Study reveals trigonelline as a therapeutic agent for mitochondrial dysfunction in aging

Trending 3 weeks ago

A recent study published in the journal Nature Metabolism reported that low levels of nicotinamide adenine dinucleotide (NAD+) and mitochondrial dysfunction observed in sarcopenia and during the aging of skeletal muscles were functionally linked to serum levels of trigonelline, a natural alkaloid.

 BigBlueStudio/Shutterstock.comStudy: Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Image Credit: BigBlueStudio/


Sarcopenia is the age-related decline in skeletal muscle due to the wasting of myofiber, resulting in impaired contraction of muscle fibers, decreased mobility, and disability.

The clinical manifestations of sarcopenia include reduced muscle mass, and, consequently, decreased gait speed and strength. Studies have found that mitochondrial dysfunction plays a significant role in the development of sarcopenia.

Phenotypes of muscle aging are driven by factors such as lower mitochondrial biogenesis, decreased cellular respiration and adenosine triphosphate (ATP) production, and changes in mitochondrial dynamics.

Recent research has been focused on understanding the role of systemic factors such as pro-inflammatory cytokines, circulating anabolic amino acids, and fluctuations in lipid, vitamin, and glucose metabolism in influencing mitochondrial function and impacting muscle strength.

Low levels of NAD+ have been identified recently as being one of the hallmarks of muscle aging and sarcopenia, along with mitochondrial dysfunction.

However, whether decreasing levels of NAD+ are linked to circulating molecular markers that can be used as clinical biomarkers remains unknown.

About the study

In the present study, the researchers investigated whether individuals with sarcopenia had varying serum levels of vitamin B or kynurenine metabolome as compared to healthy individuals to determine systemic changes linked to NAD+ metabolism alterations and mitochondrial dysfunction.

NAD+ is derived from vitamin B3 precursors and is an essential cofactor for organismal and cellular metabolism.

In mammals, NAD+ can be produced from dietary precursors such as nicotinamide mononucleotide and nicotinamide riboside through the nicotinamide riboside kinase pathway, nicotinic acid or niacin through the nicotinate phosphoribosyltransferase-dependent Preiss–Handler pathway, and from tryptophan and nicotinamide.

Rodent studies have also corroborated the findings from human studies that aging skeletal muscles show declining NAD+ levels.

The present study included participants above the age of 60 who had sarcopenia and an equal number of age-matched, healthy controls. Muscle biopsy samples were collected for analysis from all participants. A digital dynamometer was used to measure grip strength, while dual-energy X-ray absorptiometry was used to measure the appendicular lean mass index.

A 24-hour recall method was employed to assess the dietary intake, and household portions of all reported foods and beverages were converted to grams using standard references.

Ribonucleic acid (RNA) sequencing was performed using the vastus lateralis muscle biopsies, and the genetic dataset obtained was used for pathway analysis.

Additionally, the concentration of NAD+ from tissue samples was quantified enzymatically, and liquid chromatography-mass spectrometry was used for the high-resolution analysis of the NAD+ metabolomes in the in vivo samples and cells.

A wide range of cellular assays were performed to assess cell death, mitochondrial function, knockdown of nicotinate phosphoribosyltransferase gene, G-protein coupled receptor agonism, and stability of the NAD+ precursor.

Muscle tissues from the biopsies were also stained for histological assessments to observe muscle architecture.

The nicotinate phosphoribosyltransferase knockdown studies were performed using rodent models, and RNA extracts from the rodent tissue were used for quantitative polymerase chain reaction (qPCR) and immunoblot assays.


The results showed that although the vitamin B3 metabolites or any of the other metabolites analyzed in the study showed no alterations linked to sarcopenia, the individuals with sarcopenia had low levels of trigonelline, a natural alkaloid produced by mammals and plants.

The appendicular lean mass index, as well as gait speed and grip strength measurements, showed a correlation between muscle mass and levels of trigonelline. Additionally, serum trigonelline levels were found to be linked to the levels of NAD+ in the skeletal muscles.

The pathway enrichment studies from the rodent tissues also indicated that numerous signaling and metabolic pathways, such as the mitochondrial oxidative phosphorylation pathway, were positively associated with serum trigonelline levels.

The dietary intake analysis found that caffeine consumption was not associated with changes in trigonelline levels in the serum. Still, it indicated that fiber and folate intake could influence the circulating levels of trigonelline.

Changes in vitamin B3 intake also did not seem to influence the association between muscle strength and trigonelline levels. These findings suggested that trigonelline was a new metabolite that could be used as a biomarker to assess NAD+ levels, mitochondrial metabolism, and muscle strength.


To summarize, the study investigated the association between the levels of vitamin B3 metabolome and NAD+ levels, muscle mass, and mitochondrial dysfunction related to sarcopenia through RNA sequencing, histological analyses, animal studies, and numerous assays.

While the results showed no associations between the hallmarks of sarcopenia and the vitamin B3 metabolome, low levels of trigonelline, a natural alkaloid found in humans, were found to be associated with a decrease in NAD+ levels, muscle mass decline, and mitochondrial dysfunction.

Journal reference:

  • Membrez, M., et al. (2024). Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nature Metabolism, [online] 6(3), pp.433–447. doi: