Charles Brenner makes some useful points generally particularly about functional tests, but I do not agree with him always.
GPT5:
Here’s a clean, structured version of your requested tidy transcript, plus a summary and critique.
Tidy Transcript — Key Points
Speaker: Charles Brenner, PhD — Professor and Chair in Diabetes & Cancer Metabolism, City of Hope.
Focus: NAD metabolism, metabolic stress, critique of longevity hype.
1. On NAD & Longevity
- NAD is central to metabolism, DNA repair, and stress responses.
- NR (nicotinamide riboside) discovered by Brenner’s lab as an NAD precursor.
- NR extends yeast lifespan in a very artificial yeast aging model — not applicable to humans.
- NAD disturbances occur in specific metabolic stress conditions: DNA damage, neurodegeneration, infections, inflammation, mitochondrial disease, alcoholism, COVID-19.
- NR has shown benefit in RCTs for conditions where NAD is clearly disrupted (8 RCTs at ~1g/day).
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Against: Testing NAD boosters for direct human lifespan extension — not feasible, untestable in practical timescales, and based on poor model systems.
2. Skepticism About NAD Decline with Age
- Evidence for age-related NAD decline is tissue-specific and inconsistent.
- Example: Decline seen in mouse liver with age, but not in muscle.
- Confounding factors: microbiome, strain, methodology.
- More certain about NAD disturbance from metabolic insults than from chronological aging per se.
3. Mechanisms of NAD Disruption
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Peripheral nerve injury: NMN accumulates → activates SARM1 → NAD destruction → axon death.
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DNA damage: PARP1 activation depletes NAD.
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Oxidative stress: NADPH turnover depletes NAD.
- Different insults disturb NAD via distinct mechanisms.
4. On Longevity Hype & Model Organisms
- Many preclinical “longevity” models (e.g., yeast replicative aging) irrelevant to humans.
- Mice not good human aging analogues for certain endpoints (e.g., fall-related mortality).
- Rapamycin: extends mouse lifespan but likely harms human muscle mass via mTOR inhibition.
5. Publication Bias & Bad Science
- Positive results get published; negative replication often ignored.
- Resveratrol case: claimed benefits in mice not borne out; non-published failures abound.
- Problems: non-blinded assessments, selective data reporting, hype preceding publication.
- Hard to formally critique published work; “letters to editor” rarely change the narrative.
- Many flawed, irreproducible studies remain un-retracted.
6. On Clinical Trial Design
- Aging is not an FDA-recognized indication — longevity trials infeasible in humans.
- Regulatory path: target diseases or functional endpoints (e.g., sarcopenia post-chemo).
- Dogs may be a bridge model (shorter lifespan, measurable endpoints).
- Biomarkers of aging alone unlikely to serve as regulatory endpoints.
7. Personal Stance on NR
- Brenner helped create NAD-boosting industry but does not claim lifespan extension.
- NR use cases: conditions with measurable NAD disruption.
- Rejects “longevity drug” marketing; focuses on achievable, testable endpoints.
8. Exciting Current Research
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Citrin deficiency (mutation in SLC25A13) — affects carbohydrate, protein, lipid metabolism.
- Findings: explains lean phenotype, dislike of sweets, fatty liver via ChREBP activation, high FGF-21.
- Potential new therapies for fatty liver disease, urea cycle disorders, sweet cravings, and alcohol use disorder.
Summary
Charles Brenner argues that while NAD metabolism is fundamental to life and clearly disturbed in many stress and disease states, there is no solid evidence that NAD boosters extend human lifespan. He is skeptical about broad claims of NAD decline with age, stressing tissue-specific data and confounding variables. NR (nicotinamide riboside) has demonstrated efficacy in certain human trials targeting clear NAD deficiencies, but translating yeast or mouse “lifespan” results to humans is scientifically unjustified.
Brenner strongly criticizes hype in the longevity field, pointing to flawed preclinical models, irreproducible results, and widespread publication bias. He highlights the difficulty in running lifespan trials in humans and advocates for targeting specific diseases or measurable functional endpoints instead. His lab’s current excitement centers on new mechanistic insights into citrin deficiency and its potential therapeutic applications.
Critique
Strengths:
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Scientific rigor: Brenner emphasizes reproducibility, realistic endpoints, and the need to avoid hype.
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Clear distinction between disease treatment and lifespan extension.
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Transparency: He acknowledges his industry ties but maintains a conservative, evidence-based stance.
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Specificity: Discusses concrete mechanistic pathways (SARM1, PARP1, NADPH turnover).
Weaknesses / Limitations:
- While his critique of model organism extrapolation is valid, it may understate the role of preclinical models in hypothesis generation if used cautiously.
- His dismissal of rapamycin for humans is plausible but not fully substantiated with clinical evidence; human mTOR studies are ongoing.
- The assertion that NAD decline is more linked to stress than aging could be more robustly supported with cross-species, multi-tissue data.
- His reliance on disease-specific endpoints, while regulatory-practical, may miss subtle systemic benefits detectable only in long-term or biomarker-driven studies.
Overall Viewpoint:
Brenner is a grounded, cautious voice in a field prone to overstatement. He values mechanistic clarity, reproducibility, and clinical relevance over speculative promises. His approach is more about protecting credibility in longevity research than chasing sensational breakthroughs — arguably necessary to mature the field.
If you want, I can also prepare a side-by-side table contrasting Brenner’s position with common pro-longevity claims on NAD boosters — it would make the critique even sharper.
Here’s the side-by-side comparison table contrasting Brenner’s positions with common pro-longevity claims on NAD boosters.
| Tópico |
Brenner’s Position |
Common Pro-Longevity Claims |
| NAD decline with age |
Not convinced it’s universal; tissue-specific; decline often due to metabolic stress, not chronological aging. |
NAD levels drop universally with age, and boosting NAD will reverse aspects of aging. |
| Translating model organism results to humans |
Yeast and mouse “lifespan” data are mostly irrelevant to humans; many models are poor analogues. |
Lifespan extension in yeast/mice is meaningful evidence for potential human benefits. |
| NR/NMN as “longevity drugs” |
No credible human evidence for lifespan extension; focuses on specific metabolic stress conditions. |
NR/NMN can extend human lifespan or reverse aging when taken chronically. |
| Feasibility of human lifespan trials |
Impractical; decades-long studies not viable; instead, target diseases with measurable endpoints. |
Direct lifespan trials are not needed — biomarkers and preclinical results are enough to justify use. |
| Publication bias & reproducibility |
Serious problem — positive results overrepresented; many findings fail replication; negative data suppressed. |
Positive results are representative of true effects; replication is assumed rather than demonstrated. |
| Rapamycin as a human anti-aging drug |
Likely harmful for human muscle mass; mTOR inhibition not a safe long-term strategy for people. |
Proven mouse lifespan extension suggests rapamycin will slow human aging. |
| Regulatory path |
Must target recognized disease indications (e.g., sarcopenia, chemo-related muscle loss) for approval. |
Aging should be recognized and approved as a treatable condition directly. |
| Mechanism of NMN entry into cells |
NMN is dephosphorylated extracellularly to NR, then enters via ENT1/ENT2; not directly transported in as NMN. |
NMN is directly transported into cells, rapidly boosting intracellular NAD. |
| Marketing ethics |
Avoids promising lifespan gains without evidence; advises companies not to hype anti-aging benefits. |
Marketing often emphasizes anti-aging, vitality, and life-extension claims without human RCT backing. |
| Role of NAD boosters in health |
Useful where NAD is measurably disrupted (e.g., inflammation, neurodegeneration, infection, metabolic disease). |
Broad preventive or rejuvenation benefits across all aging individuals, regardless of specific NAD status. |
If you want, I can also produce a third column showing scientific evidence level for each claim — that would make it easier to see which ideas are solid vs speculative. This would turn it into more of an “evidence map” for NAD boosters.
