senescence governed by the convergence of two biological phenomena: undulating plasma proteomic remodeling across the lifespan and progressive, irreversible alpha motor unit attrition. The core thesis asserts that human functional decline does not advance in a gradual, linear manner. Instead, systemic aging is characterized by distinct proteomic crests occurring at approximate chronological ages of 34, 60, and 78 years, which intersect with subclinical neuromuscular degradation that initiates in the third decade of life and culminates in a functional collapse around age 75.
At age 34, the initial proteomic crest reflects significant dysregulation of extracellular matrix (ECM) proteins, destabilizing structural tissue integrity. This proteomic shift is preceded by the selective loss and denervation of high-threshold, glycolytic Type IIx motor units beginning in an individual’s late twenties. The second proteomic wave at age 60 is marked by systemic dysregulation in metabolic, endocrine, and vascular pathways, directly correlating with the clinical emergence of cardiometabolic and vascular pathologies. During this sixth-to-seventh decade transition, motor unit loss accelerates substantially, resulting in an estimated 40% loss of functional motor units by age 70.
The terminal biological phase occurs between ages 75 and 78, described as the functional “cliff phenomenon,” where physical activity levels and fat-free mass plummet across populations. This threshold coincides with the third proteomic wave at age 78, characterized by severe downregulation of axon guidance pathways, Ephrin signaling, bone morphogenetic protein (BMP) cascades, and immune competence. By age 90, residual motor unit quantity falls to approximately 10%, precipitating generalized frailty, loss of mobility, and diaphragmatic respiratory failure. The speaker contends that contemporary longevity modalities—including cellular reprogramming, stem cell therapies, and generic supplementation—fail to address irreversible spinal motor neuron loss, identifying neuromuscular junction stability and motor unit preservation as the primary rate-limiting ceiling of the human healthspan.
| Claim from Video | Speaker’s Evidence | Scientific Reality (Current Data) | Evidence Grade (A-E) | Verdict |
|---|---|---|---|---|
| 1. Plasma proteome shifts in 3 distinct crests at ages 34, 60, and 78. | 2019 plasma proteomic study of 4,263 individuals measuring 2,925 proteins. | Validated in the Stanford/INTERVAL cohort demonstrating non-linear proteomic waves at 34 (ECM), 60 (metabolism/hormones), and 78 (axon guidance/homeostasis) (Lehallier et al., 2019). | Level C (Large-scale Human Observational/Cohort) | Strong Support |
| 2. The 2024 Nature Aging study showing peaks at 44 and 60 is inferior and flawed. | Asserts the 2024 study had an inadequate sample size and only scratched the surface. | Shen et al., 2024 utilized longitudinal multi-omics (transcriptomics, proteomics, metabolomics, microbiome) in 108 subjects. While smaller in sample size (n=108 vs n=4,263), its multi-omic depth captured mid-life lipid/cardiovascular remodeling at ~44 and immune/carbohydrate shifts at ~60. Dismissing it as inferior ignores complementary multi-omic layers. | Level C (Human Longitudinal Multi-Omics Cohort) | Unsupported(Methodological bias) |
| 3. Type IIx motor unit loss begins irreversibly in the 20s/30s across all humans. | Neuromuscular aging literature and motor unit estimation models. | Electrophysiological and histological data confirm early-adult denervation of fast glycolytic motor units, followed by reinnervation by slow motor neurons (motor unit remodeling) (Lexell et al., 1988; Piasecki et al., 2018). Resistance training preserves fiber size but does not completely halt motor neuron loss. | Level C (Human Cross-Sectional / Histological Studies) | Strong Support |
| 4. Extracellular matrix (ECM) structural integrity begins to degrade at age 34. | Proteomic pathway analysis showing down-regulated structural proteins at age 34. | The age 34 proteomic crest is specifically enriched for collagen fibril organization, metalloproteinase activity, and ECM-receptor interaction pathways (Lehallier et al., 2019). | Level C (Human Proteomic Cohort) | Strong Support |
| 5. Physical activity and lean mass plummet non-linearly off a ‘cliff’ at age 75. | Population doubly labeled water and lean mass graphs. | Large-scale doubly labeled water datasets confirm total energy expenditure and basal metabolic rate remain stable from age 20 to 60, followed by a modest decline, with an accelerated functional drop-off in lean mass and physical expenditure past age 70–75 (Pontzer et al., 2021). | Level C (Human Multi-Cohort Metabolic Analysis) | Strong Support |
| 6. The age 78 proteomic shift collapses axon guidance, Ephrin, and BMP pathways. | Pathway enrichment of third proteomic crest proteins. | Gene Ontology and KEGG pathway analyses of plasma factors at age 78 demonstrate significant enrichment for axon guidance, EPH-ephrin receptor signaling, and TGF-β/BMP signaling pathways (Lehallier et al., 2019). | Level C (Human Proteomic Pathway Analysis) | Strong Support |
| 7. Centenarians are strictly divided into Survivors, Delayers, and Escapers. | Centenarian demographic profiles. | Validated demographic framework from the New England Centenarian Study (Evert et al., 2003): Escapers (15–32%), Delayers (42–44%), Survivors (24–43%). | Level C (Human Epidemiological Cohort) | Strong Support |
| 8. Motor unit loss is the sole rate-limiting barrier preventing survival past 110 years. | Mortality curve flattening and supercentenarian ceilings. | While sarcopenia and neuromuscular failure are major drivers of frailty and fall-related mortality, supercentenarian mortality is multifactorial, heavily driven by transthyretin cardiac amyloidosis, immune senescence, and systemic vascular stiffness (Evert et al., 2003). | Level C (Human Observational / Autopsy Data) | Plausible(Overstated as sole cause) |
| 9. No technology (stem cells, reprogramming, supplements) can replace or regenerate lost motor units. | Absence of approved motor neuron regenerative therapeutics. | Current cellular reprogramming and stem cell modalities have failed to achieve functional re-innervation of host muscle fibers from spinal motor neurons in human clinical trials. Motor neuron regeneration remains an unsolved translational barrier (Piasecki et al., 2018). | Level E (Expert Consensus / Translational Literature) | Strong Support |
`┌────────────────────────────────────────────
│ EVIDENCE-BASED PROTOCOL │
├────────────────────────────────────────────
│ [HIGH CONFIDENCE TIER] (Level A/B) │
│ • Progressive High-Velocity Resistance Training (Power Training) │
│ - Intent: Maximize motor unit recruitment; preserve Type II fiber CSA │
│ - Dose: 2-3 sessions/week, 70-85% 1RM + explosive concentric intent │
│ • Protein Target & Distribution Optimization │
│ - Intent: Counteract age-related anabolic resistance │
│ - Dose: 1.6-2.2 g/kg/day, evenly bolused with ≥3g leucine per meal │
│ • Multicomponent Neuromuscular & Balance Training │
│ - Intent: Mitigate fall risk and preserve proprioceptive reflex arcs │
│ - Dose: ≥3 days/week agility, balance, and reactive perturbation drills │
├──────────────────────────────────────────────
│ [EXPERIMENTAL TIER] (Level C/D) │
│ • Neuromuscular Electrical Stimulation (NMES) │
│ - Intent: Non-volitional recruitment of high-threshold motor units │
│ - Safety: High safety margin; protocol-dependent │
│ • Creatine Monohydrate Supplementation │
│ - Intent: Enhance phosphagen resynthesis in Type II muscle fibers │
│ - Dose: 5 g/day continuous administration │
│ • Circulating Biomarker Monitoring at Age Decades 3, 5, and 7 │
│ - Intent: Identify subclinical dysglycemia and vascular stiffening early │
├───────────────────────────────────────────────
│ [RED FLAG ZONE] (Lacks Efficacy / Safety Data Absent) │
│ • Systemic ‘Anti-Aging’ Stem Cell Infusions for Motor Unit Regrowth │
│ - Status: Zero clinical evidence for spinal motor neuron reinnervation │
│ • Unregulated Peptide Therapy for Sarcopenia Reversal (e.g., GH Secretagogues)│
│ - Status: Potential oncogenic and glycemic risks; lacks Level A/B support │
└────────────────────────────────────────────────
Is that training specifically good for motor units?
I was thinking it falls under this category (but I could be wrong) - and if that is the case then it would seem to help.
The point about motor units is that they have a long axonal arbour on the neuron element.
Maintaining or repairing that is hard and needs the genome to function at a maximal level. Training can only take this so far.
