In Vincenzo Sorrentino’s laboratory at the National University of Singapore, Vincenzo and his team have been exploring an intriguing molecule known as trigonelline powder—methyl nicotinic acid—which shows remarkable promise in enhancing intracellular NAD levels, muscle function, and longevity. The noticeable stability of this compound compared to NMN or NR posits it as a potentially superior candidate for supporting healthy aging. Their collaborative efforts, bridging academia and industry, have culminated in exciting discoveries that will soon be published, showcasing translational research that benefits both the scientific community and the wider public.
Vincenzo Sorrentino Introduction
Vincenzo Sorrentino is a distinguished Italian scientist renowned for his contributions to studying aging, mitochondrial function, and neuromuscular disorders. He completed his PhD with distinction in medical biochemistry at the University of Amsterdam, followed by postdoctoral research at the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland.
His research has primarily concentrated on the role of mitochondria and NAD+ metabolism in Alzheimer’s disease and the aging of muscle tissue. His significant findings have been published in esteemed journals such as Nature in 2017 and Cell Reports in 2021. Between 2019 and 2022, Sorrentino served as a Group Leader at the Nestlé Institute of Health Sciences in Switzerland, where he spearheaded research aimed at bridging fundamental insights into natural bioactive compounds that influence NAD+, mitochondrial dynamics, and protein balance with their potential clinical implications.
He holds the position of Assistant Professor and has established his research laboratory at the National University of Singapore (NUS) within the Department of Biochemistry and the Healthy Longevity Translational Research Program at the Yong Loo Lin School of Medicine. Additionally, he maintains a role as an Adjunct Assistant Professor at the University of Amsterdam.
Sarcopenia, characterized by a decline in muscle function and mass, is a prevalent age-associated condition that increasingly affects our super-aging societies, such as in Singapore, where he is currently based. Molecularly, sarcopenia shares typical hallmarks with aging, such as increased inflammation in muscles, mitochondrial dysfunction, oxidative stress, and an imbalance in protein turnover, all contributing to muscle deterioration. Factors like gait speed, grip strength, and appendicular lean mass are clinically integral to its assessment. Highlighting the pivotal role of NAD+ in aging, our research intersects with understanding how maintaining NAD+ levels can boost muscle health, as observed in earlier studies and further supported by our current findings on trigonelline.
What is Trigonelline?
Trigonelline, a naturally occurring alkaloid with the molecular formula C7H7NO2, is a unique zwitterionic compound produced through the methylation of niacin’s (vitamin B3) nitrogen atom. As a metabolite of niacin, trigonelline is commonly found in the urine of mammals as a byproduct of the body’s metabolic processes. Its official IUPAC designation is 1-Methylpyridinium-3-carboxylate. This compound is also known by various other names, including Nicotinic acid N-methylbetaine, Coffearine, Caffearine, Gynesine, and Trigenolline, among others. Trigonelline is identified in scientific and commercial contexts by its CAS Number, 535-83-1.
Trigonelline is a prevalent alkaloid found across a variety of plant species. It has been extracted from numerous sources such as the Sakurajima Daikon variety of Japanese radish (Raphanus sativus), the seeds of fenugreek (Trigonella foenum-graecum)—which is the inspiration for its name—as well as garden peas, hemp seeds, oats, potatoes, various Stachys species, dahlias, Strophanthus species, and Dichapetalum cymosum. Additionally, trigonelline is a notable component of coffee, with arabica beans exhibiting exceptionally high concentrations.
Researchers Holtz, Kutscher, and Theilmann have documented the occurrence of trigonelline in several animal species. On the commercial front, fenugreek extract supplements, readily available in the market, often contain trigonelline as a significant constituent.
Trigonelline: Enhancements in Muscular Health and Longevity
Trigonelline, or methyl nicotinic acid, has been identified as a promising compound for improving health outcomes related to aging. Understanding the context of muscle aging and the prior research that has set the stage for this discovery is essential. Muscle aging, characterized by reduced strength and functionality, is an inevitable part of the aging process; this concept is termed sarcopenia. The complication is of particular concern in populations experiencing longer life expectancies.
From a molecular perspective, aging can be seen as a decline across various cellular functions. Sarcopenia embodies these hallmarks, with symptoms such as increased inflammation, mitochondrial dysfunction, and heightened oxidative stress. These lead to reduced muscle elasticity and the ability to regenerate muscle mass effectively.
Clinical Measurement of Sarcopenia:
- Gate speed: Speed at which you walk, a decline points towards sarcopenia.
- Grip Strength: A measure of hand and arm strength.
- Appendicular Lean Mass: Mass of arms and legs, when reduced, can indicate sarcopenia.
The Role of NAD+ in Muscle Health:
Research has recognized that coenzyme NAD+ is integral in supporting mitochondrial function and DNA repair, among over 500 other reactions in the body, many of which are connected to these aging hallmarks. A prior observational study highlighted a correlation: higher concentration of muscle NAD+ was associated with better muscle health.
The Discovery of Trigonelline:
In this context comes the insight into trigonelline. A significant finding was made while comparing molecular signatures of muscle tissues in the elderly and those diagnosed with sarcopenia. Trigonelline levels were decidedly lower in individuals with sarcopenia. Your muscular health – grip strength, walking speed, and lean mass – correlates positively with serum trigonelline concentrations.
The overall goal of boosting NAD+ levels is to enhance muscle function and longevity. The connection between higher NAD+ levels, improved muscle health, and the presence of trigonelline offers a targeted approach to therapeutic intervention. Research is ongoing, but the potential benefits of this compound in combating muscle degeneration with age are significant.
Trigonelline’s Influence on Muscular Health and Age-Related Degeneration
Muscle Deterioration with Aging
As individuals age, a noticeable decline in muscle function often occurs, not solely attributed to reduced muscle size but also decreased strength and mobility. This progression, associated with the aging population, is becoming more common as society advances in age, especially notable in nations with rising average ages, such as Singapore.
Cellular Indicators of Aging and Muscle Performance
Aging at the cellular level is marked by various deteriorations in cell functions. For muscles specifically, this includes several characteristics, such as heightened inflammation, inefficient energy-producing organelles (mitochondria), and elevated oxidative stress. These lead to muscle tissue damage, impacting flexibility and performance. A critical aspect is the reduced function of muscle satellite cells, vital for regeneration and maintenance of muscle mass, alongside disturbances in protein balance – a shift towards protein breakdown over synthesis.
Muscle Precursors and Protein Dynamics
Tracking the health state of muscles from a clinical standpoint can be done using gate speed, grip strength, and the muscle mass of the limbs (appendicular lean mass). Developing a lower score than specified thresholds in these areas indicates sarcopenia. It has been discovered that NAD+, a coenzyme implicated in over 500 bodily reactions and closely tied with aforementioned aging hallmarks, plays a pivotal role in maintaining mitochondrial functionality, reducing inflammation, and supporting DNA repair. Approaches such as exercise, diet adjustments, or NAD+ boosting supplements have been preclinically shown to improve overall organ function, with implications for age-related conditions.
Efforts to identify biomarkers or new therapeutic targets for muscle aging have yielded insights such as the link between systemic NAD+ levels and sarcopenia. An intriguing finding from serum samples of a previous study indicated that levels of a molecule named trigonelline were reduced in individuals with sarcopenia and that higher serum trigonelline levels were positively correlated with better muscle health, similar to the relationship discovered between higher NAD+ levels in muscles and healthier muscle function.
Assessing Sarcopenia Through Established Metrics
Walking Speed Assessment
To quantify your mobility, walking speed is an essential gauge. It reflects your capacity to move effectively and is a straightforward yet powerful indicator of lower limb function. Clinically, a diminished pace below established thresholds signifies a potential decline in muscular performance, alerting us to sarcopenic conditions.
|Walking Speed Threshold
|Below threshold value
Evaluation of Handgrip Power
Handgrip strength serves as a direct measure of your muscular strength. It is determined using a dynamometer to evaluate the force exerted by your hand muscles. Clinically, lower values than the standard cutoffs can indicate sarcopenia, shedding light on muscle health and functionality.
|Handgrip Strength Standard
|Suggestive of sarcopenia
Examination of Muscle Mass
Appendicular lean mass, concerning your limbs, is a critical indicator of muscular volume and health. Measurements falling below-specified values may indicate sarcopenia. This examination helps discern the muscular mass distribution and is pivotal in the clinical assessment of sarcopenia.
|Appendicular Lean Mass Benchmark
|Below standard reference value
|Implicative of sarcopenia
NAD+ Significance in Cellular Aging
Bolstering Energy Powerhouses
Your cells have powerhouses called mitochondria, and NAD+ is crucial in supporting their efficiency. Maintaining NAD+ levels is essential for ensuring that these bioenergetic factories operate effectively, supporting muscle function and vitality as organisms age. Higher mitochondrial efficiency is linked to improved muscle health and reduced aging symptoms.
Mitochondrial Function Indicators
- Transcription Pathways: Essential for mitochondrial gene expression.
- Oxidative Respiration Proteins: Indicate the activity of complexes involved in energy generation.
Contribution to Oxidation-Reduction Equilibria
NAD+ is integral in oxidation-reduction (redox) reactions within your cells. These reactions are responsible for energy conversion and are fundamental to maintaining cellular health, reducing inflammation, and facilitating other cellular functions critical to longevity.
Redox Reaction Aspects
|Function in Aging
|Preserves cell vitality
|Decreases age-related risks
|Cellular process management
|Helps prevent decline in cell operation
DNA Preservation Mechanisms
Repairing your DNA is one of the most vital tasks in which NAD+ is involved. As you age, increased DNA damage contributes to the aging process and the functional decline of tissues, including muscle. A stable NAD+ pool ensures efficient DNA repair mechanisms remain operational, vital for longevity and health.
DNA and Muscle Health Correlation
- DNA Repair: High NAD+ levels have been associated with better DNA maintenance.
- Tissue Function: Links between DNA repair efficiency and overall muscle health have been observed.
The investigations highlighted here convey how NAD+ coenzymes are indispensable across multiple aging-related cellular functions. Specifically, maintaining NAD+ levels has shown positive correlations with critical aspects of muscle health, indicating its essential role in the biology of aging and potential therapeutic targets.
Prior Investigations and Observations in Muscle Health
Energy Production Breakdown and Age-Related Muscle Weakening
Within age-related muscle weakening, energy-producing organelles in your cells losing their functionality has been a consistent concern. This cellular energy breakdown is critical because these organelles, notably known as the powerhouses of the cell, are fundamental in maintaining muscle vitality and overall metabolic processes. When considering muscular aging and the specific condition signified by the decline in muscle mass and function, the research underscores this decline as a shared attribute with various biological aging markers. The latter include heightened inflammatory responses within muscle tissues, escalated oxidative damage leading to impaired muscle resilience and functionality, and notably, a decline in the regenerative capacity of satellite cells – your muscle stem cells crucial for sustaining muscle mass and promoting healing. Concurrent with this muscle catabolism, or loss, protein synthesis is reduced, further eroding muscle health.
Gauging this condition clinically involves tracking specific physiological indicators. These include an assessment of your walking speed, handgrip strength, and lean muscle mass, all of which are critical in determining whether a decline beyond set thresholds signifies a diagnosable state of muscle weakening.
Correlation Between an Essential Coenzyme and Muscular Well-being
The association between intracellular levels of a pivotal coenzyme, instrumental in over 500 bodily reactions, and muscle health has surfaced prominently in the medical literature. This particular coenzyme, vital for mitochondrial support, antioxidative reactions, and inflammation reduction, plays a central role in seemingly every hallmark of cellular aging. Preclinical investigations suggest that various interventions, such as adequate exercise, nutritional adjustments, and specific supplements that boost this coenzyme, can significantly bolster nearly every organ’s function during aging and in age-related conditions.
Observational studies focused mainly on aging individuals diagnosed with muscle weakening, examining muscle tissue samples for molecular health indicators. Findings included reduced energy generation at the cellular level and a noticeable depletion of this vital coenzyme within the muscles. Furthermore, clinical parameters of muscle health – such as muscle mass, strength, and ambulatory capabilities – demonstrated a positive inclination linked to higher levels of this coenzyme in the muscle. This substantiation aligns with the hypothesis that maintaining adequate levels of this coenzyme is fundamental for muscle health as one ages.
Secondary to these findings, systemic metabolomic analyses aimed to recognize potential biomarkers of muscle health decline. Among various scrutinized metabolites, including subsets of vitamin B3 precursors contributing to coenzyme synthesis, one specifically demonstrated a marked decrease in individuals with weakened muscles. Moreover, systemic levels of this metabolite exhibited a positive connection with all three clinical indicators of muscle health, mirroring the beneficial correlation seen with coenzyme levels in muscle tissue.
Insights on Trigonelline: Biomarker and Therapeutic Perspectives Evaluating Metabolic Profiles
Our current research focuses on metabolomics, which enables us to dissect systemic changes correlating with muscle aging. This approach allows the identification of pivotal compounds whose levels in the bloodstream may signal deteriorating muscle health. Among various metabolites screened, certain B vitamin derivatives show particular promise.
One such compound of interest is trigonelline, a derivative of vitamin B3 and a precursor of NAD+. In those with observed muscle weakening—a condition often tied to aging—trigonelline is notably reduced. Intriguingly, where trigonelline is present in higher concentrations, muscle health indicators show improvement, suggesting a potential role for trigonelline in muscle maintenance.
Linking Trigonelline to Muscle Health
Your muscle vitality is often reflected in key health indicators: muscle mass, grip strength, and walking speed. Findings in our research indicate that elevated trigonelline levels in serum are associated with enhanced performance across these parameters. Like NAD+ within muscle tissue, higher systemic trigonelline aligns with better muscle health.
The implications of this correlation are significant. Trigonelline is a potential non-invasive biomarker for muscle health, offering a window into an individual’s muscular condition. Moreover, its role as a precursor to NAD+ signifies that it may not only signal health status but also serve as a therapeutic agent for muscle longevity, hinting at clinical applications for preventing or counteracting age-related muscle decline.
Current Findings and Prospects
In our recent investigations, we’ve observed remarkable insights into the role of trigonelline in enhancing intracellular NAD levels and improving muscle function and longevity. These findings provide a promising new perspective on the potential of trigonelline as a stable NAD precursor, possibly surpassing known compounds like NMN or NR in terms of stability.
The condition of sarcopenia, characterized by the loss of muscle function and strength with age, is becoming more prevalent in aging societies globally. Our research underscores the importance of understanding sarcopenia not as a mere decline in muscle mass but as a comprehensive decline in muscular health. We’ve pinpointed several clinical measures central to diagnosing sarcopenia, including gate speed, grip strength, and appendicular lean mass. These parameters are essential to remember, as they provide a concrete means to identify sarcopenic conditions clinically.
We’ve established a link between NAD+ levels and muscle health through a multidisciplinary approach combining molecular biology and clinical research. NAD+, a coenzyme engaged in over 500 bodily reactions, is now understood to be integral in countering aging-related cellular declines. By using NAD+ boosters or adopting specific lifestyle interventions, there is potential to elevate muscular well-being and overall organ function.
Our prior work has illuminated a notable correlation between NAD+ levels within the muscle tissue and overall muscle health, indicating a potential pathway to counteract sarcopenia. Moreover, systemic metabolomic analyses have highlighted the compound trigonelline. This metabolite is associated with declining levels in sarcopenic individuals and shows a promising correlation with positive muscle health outcomes.
These insights have broadened our understanding of the possible therapeutic avenues for mitigating age-related muscle decline. By exploring the systemic biomarkers that reflect cases of sarcopenia, such as trigonelline, we aim to develop targeted interventions that could transform clinical practices related to muscular aging and sarcopenia.
As we advance, we strive to elucidate further how trigonelline and NAD+ interact and work to reinforce muscle health. There’s a robust path ahead to translate these findings into viable, broadly accessible interventions. With a focus on the continuous quest for understanding and tackling sarcopenia, the prospects of enhancing life quality for aging populations worldwide are substantial.
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- Zhou J, Chan L, Zhou S. Trigonelline: a plant alkaloid with therapeutic potential for diabetes and central nervous system disease. Curr Med Chem. 2012;19(21):3523-31. https://doi.org/10.2174/092986712801323171