Youtube has a setting that prevents it from being “embedded” in other discussions, pages, etc. Most YouTube people don’t turn on this setting. And Mike didn’t use to, but now it appears he has. You can still just provide a link to the video, but put it on a line with other text so people have to click on it and go to Youtube to watch it.
See this discussion for More on Tony Ruggia and his theory on Motor Units: Motor Units as determinants of Aging
If We Escape All Major Diseases, Neurodegeneration And Respiratory Failure Is Likely
Like this: https://www.youtube.com/watch?v=poEP7cQBCn4
AI Summary
A. Executive Summary
The video argues that for people who escape the major age-related killers (CVD, cancer, diabetes, Alzheimer’s), the ultimate bottleneck to “super-longevity” may be respiratory failure driven by age-related motor neuron and motor unit loss—particularly in the diaphragm. Using supercentenarian Maria Branyas Morera (117 y) as an example, the presenter builds on a prior hypothesis (from “I Am Longevity” channel) that terminal death could result from diaphragm denervation and failure during sleep.
Mechanistically, he reviews data (mainly in rodents) showing: (1) motor units decline sharply after midlife; (2) phrenic motor neurons innervating the diaphragm are lost with age; (3) diaphragm fast-twitch fibers (type IIx/IIb) atrophy and diaphragm force production falls in old animals. In humans, he uses ALS as an extreme model of neurodegeneration where respiratory failure is the leading cause of death. ALS lifetime risk is non-trivial (~1 in 350 men, ~1 in 400 women), and its mechanisms—proteostasis disruption, mitochondrial dysfunction, oxidative stress, neuroinflammation—overlap with hallmarks of aging.
He then centers on neurofilament light chain (NFL) as a blood biomarker of axonal injury. NFL is ~2× higher in ALS vs controls and rises with age even in “healthy” cohorts. By extrapolating regression models from studies that only go to 65–85 y, he estimates that average NFL levels in 100–135+ year-olds could reach ranges seen in ALS patients, implying substantial neurodegeneration even without a formal ALS diagnosis.
Because direct NFL testing is expensive, he proposes tracking specific ALS-associated diacylglycerides (DGs), some of which are 6–18× higher in ALS and correlate with NFL. He shows his own longitudinal metabolomics data suggesting relatively low and stable DG levels, and speculates that interventions like exercise and metabolic optimization that keep DGs low may indirectly preserve motor units and delay respiratory failure.
B. Bullet Summary
- The video hypothesizes that in disease-free super-agers, death may often occur via respiratory failure caused by diaphragm motor unit loss.
- Motor unit number is relatively stable until ~midlife, then declines steeply with age, underpinning sarcopenia and loss of function.
- The diaphragm is a skeletal muscle innervated by phrenic motor neurons; age-related phrenic neuron loss is documented in rats and associated with reduced diaphragm mass and force.
- Fast-twitch diaphragm fibers (type IIx/IIb) are preferentially lost with age, leading to reduced maximal inspiratory force in old animals.
- ALS is used as a model of accelerated neurodegeneration where respiratory failure, not cancer/CVD, is the primary cause of death.
- ALS lifetime risk is on the order of 1/350 men and 1/400 women, showing it is rare but not vanishingly so.
- ALS pathophysiology overlaps with hallmarks of aging, including proteostasis disruption, mitochondrial dysfunction, oxidative stress, and neuroinflammation.
- Neurofilament light chain (NFL) is a structural axonal protein released into blood/CSF when axons are damaged, and is elevated in ALS and other neurodegenerative diseases.
- ALS patients have roughly 2× higher serum NFL than age-matched controls; the video focuses on typical and extreme values (~20, ~40, ~110 pg/mL).
- Multiple cohorts show serum NFL rises with age, particularly after ~60, even in people without diagnosed neurodegenerative disease.
- The presenter extrapolates NFL-age regressions (fit only to ≤65–85 y samples) out to 100–150 y and finds predicted NFL values overlapping ALS ranges—explicitly labeling this as speculative.
- He suggests that in extreme old age, NFL may reflect subclinical, diffuse neurodegeneration sufficient to compromise respiratory muscle innervation even without ALS.
- A plasma lipidomics study in ALS found several diacylglycerides, particularly DG(18:1/18:1), to be 6–18× higher than controls and strongly correlated with NFL.
- He uses an at-home metabolomics panel (Iollo/“IO”) to track four of these ALS-linked DG species and aims to keep their summed level low and stable across years.
- Exercise and other yet-to-be-detailed interventions are proposed as candidate strategies to maintain motor units, lower DGs/NFL, and potentially delay neurodegenerative respiratory failure.
D. Claims & Evidence Table
| Claim |
Evidence given in video |
Assessment |
| 1. Motor units decline steeply after ~55 y, driving sarcopenia and functional loss. |
Human motor unit counts in a foot muscle vs age: flat to ~55, then sharp decline toward 100 y. |
Strong for age-related motor unit loss; consistent with broader neuromuscular literature. |
| 2. Phrenic motor neurons decline with age, leading to diaphragm muscle atrophy and weakness. |
Rat data: fewer phrenic motor neurons in old vs young; lower diaphragm CSA and force, especially in fast fibers. |
Strong (animals, translational caveats); well documented in aged rat diaphragm and phrenic MN studies. |
| 3. Respiratory failure is the main cause of death in ALS. |
Cites ALS clinical data; notes respiratory failure, not CVD/cancer, is typical terminal event. |
Strong; confirmed by multiple ALS cohorts and reviews. |
| 4. ALS lifetime risk ≈ 1/347 for men and 1/436 for women. |
States these precise ratios without source details. |
Strong (minor rounding differences); aligns with ~1/350 and ~1/400 estimates from population studies. |
| 5. NFL is about 2× higher in ALS than in controls, with ALS extremes ~110 pg/mL. |
Shows a case–control NFL plot (≈20 vs ≈40 pg/mL, with outliers ≈110). |
Strong directionally; magnitude and ranges are plausible, though exact values vary by assay and cohort. |
| 6. Serum NFL rises steadily with age in non-ALS populations. |
Two studies plotted: increasing NFL vs age up to 65 and 85 y; median and upper-range values climb in older groups. |
Strong; many independent cohorts show robust age–NFL associations. |
| 7. Extrapolating NFL-age regression suggests 100–106 y adults could have average NFL ≈40 pg/mL (ALS-like). |
Uses linear regression derived from 20–65 or 20–85 y data; plugs in 104–106 y to get ≈40 pg/mL. |
Speculative; regression beyond observed data is statistically fragile, and there is little direct NFL data in centenarians/supercentenarians. |
| 8. At 135–150 y, extrapolated NFL ≈110 pg/mL (ALS extreme range). |
Same regression pushed far beyond observed age range. |
Highly speculative/unsupported in practice; no humans live routinely at these ages, and model behavior is unknown there. |
| 9. Several DG species, especially DG(18:1/18:1), are 6–18× higher in ALS and correlate strongly with NFL. |
Shows lipidomics data: seven DGs with log2 fold-change ≈2.6–4.2 and one (DG(18:1/18:1)) correlating with NFL. |
Moderately strong; matches published ALS lipidomics, but findings are from relatively small cohorts and need replication. |
| 10. Lowering these DGs over time might help keep NFL low and slow neurodegeneration. |
Presenter’s own longitudinal DG data and mechanistic plausibility (lipid dysregulation in ALS/aging). |
Speculative; correlation ≠ causation, and no direct interventional data yet show that DG reduction lowers NFL or alters clinical outcomes. |
| 11. Neurodegeneration plus diaphragm motor unit loss will likely be the terminal bottleneck for “super-longevity” even without ALS. |
Conceptual extrapolation from ALS, aging motor neuron data, and NFL age-trajectories. |
Speculative but plausible; mechanism is coherent, but not empirically demonstrated in supercentenarian cohorts. |
E. Actionable Insights (for a longevity-focused viewer)
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Prioritize lifelong neuromuscular preservation. Heavy focus on preventing motor unit and muscle loss—especially in respiratory and postural muscles—supports sustained resistance training, power training, and regular physical activity across the lifespan as non-negotiables.
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Include respiratory-focused training. Given diaphragm vulnerability, adding inspiratory muscle training (threshold devices, resisted breathing), high-ventilation exercise, and attention to posture/chest mobility is rational, even though direct human outcome data are sparse.
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Assume neurodegeneration risk even if “healthy.” Age-related increases in NFL in non-ALS populations imply that subclinical neuronal injury accumulates; don’t treat “no diagnosis” as “no neurodegeneration.”
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Use NFL selectively as a high-value biomarker. Serum NFL can be informative for neurodegenerative activity and aging biology, but tests are expensive; if used, it makes more sense as an infrequent, high-signal measurement (e.g., every 1–2 years) or in structured n=1 protocols rather than routine monthly labs.
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Leverage lower-cost proxies and panels. ALS-linked lipid species (DGs, other complex lipids) on metabolomic panels could serve as exploratory proxies for neurodegenerative stress. Treat them as hypothesis-generating, not diagnostic.
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Target systemic drivers of lipid and mitochondrial dysregulation. Interventions that improve insulin sensitivity, reduce ectopic lipid deposition, and stabilize mitochondrial function (exercise, weight management, sleep quality, limited ultra-processed food, cautious alcohol use) are likely beneficial for both lipids and neurodegeneration risk, even if DG→NFL causality is unproven.
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Think in terms of “rate control,” not elimination. Given that age-related neurodegeneration appears universal (rising NFL with age), realistic goals are slowing trajectory and delaying functional thresholds (e.g., diaphragm failure), not reaching “zero” degeneration.
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Track longitudinally, not just once. For advanced self-tracking, repeated measures of DGs and (if affordable) NFL over years are more informative than single snapshots—particularly to detect whether your personal interventions materially change slope vs age norms.
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Integrate neuro markers with functional testing. Complement biochemical markers with simple field tests: maximal inspiratory pressure, breath-hold times, VO₂max/CPET where feasible, grip strength, gait speed, and balance—since ultimately diaphragm and motor unit failure are functional events.
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Recognize the limits of extrapolation. Treat extreme-age projections (106–150 y NFL levels) as scenario planning, not quantitative forecasts. Use them to prioritize neuroprotection and respiratory function, not to assume specific numeric thresholds.
H. Technical Deep-Dive
Motor units, diaphragm, and aging
A motor unit comprises a single α-motor neuron and the muscle fibers it innervates. Aging is associated with loss of motor neurons, collateral reinnervation, and eventual failure of that compensatory process, yielding fewer and larger, then fewer and dysfunctional, motor units.
The diaphragm is a mixed-fiber skeletal muscle with slow (type I) and fast (type IIa/IIx/IIb) fibers, innervated by phrenic motor neurons in cervical spinal cord segments C3–C5. Rodent studies show:
- ~20% loss of phrenic motor neurons by 24 months (old) vs 6 months (young), with selective vulnerability of large, fast-motor units.
- Preferential atrophy of type IIx/IIb diaphragm fibers and decreased maximal specific force, mirroring limb muscle sarcopenia but with direct implications for ventilation capacity.
ALS as an accelerated model
ALS involves progressive degeneration of upper and lower motor neurons, leading to paralysis of limb, bulbar, and respiratory muscles. Respiratory failure due to diaphragm and accessory muscle weakness is the predominant cause of death.
Mechanistically, ALS shows:
- Disrupted proteostasis (misfolded SOD1/TDP-43/FUS),
- Mitochondrial dysfunction and oxidative stress,
- Axonal transport defects,
- Neuroinflammation (activated microglia/astrocytes),
which overlap with canonical hallmarks of aging and neurodegeneration more broadly.
Neurofilament light chain (NFL)
NFL is a structural component of large myelinated axons; injury triggers its release into CSF and then blood. Elevated serum/CSF NFL is now a pan-neurodegenerative marker, prognostic in ALS, Alzheimer’s, MS, and others.
Normative studies show:
- sNFL rises non-linearly with age, especially >60, and is influenced by sex, BMI, and kidney function.
- Older adults without diagnosed neurodegeneration can have sNFL overlapping ranges seen in mild disease.
The video’s key move is linear extrapolation of age–NFL regressions from data fit only up to 65–85 y out to 100–150 y. Statistically, this assumes a stable linear slope well beyond observed data, which is rarely guaranteed—particularly if survival bias and competing risks alter the population at extreme ages. That’s why those specific numbers (e.g., “40 pg/mL at 104–106 y”) should be treated as illustrative rather than as hard forecasts.
Lipidomics and DG(18:1/18:1)
High-resolution lipidomics in ALS has identified alterations in multiple lipid classes, including diacylglycerols (DGs). The cited work reports:
- Several DG species significantly higher in ALS plasma vs controls (log₂ fold-change ≈2.6–4.2, i.e., ≈6–18×).
- A particularly strong correlation between DG(18:1/18:1) and NFL levels, suggesting co-tracking of membrane/lipid dysregulation with axonal damage.
The mechanism is unclear: DG accumulation may reflect altered membrane turnover, impaired mitochondrial β-oxidation, or generic metabolic stress. It is not yet known whether lowering these DG species causally reduces NFL or slows neurodegeneration.
I. Fact-Check of Key Claims
- ALS lifetime risk (≈1/347 men, 1/436 women)
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Evidence: Large epidemiologic analyses in European and US cohorts estimate lifetime ALS risk at ~1 in 350 for men and ~1 in 400 for women.
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Verdict: Accurate in magnitude. Minor differences in denominators are just rounding and cohort variation.
- Respiratory failure is the leading cause of death in ALS
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Evidence: Multiple clinical studies and reviews identify respiratory failure secondary to respiratory muscle weakness as the predominant cause of ALS mortality.
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Verdict: Accurate. Strong consensus.
- NFL increases with age in non-ALS populations
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Evidence: Several large cohorts (e.g., Khalil et al., Ladang et al., NHANES-based sNFL norms) show robust positive correlations between age and serum NFL, with steeper increases after age 60.
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Verdict: Accurate. The direction and qualitative implication are well supported.
- Extrapolated NFL at 100–135+ years matches ALS ranges
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Evidence: The underlying regressions are derived from samples up to 65–85 y; there is essentially no population-level NFL dataset spanning 100–135+ y to validate the extrapolated values. Supercentenarians are extremely rare and heavily survival-selected.
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Verdict: Speculative. The extrapolation is mathematically simple but biologically uncertain. Real trajectories could flatten, steepen, or diversify at extreme ages. The video correctly labels this as speculative, but viewers should not treat the precise numbers as established fact.
- DG(18:1/18:1) and other DGs are 6–18× higher in ALS and correlate with NFL
-
Evidence: ALS lipidomics work reports significantly elevated diacylglycerol species and a strong positive correlation between DG(18:1/18:1) and NFL.
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Verdict: Directionally accurate, but early-stage. These are statistically solid findings in specific cohorts, but sample sizes are modest and causality is unknown.
- Maintaining low DG levels will likely help preserve motor units and delay respiratory failure
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Evidence: No interventional human data yet show that targeting ALS-linked DGs alters NFL, clinical progression, or respiratory outcomes. DGs probably reflect a mixture of diet, metabolism, and disease-related processes rather than a single causal axis.
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Verdict: Speculative. Reasonable as a hypothesis to test in n=1 or trials but not evidence-based guidance at this stage.
Overall, the mechanistic framing—motor unit loss, diaphragm vulnerability, ALS as a model, NFL as an axonal injury biomarker, and lipid dysregulation as a correlated feature—is well grounded. The main weak points are the aggressive age extrapolations for NFL and the implied causal link between specific DG reductions and neuroprotection, which remain unproven and should be treated as hypotheses rather than established longevity strategies.
Corrected Text: Preserving Diaphragm Motor Units
The “Respiratory Longevity” Weekly Protocol