Thank goodness - I can enjoy 4 espresso cups of arabica coffee (if slightly twitchy by the fourth cup 
)
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Too bad, so sad
https://www.sciencedirect.com/science/article/abs/pii/S0308814623021611
TL;DR various decaffeination procedures decrease or, depending on the procedure, entirely eliminate trigonelline from coffee.
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Medaura, it might have been worse I believe. It is not clear if green decaff has 25% or 75% (25% lower) the trigonelline of regular coffee. During roasting trigonelline is lost anyway and we don’t know if lower concentrations have equal or minor loss.
All in all, even in the worst scenario, I would behappy with 1/4 the amount in decaff, since we can drink of it ad libitum. Sometimes I drink 10 decaffs, done with my home automatic espresso machine. That would be equal to 2.5 regular cups.
Analysis of the decaffeination-induced changes in nonvolatile compounds revealed that decaffeinated green coffee beans had significantly lower concentrations of trigonelline (25%)
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That was just one source I cited. Others say that certain common procedures of decaffeination entirely remove the trigonelline (e.g., chemical solvents) so ad libitum consumption by times zero trigonelline concentration equals zero trigonelline. I think dry roasting fenugreek seeds then grinding them into powder to add to soups is the way to go. Fenugreek seeds can also be sprouted.
It would be useful to know all the details of chemical trigonelline removal since AFAIK there are several industrial decaffeination processes. At least two, the so-called swisswater, and supercritical CO2 use no solvent. Usually, the producer declares the specific process used, commonly ethyl acetate or Swisswater, so choosing the latter we may hypothetically enjoy the trigonelline.
Re. fenugreek seeds, that’s of course the direct nonsense way, I used to sprout them and remember the taste was spicy and good. I don’t know about soups, it may require some stoicism.
An alternative would be to fill large dimension capsules with the powder.
Technically what requires stoicism would be accepting our inevitable demise with magnanimous indifference instead of going to fenugreek-seed-grinding lengths in the dubious hope of staving it off, but I digress. 
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Conquer Aging Or Die Trying!
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You do! But at least @A_User found it inspirational. And I found his clip inspirational…chain reaction.
But in terms of trigonelline and NAD. Keep in mind that for Michael Lustgarten @ConquerAging trigonelline didn’t increase NAD.
https://www.youtube.com/watch?v=-jt4CcT_pRU
Also trigonelline is newly listed on Amazon as a powder, also capsules from RBS (that Lustgarten used).
https://www.amazon.com/Trigonelline-535-83-1-Purity-Reference-Substance/dp/B0BQVS8WB8
It was likely a dose insufficiency issue on his end, underscoring how these mouse-to-human dose translation charts are very rough rules of thumb. But it’s nice to see it on Amazon — albeit from a Chinese manufacturer but then again, that’s who’s probably sourcing the ingredients behind most trusted supplement brands.
Oh and as a snack today I soaked a cup or two of fenugreek seeds in water and drained it a few hours later, drinking the “tea.” It tasted like nothing except the last gulp, which has a bitterness to the aftertaste consistent with the alkaloid contents of the seed (including its trigonelline). The seeds themselves I roasted slowly on low heat with olive oil and some spices. Garnished with fresh onion and tomato they were pretty appetizing — no stoicism required if you don’t mind a tiny bit of bitterness.
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Great recipe, it’s good to take advantage of functional foods in such a way, the only drawback being perhaps the time required.
It really took almost no time at all. I asked ChatGPT for ways to prepare fenugreek seeds so as to maximize trigonelline retention. Oh and it seems that whatever trigonelline in coffee, whether it made it past the decaffeinating process or not, gets converted into niacin from roasting. So the minimally processed fenugreek seeds look like the way to go, short of Chinese vendors on Amazon. That’s an interesting development by the way, these raw powders on Amazon from Chinese suppliers. They’ll soon be competing with the supplement brands who are the usual middlemen capturing the greatest margins, unless they’re booted off the platform somehow.
Edit: I just saw the price—$60 for 20 mg? Pfff. Sticking to fenugreek seeds.
I checked my local Amazon store, and either the powder or the whole seeds vary widely in price and can cost as little as 17 Euros /kg, which is pretty inexpensive.
It takes about a cup or two of fenugreek seeds properly cooked to yield 200-1200mg of trigonelline as per gpt, depending on local variability, so I think the powder is useless as can’t be consumed at sufficient scale. I take it still as it allegedly supports milk production, but for trigonelline? Fuhgeddaboudit — seeds all the way.
The following table identifies the lowest-cost sources for standardized or purified Trigonelline capsules available for shipping to the USA, updated to include Mortalis Labs.
Analysis of Results:
- New Top Contender: Mortalis Labs has taken the #1 spot (by a fraction of a cent) and offers excellent value. It provides a higher potency per capsule (300mg) compared to the runner-up, Codeage (250mg), and has a lower upfront bottle price ($39.99 vs $49.99).
- Best Value Tier: Both Mortalis Labs and Codeage represent the “Gold Standard” tier, offering pure Trigonelline for ~$0.22 per 100mg. This is ~90% cheaper per active milligram than buying standard Fenugreek seed extracts.
- Shipping Consideration: While Mortalis Labs is technically cheaper per mg, **Codeage (via Target/Nordstrom)**includes free shipping. Mortalis Labs typically charges for shipping on single bottles (under ~$50), which may make Codeage the lower “out-the-door” price for a single unit purchase.
Top Sources for Trigonelline (Sorted by Lowest Cost Per 100mg)
| Rank | Product Name | Vendor | Total Weight (Capsules) | Total Price (USD) | Cost Per 100mg Active Trigonelline | Capsules to get 100mg |
|---|---|---|---|---|---|---|
| 1 | Trigonelline Supplement 300mg | Mortalis Labs | 60 Caps (18,000mg Total Active) | $39.99 | $0.22 *($39.99 / 180)_ | 1 (1 cap = 300mg) |
| 2 | Liposomal Trigonelline 250mg | Target / Codeage | 90 Caps (22,500mg Total Active) | $49.99 | $0.22 _($49.99 / 225)* | 1 (1 cap = 250mg) |
| 3 | Liposomal Trigonelline 250mg | Nordstrom | 90 Caps (22,500mg Total Active) | $49.99 | $0.22 *($49.99 / 225)_ | 1 (1 cap = 250mg) |
| 4 | Trigonelline (Methylated Niacin) 250mg | Renue By Science | 90 Caps (22,500mg Total Active) | $51.95 | $0.23 _($51.95 / 225)* | 1 (1 cap = 250mg) |
| 5 | Fenugreek Seed + 3% Trigonelline | eBay (Neurogan) | 60 Caps (900mg Total Active)* | $17.99 | $2.00 *($17.99 / 9)_ | 7 (7 x 15mg = 105mg) |
| 6 | Fenugreek Seed + 3% Trigonelline | Neurogan Health | 60 Caps (900mg Total Active)* | $22.99 | $2.55 _($22.99 / 9)* | 7 (7 x 15mg = 105mg) |
| 7 | Fenugreek Extract (3% Trigonelline) | Nootropics Depot | 60 Caps (900mg Total Active)* | $24.99 | $2.78 *($24.99 / 9)_ | 7 (7 x 15mg = 105mg) |
| 8 | Fenugreek Extract (Standardized) | Swanson | 60 Caps (~600mg Total Active)** | $19.50 | ~$3.25 *(Est. based on 2-3%)_ | ~7 |
** Note on Standardized Extracts: “Total Active” for fenugreek extracts is calculated as: Capsule Size (500mg) × Standardization % (3%) = 15mg actual Trigonelline per capsule.* *** Note on Swanson: Estimated based on industry standard 2-3% for “standardized fenugreek” when not explicitly listed.*
Shipping Summary
- Target: Free shipping on orders over $35 (Rank #2 qualifies).
- Nordstrom: Free standard shipping on all orders.
- Renue By Science: Free shipping on US orders over $50.
- Mortalis Labs: Shipping is calculated at checkout (typically ~$5-8 for orders under $50).
- Neurogan / Nootropics Depot: Shipping typically calculated at checkout; often free over $50.
A summary and analysis of the initial paper that started this thread:
Open Access Paper: Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia
The “Orphan” NAD+ Booster: Coffee Compound Trigonelline Restores Muscle Mitochondria via a Forgotten Pathway
In a significant metabolic breakthrough, a multi-institutional team led by Nestlé Research and the National University of Singapore has identified trigonelline—a natural alkaloid found abundantly in coffee beans and fenugreek—as a potent, novel NAD+ precursor. While the “NAD+ Gold Rush” has focused heavily on Nicotinamide Riboside (NR) and NMN, this study reveals that trigonelline operates through a distinct biological “side door”—the Preiss-Handler pathway—to restore cellular energy in aging muscle.
The researchers discovered that circulating levels of trigonelline are significantly depleted in humans with sarcopenia(age-related muscle wasting), correlating directly with reduced grip strength and mitochondrial decline. In pre-clinical trials, supplementing with trigonelline did not just boost NAD+ levels; it extended lifespan in C. elegans by ~20% and, crucially, protected aged mice from muscle fatigue and mitochondrial collapse. Unlike Niacin (Vitamin B3), which shares a similar pathway, trigonelline does not trigger the uncomfortable “flushing” side effect, positioning it as a highly translational candidate for geriatric frailty.
Impact Evaluation:
- Journal: Nature Metabolism
- Impact Factor: ~18.1–20.8 (2024)
- Assessment: This is an Elite impact journal, publishing high-significance metabolic research comparable to Cell Metabolism. The rigorous cross-species validation (Human/Mouse/Worm/Cell) lends this paper high credibility.
Part 2: The Biohacker Analysis
Study Design Specifications
- Type: Multi-modal (Human Cohort Observation + In Vivo Murine/Nematode Intervention + In Vitro Mechanistic).
-
Subjects:
- Humans: 40 participants (20 Sarcopenic vs. 20 Healthy Controls, matched for age/gender).
- Mice: Male C57BL/6J, Aged (20 months old). N=13–15 per group.
- Worms: C. elegans (N2 wild-type).
-
Intervention:
- Mice: 12 weeks of dietary supplementation at 300 mg/kg/day.
- Cells: Primary human myotubes (healthy & sarcopenic donors).
Lifespan & Healthspan Data
-
Worms (C. elegans):
- Median Lifespan Extension: +21.4% (Trigonelline treated vs. Control).
- Significance: High (P<0.001).
-
Mice (C57BL/6J):
- Lifespan: Data Absent. The study was a healthspan intervention (12 weeks), not a longevity survival study.
- Context: Standard C57BL/6J median lifespan is ~850–900 days. These mice were treated from ~600 days to ~700 days.
- Healthspan Findings: Significant improvement in grip strength and muscle fatigue resistance (approx. 50% protection against age-related decline). No change in muscle mass, only muscle function (quality over quantity).
Mechanistic Deep Dive
The study rewrites the map of NAD+ biology by characterizing trigonelline as a Preiss-Handler pathway agonist.
- The “Demethylation” Step: Trigonelline is chemically N-methylnicotinate. To enter the NAD+ cycle, it must first be demethylated to Nicotinic Acid (NA). The enzyme responsible is currently unknown (an “orphan” enzyme), but the study confirms this conversion happens rapidly in the liver.
- Pathway Entry: Once converted to NA, it utilizes the enzyme NAPRT to generate NAD+, bypassing the NAMPTenzyme (the bottleneck for Nicotinamide/NAM) and the NRK pathway (used by NR/NMN).
- Mitochondrial Respiration: Trigonelline treatment specifically upregulated Complex I and II activity in aged muscle, restoring mitochondrial membrane potential (ΔΨm).
- No Flushing: Unlike NA (Niacin), Trigonelline does not activate the GPR109A receptor, meaning it boosts NAD+ without the cutaneous vasodilation (flushing) associated with high-dose Niacin.
Novelty
- First demonstration of trigonelline as a direct NAD+ precursor in mammals using isotope tracing (13C-labeling).
- Identifies low serum trigonelline as a specific blood biomarker for sarcopenia.
- Establishes a therapeutic avenue for NAD+ restoration that works even when the NAMPT salvage pathway is compromised (common in inflamed/aged tissue).
Critical Limitations
- No Mouse Lifespan: We do not know if the functional muscle improvements translate to overall extended life in mammals.
- The “Orphan” Enzyme: The specific demethylase enzyme required to activate trigonelline is unidentified. If human expression of this enzyme varies (genetic polymorphisms), “responder” vs. “non-responder” rates could be high.
- Sex Bias: The human cohort and mouse study used only males. Given known sexual dimorphism in NAD+ metabolism and sarcopenia, this is a major gap.
- Effect Size: While statistically significant, the functional muscle recovery in mice was partial, not complete restoration to youthful levels.
Part 3: Claims & Evidence Hierarchy
| Claim | Verification Status | Evidence Level | Notes |
|---|---|---|---|
| “Trigonelline boosts NAD+ levels in human muscle.” | Verified | Level D (Ex Vivo) | Demonstrated in primary human myotubes (ex vivo), not yet in live human muscle biopsies via RCT. |
| “Trigonelline is reduced in human sarcopenia.” | Verified | Level C(Observational) | Strong correlation (r=0.52) in human cohorts. Does not prove causality (could be reverse causality due to diet/frailty). |
| “Trigonelline improves muscle strength and fatigue resistance.” | Verified | Level D(Murine) | Robust data in aged C57BL/6J mice. Translational Gap: Human RCT data absent. |
| “Trigonelline extends lifespan.” | Verified (Worms only) | Level D (Pre-clinical) | ~20% extension in C. elegans. Translational Gap: No mammalian lifespan data exists. |
| “Trigonelline does not cause flushing.” | Verified | Level D (In Vitro) | Confirmed lack of GPR109A receptor activation in cell assays. |
Part 4: Actionable Intelligence
The Translational Protocol (Rigorous Extrapolation)
- Compound: Trigonelline (often sourced from Fenugreek extract or standardized Coffea arabica extract).
-
Human Equivalent Dose (HED):
- Mouse Dose: 300 mg/kg/day.
- Conversion: 300×(3/37)≈24.3 mg/kg.
- For 70 kg Human: ≈ 1,700 mg (1.7 g) per day.
- Note: This is a pharmacological dose, significantly higher than dietary intake (coffee contains ~40–60 mg per cup). Drinking 40 cups of coffee is not a viable protocol.
- Proposed Protocol: 850 mg taken twice daily (AM/PM) to match the chronic exposure model.
Pharmacokinetics & Biomarkers
- Bioavailability: High oral bioavailability; rapidly appears in plasma/urine.
- Half-life: Short (~5 hours in plasma). Requires split dosing.
-
Target Engagement Markers:
- Primary: RBC NAD+ levels (measurable via specialized functional medicine panels).
- Secondary: Grip strength (dynamometer tracking) and gait speed.
- Safety: Monitor Homocysteine (due to methyl-group metabolism) and Liver enzymes (ALT/AST).
Safety & Toxicity Check
- NOAEL (Rat): 500–1000 mg/kg/day (Safety margin is adequate for a 24 mg/kg human dose).
- LD50: >2000–5000 mg/kg (Low acute toxicity).
-
Contraindications:
- Methylation Issues: Trigonelline is a methylated compound. Its metabolism releases methyl groups (via unknown demethylase) or consumes them? Correction: It is a methyl donor candidate, but in this pathway, it is demethylated to form Nicotinate. The fate of the methyl group is crucial. If it enters the one-carbon cycle, it might affect methylation status.
- Hypoglycemia: Fenugreek (rich in trigonelline) is traditionally used to lower blood sugar. Users on Metformin or Insulin should monitor glucose closely.
Sourcing & Feasibility
-
Commercial Availability: Available as “Fenugreek Extract” standardized for Trigonelline (usually 10–20% concentration).
- Calculation: To get 1.7g Trigonelline from a 20% extract, one would need 8.5g of extract daily. This is high volume but feasible.
- Cost: Low/Moderate compared to NR/NMN.
Part 5: The Strategic FAQ
1. Is this better than taking NMN or NR? Answer: It is likely complementary, not necessarily “better.” NMN/NR use the salvage pathway (NRK/NAMPT). Trigonelline uses the Preiss-Handler pathway (NAPRT). In aged tissues where NAMPT is downregulated (inflammaging), Trigonelline might offer a “bypass” route that NR/NMN cannot access effectively.
2. Why not just take Niacin (Vitamin B3)? It uses the same pathway. Answer: Flushing. To achieve the NAD+ boost seen in this study, you would likely need gram-level doses of Niacin, which causes severe cutaneous flushing (GPR109A activation). Trigonelline provides the pathway benefits of Niacin without the flush.
3. Can I just drink more coffee? Answer: No. A strong cup of coffee contains ~50 mg of trigonelline. The human equivalent dose for muscle preservation derived from this study is ~1,700 mg. You would need to drink ~34 cups of coffee daily, which would be toxic due to caffeine.
4. Does Trigonelline interact with Rapamycin? Answer: No negative interactions are documented. In fact, they may be synergistic. Rapamycin inhibits mTOR (mimicking calorie restriction), while Trigonelline restores mitochondrial NAD+ (mimicking exercise/energy abundance). This covers two distinct “Hallmarks of Aging.”
5. Is there a risk of “methyl trap” or homocysteine issues? Answer: [Confidence: Medium] Theoretically, yes. Trigonelline is N-methylnicotinate. To become NAD+, it must lose that methyl group. If that methyl group is dumped indiscriminately, it could hypothetically affect the methylation cycle. Monitoring homocysteine is prudent until human safety data at 1.7g/day is established.
6. Will this break my fast? Answer: Pure trigonelline is a non-caloric alkaloid and should not spike insulin or mTOR. However, if sourced from fenugreek seeds, the accompanying fibers and amino acids (4-hydroxyisoleucine) might have a small metabolic impact.
7. Does it affect blood sugar? Answer: Yes. Trigonelline has established hypoglycemic (glucose-lowering) properties. Longevity enthusiasts already on acarbose, SGLT2 inhibitors, or metformin should watch for hypoglycemia.
8. Is the “unknown demethylase” a problem? Answer: It is a translational risk. If you genetically lack this enzyme (polymorphisms), you might just excrete the trigonelline unchanged in urine (expensive pee) without getting the NAD+ boost. We currently have no test for this enzyme’s activity in humans.
9. How does it compare to 17-alpha estradiol for muscle? Answer: 17-alpha estradiol is far more potent for male mouse lifespan and muscle preservation but is a synthetic drug intervention. Trigonelline is a dietary nutrient. 17-alpha estradiol is a “sledgehammer”; Trigonelline is a “tune-up.”
10. What is the next immediate step for a biohacker? Answer: If you are dealing with sarcopenia or statin-induced myopathy, consider adding a standardized Fenugreek extract (titrated to ~500mg Trigonelline) to your stack. Monitor functionality (grip strength) and glucose levels.
This sounds like a new compound being worked on in Bryan Kennedy’s group:
NATIONAL UNIVERSITY OF SINGAPORE, YONG LOO LIN SCHOOL OF MEDICINE
A research consortium led by Nestlé Research in Switzerland and the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) made a recent discovery that the natural molecule trigonelline present in coffee, fenugreek, and also in the human body, can help to improve muscle health and function. In an international collaboration among the University of Southampton, University of Melbourne, University of Tehran, University of South Alabama, University of Toyama and University of Copenhagen, the work builds on a previous collaborative study that described novel mechanisms of human sarcopenia.
Sarcopenia is a condition where cellular changes that happen during ageing gradually weaken the muscles in the body and lead to accelerated loss of muscle mass, strength and reduced physical independence.
One important problem during sarcopenia is that the cellular cofactor NAD+ declines during ageing, while mitochondria, the energy powerhouses in our cells, produce less energy. The study team discovered that levels of trigonelline were lower in older people with sarcopenia. Providing this molecule in pre-clinical models resulted in increased levels of NAD+, increased mitochondrial activity and contributed to the maintenance of muscle function during ageing.
NAD+ levels can be enhanced with different dietary precursors like the essential amino acid L-tryptophan (L-Trp), and vitamin B3 forms such as nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).
Assistant Professor Vincenzo Sorrentino from the Healthy Longevity Translational Research Programme at NUS Medicine added, “Our findings expand the current understanding of NAD+metabolism with the discovery of trigonelline as a novel NAD+ precursor and increase the potential of establishing interventions with NAD±producing vitamins for both healthy longevity and age-associated diseases applications”.
Nutrition and physical activity are important lifestyle recommendations to maintain healthy muscles during ageing. “We were excited to discover through collaborative research that a natural molecule from food cross-talks with cellular hallmarks of ageing. The benefits of trigonelline on cellular metabolism and muscle health during ageing opens promising translational applications,” said Jerome Feige, Head of the Physical Health department at Nestlé Research.
The journal paper, titled Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia, was published in Nature Metabolism on 19 March 2024.
Trigonelline is an alkaloid with chemical formula C7H7NO2. It is a zwitterion formed by the methylation of the nitrogen atom of niacin (vitamin B3). Trigonelline is a product of niacin metabolism that is excreted in the urine of mammals.[1]
Trigonelline occurs in many plants. It has been isolated from the Japanese radish[2] (Raphanus sativus cv. Sakurajima Daikon), fenugreek seeds (Trigonella foenum-graecum, hence the name),[3] garden peas, hemp seed, oats,[4] potatoes, Stachys species, dahlia,[5] Strophanthus species,[6] and Dichapetalum cymosum.[7] Trigonelline is also found in coffee.[8] Higher levels of trigonelline are found in arabica coffee.
Holtz, Kutscher, and Theilmann have recorded its presence in a number of animals.[9]
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FWIW
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/trigonelline
Vincenzo Sorrentino is an Italian-born scientist in the fields of aging, mitochondrial biology, and neuromuscular degeneration. He is an Assistant Professor at the NUS, in the Department of Biochemistry and the Healthy Longevity TRP, Yong Loo Lin School of Medicine, where he develops his research on the link between metabolism, nutrition, and proteostasis, and their impact on health and aging. At the 6th #TimepieLongevityForum, Dr. Sorrentino highlighted #trigonelline as a novel, stable NAD⁺ modulator, showing that supplementation consistently increases #NAD⁺ levels across species—from human cells to C. elegans and mice.
Gemini Pro AI Summary and Analysis of this video:
Here is the summary and analysis of the provided transcript.
Trigonelline: A Novel NAD+ Precursor for Sarcopenia and Kidney Disease
A. Executive Summary
This presentation by Dr. Vincenzo Sorrentino (National University of Singapore, formerly Nestlé Research) introduces Trigonelline as a newly identified NAD+ precursor with specific efficacy for muscle aging (sarcopenia) and diabetic kidney disease. The speaker begins by establishing the “NAD+ deficit” theory of aging, noting that while current precursors like Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN) are popular, they suffer from instability in serum and rapid degradation into Nicotinamide (NAM).
Through metabolomic screening of human sarcopenic cohorts, Sorrentino’s team discovered that serum levels of Trigonelline were significantly depleted in frail elderly individuals and correlated positively with muscle strength and mitochondrial function.
Mechanistically, the presentation demonstrates that Trigonelline enters the NAD+ cycle via the Preiss-Handler pathway(distinct from the salvage pathway used by NR/NMN) and is chemically stable in serum. In preclinical models (C. elegans, mice, and zebrafish), Trigonelline treatment restored NAD+ levels, improved muscle grip strength, and protected kidney proximal tubules from diabetic damage. The core thesis is that Trigonelline represents a stable, bioavailable alternative to current NAD+ boosters, specifically targeting mitochondrial health in muscle and kidney tissues.
B. Bullet Summary
- Sarcopenia Definition: Defined clinically not just by low muscle mass, but by the triad of low mass, low grip strength, and slow gait speed.
- NAD+ Instability: The speaker presents data showing that popular precursors NR and NMN degrade rapidly (within hours) into Nicotinamide (NAM) when exposed to human serum at 37°C.
- Trigonelline Discovery: Identified via metabolomics as a metabolite significantly reduced in humans with sarcopenia and diabetic kidney disease (DKD).
- Mechanism of Action: Unlike NR/NMN (Salvage Pathway), Trigonelline utilizes the Preiss-Handler Pathway(similar to Niacin) to synthesize NAD+.
- Mitochondrial Link: Trigonelline levels correlates strongly with the upregulation of mitochondrial gene sets involved in bioenergetics.
- Muscle Efficacy: In aged mice, dietary Trigonelline supplementation for 12 weeks preserved muscle strength and reduced fatigue.
- Kidney Protection: In diabetic models, Trigonelline protected the proximal tubules (the most metabolically active part of the kidney) and reduced albuminuria (protein leakage).
- Zebrafish Model: A transgenic zebrafish model visually demonstrated that Trigonelline prevents protein leakage from the kidney into the water during cisplatin-induced injury.
- Stability Advantage: Trigonelline is chemically stable in the blood, avoiding the rapid breakdown seen with nucleotide-based precursors (NR/NMN).
- Clinical Gap: While human observational data exists (correlation), interventional clinical trials for Trigonelline in humans are still needed.
D. Claims & Evidence Table (Adversarial Peer Review)
| Claim from Video | Speaker’s Evidence | Scientific Reality (Best Available Data) | Evidence Grade | Verdict |
|---|---|---|---|---|
| “Trigonelline is a novel NAD+ precursor.” | Blockade of Salvage vs. Preiss-Handler pathways in vitro confirms NAD+ synthesis via the latter. | Validated in Nature Metabolism(Sorrentino et al., 2024). It is methylated niacin. | A (Peer-Reviewed) | Strong Support |
| “NR and NMN degrade rapidly to NAM in serum.” | Internal metabolomics data showing degradation within <24 hours. | Controversial but supported. Liu et al. (2018) showed NMN dephosphorylation to NR/NAM in plasma. Stability is a known issue. | B (Biochem) | Plausible/Strong |
| “Trigonelline improves muscle strength in aging.” | Mouse data (grip strength) and C. eleganslifespan/mobility data. | Strong preclinical data. Human association data exists, but no RCT proving causation in humans yet. | D (Animal/Obs) | Promising (Translational Gap) |
| “Trigonelline protects against Diabetic Kidney Disease.” | Mouse transcriptomics (proximal tubule) and Zebrafish leakage models. | Mechanism (mitochondrial support in high-energy tubules) is sound. Efficacy limited to animal models so far. | D (Animal) | Speculative (in Humans) |
| “Niacin cures mitochondrial myopathy.” | Cites Finnish study (Pirinen et al., 2020). | True. High-dose Niacin effectively treats adult-onset mitochondrial myopathy, though side effects (flushing) limit general use. | B (Human RCT) | Strong Support |
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E. Actionable Insights (Pragmatic & Prioritized)
Top Tier (High Confidence)
-
Focus on Mitochondrial Health for Sarcopenia:
- Insight: Muscle loss is driven by mitochondrial failure.
- Protocol: Prioritize Zone 2 cardio and Resistance Training, which are the only proven physiological drivers of mitochondrial biogenesis in humans, regardless of supplementation.
-
Monitor Kidney Function in Metabolic Disease:
- Insight: 50% of diabetics develop kidney disease.
- Protocol: If you are pre-diabetic or insulin resistant, monitor Albuminuria (uACR ratio) and Cystatin Calongside HbA1c, as kidney metabolic failure is a silent driver of aging.
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Experimental (Risk / Reward)
-
Trigonelline Sources (Coffee & Fenugreek):
- Context: While the speaker discusses purified Trigonelline, it is naturally abundant in Fenugreek seeds and Coffee (Arabica beans).
- Protocol: Consumption of moderate coffee or fenugreek extracts may provide this metabolite, though dosages for NAD+ boosting in humans are not yet established.
-
Niacin (Vitamin B3) for NAD+:
- Context: The speaker highlights Niacin’s efficacy via the same pathway (Preiss-Handler) as Trigonelline, noting it works well if you can tolerate the “flush.”
- Protocol: Low-cost alternative to NR/NMN, but requires medical supervision due to vascular effects (flushing) and potential glucose elevation.
AVOID (Safety Flags)
-
Over-reliance on Unstable Precursors:
- Insight: Be skeptical of liquid NR/NMN preparations or non-encapsulated forms, as the speaker’s data confirms rapid degradation into standard Nicotinamide (NAM).
H. Technical Deep-Dive
The NAD+ Pathway Divergence
The speaker differentiates Trigonelline from current market leaders (NR/NMN) based on the entry point into NAD+ biosynthesis.
- The Salvage Pathway (NR / NMN / NAM):
- Most commercial boosters use this route.
- Mechanism: Nicotinamide (NAM) → NMN → NAD+.
- Bottleneck: This pathway is often rate-limited by the enzyme NAMPT. The speaker argues that NR and NMN degrade back into NAM in the blood, essentially serving as expensive delivery mechanisms for NAM.
- The Preiss-Handler Pathway (NA / Trigonelline):
- Mechanism: Trigonelline (Methylated Niacin) → Niacin (NA) → Nicotinic Acid Mononucleotide (NAMN) → NAAD → NAD+.
- Enzymes: Relies on NAPRT.
- Significance: By utilizing a different enzymatic entry point, Trigonelline can bypass NAMPT bottlenecks and avoids the feedback inhibition often seen in the salvage pathway. It provides a distinct “fuel line” for mitochondrial NAD+ production.
Kidney Proximal Tubule Bioenergetics
The talk highlights the Proximal Tubule of the kidney.
- Function: This section of the kidney reabsorbs glucose, amino acids, and water. It is extremely energy-demanding and rich in mitochondria.
- Pathology: In diabetes/aging, these mitochondria fail (NAD+ depletion), leading to cell death and protein leakage (albuminuria).
- Intervention: Trigonelline specifically upregulates mitochondrial gene expression in this tissue, preserving the energetic capacity required to filter blood without cellular injury.
I. Fact-Check
- Speaker Identity: Dr. Vincenzo Sorrentino, Assistant Professor at NUS. The transcript mentions his move from Nestlé Research to Brian Kennedy’s lab, which aligns with his public CV.
- Trigonelline Chemistry: True. Trigonelline is chemically N-methylnicotinic acid. It is a major alkaloid in coffee and fenugreek.
- Nature Metabolism Study: True. The study “Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia” was published in Nature Metabolism in March 2024.
- Niacin & Mitochondria: True. The “Finnish study” referred to is Pirinen et al. (2020), Cell Metabolism, which showed Niacin cured NAD+ deficiency in mitochondrial myopathy patients.