Trigonelline Increases NAD, Improves Muscle Function, And Extends Lifespan

[RapAdmin]

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]

Trigonelline

[Joseph]

FWIW
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/trigonelline

[RapAdmin]

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.

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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.

Getty Images

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.

1. 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.

2. 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.