Brain & Neurons

New Study Reveals Coffee-Derived Molecule Trigonelline Defends Against Cognitive Decline

Japanese researchers have demonstrated that trigonelline can prevent learning and memory impairment, reduce neuroinflammation, and replenish neurotransmitter levels in a mouse model of accelerated aging.

(A ring of coffee beans surrounding a trigonelline molecule |
By Bennett M. Sherman

Key Points:

  • Trigonelline (TG), a natural compound found in coffee beans and Japanese radishes, has been found to enhance spatial cue-based learning and memory in an accelerated aging mouse model.
  • TG also reduces neuroinflammation in the hippocampus, a brain region crucial for learning and memory, by lowering levels of inflammatory molecules TNFɑ and IL6.
  • This coffee-derived molecule restores the concentrations of vital neurotransmitters — including dopamine, noradrenaline, and serotonin — in the hippocampus, which is essential for defending against cognitive decline.

Age-related cognitive decline affects ~11.7% of adults over age 65 and up to ~40% of adults over 80, with symptoms including slower problem-solving ability, reduced perceptual speed, and memory impairment. Recent research has increasingly focused on the potential of naturally occurring compounds in foods and beverages to slow down brain aging and counteract age-related cognitive impairments. Among these compounds is trigonelline (TG), an alkaloid found in coffee beans and Japanese radishes, which has previously shown promise in promoting learning and memory in Alzheimer’s disease mouse models. However, whether TG can mitigate general age-related cognitive decline has remained unexplored until now.

In a newly published study in GeroScience, Isoda and colleagues from the University of Tsukuba in Japan have shed light on TG’s capabilities to restore learning and memory in a mouse model characterized by accelerated cognitive aging, known as SAMP8 mice. Additionally, the researchers discovered that TG has the remarkable ability to reduce the levels of key inflammatory molecules associated with neuroinflammation, namely TNFɑ and IL6, in the hippocampus. Furthermore, TG supplementation proved effective in restoring the concentrations of essential neurotransmitters critical for neuronal signaling and cognitive functions, including dopamine, noradrenaline, and serotonin, in the hippocampus. These findings suggest that TG may offer a way to alleviate neuroinflammation, restore neurotransmitter levels, and promote learning and memory to counteract cognitive decline.

Trigonelline Restores Cognition, Reduces Neuroinflammation, and Increases Neurotransmitters

The research team expressed optimism about the potential of TG as a supplementary medicinal compound for addressing cognitive aging and central nervous system dysfunctions related to neuroinflammation. The study involved a regimen of oral TG supplementation at a dose of 5 mg/kg per day for 30 days, followed by a test of the mice’s learning and memory abilities using a Morris water maze.

In the Morris water maze, mice were required to navigate a cylindrical pool of water to find a submerged platform using environmental cues. After forming memories of the platform’s location, the platform was removed, and the researchers observed that non-TG-treated SAMP8 mice spent less time in the area where the platform had been and crossed over its former location fewer times. In contrast, TG-supplemented SAMP8 mice exhibited a restoration of both measures, demonstrating TG’s potential in defending against age-related spatial learning and memory impairments.

Comparison of spatial learning and memory in SAMP8 mice: SAMP8 mice (Accelerated cognitive aging model) showed decreased performance in the correct quadrant and crossings compared to naturally-aged SAMR1 mice. SAMP8 mice supplemented with TG (SAMP8 TG) exhibited improved spatial learning and memory performance.
(Aktar et al., 2023 | GeroScience) TG improves spatial learning and memory in an accelerated cognitive aging mouse model — SAMP8 mice. Compared to healthy, naturally-aged mice (SAMR1), SAMP8 mice exhibited reduced time in the correct quadrant and number of crossing where the submerged escape platform had been located. TG supplement (SAMP8 TG) restored both of these measurements of spatial learning and memory.

Given that neuroinflammation plays a significant role in age-related cognitive decline, the researchers assessed the impact of TG on two inflammation-driving molecules, TNFɑ and IL6, in the hippocampus. Compared to healthy, normally aging mice, SAMP8 mice with cognitive aging exhibited significantly higher levels of these inflammatory molecules. However, TG supplementation led to a notable reduction of approximately 30% in the levels of TNFɑ and IL6, suggesting that TG effectively diminishes neuroinflammation and helps counteract brain aging and cognitive decline.

Reduction of inflammatory molecules TNFɑ and IL6 in the hippocampus: SAMP8 mice with accelerated cognitive aging (SAMP8) exhibit over twice the hippocampal concentrations of TNFɑ and IL6 compared to normal levels. TG supplementation (SAMP8 TG) effectively lowers these inflammatory markers.
(Aktar et al., 2023 | GeroScience) TG reduces key contributing molecules for inflammation — TNFɑ and IL6 — in the hippocampus. SAMP8 mice with accelerated cognitive aging (SAMP8) show more than double the hippocampal concentrations of TNFɑ and IL6, but TG supplementation (SAMP8 TG) significantly lowers their levels.

Neurotransmitters such as dopamine, noradrenaline, and serotonin are crucial for cognitive function, as they facilitate chemical signaling between neurons. The researchers investigated whether TG supplementation could increase the concentrations of these neurotransmitters in the hippocampus, finding that SAMP8 mice with cognitive aging had significantly reduced levels of these neurotransmitters. However, TG supplementation significantly restored their concentrations, highlighting TG’s potential in replenishing essential neurotransmitter levels necessary for memory formation and learning.

Picture showing how TG helps the brain: SAMP8 mice with fast-aging brains have fewer neurotransmitters like dopamine, noradrenaline, and serotonin (5-HT) in their hippocampus. But when they take TG, it helps bring those neurotransmitters back.
(Aktar et al., 2023 | GeroScience) TG restores neurotransmitters dopamine, noradrenaline, and serotonin (5-HT) in the hippocampus. SAMP8 mice with accelerated cognitive aging show neurotransmitter levels more than cut in half, but TG supplementation restores them.

“Our study provides valuable insights into the therapeutic potential of TG in ameliorating cognitive decline associated with accelerated aging, highlighting its ability to target neuroinflammation, synaptic function, and neurotransmitter release in the hippocampus,” say Isoda and colleagues.

Ways to Supplement with Trigonelline

In summary, the study presents promising insights into the therapeutic potential of TG in mitigating cognitive decline associated with accelerated aging. TG appears to target neuroinflammation and neurotransmitter release in the hippocampus. The findings also raise the possibility that coffee consumption, which contains TG, could have cognitive benefits. Future research may further investigate whether regular coffee consumption correlates with reduced incidence of age-related cognitive decline, though existing studies have produced mixed results in this regard.

For individuals interested in supplementing with TG, fenugreek extract is available as a source of TG, though the exact TG content in these capsules remains unclear. Alternatively, consuming Arabica coffee, which has the highest TG content among coffee varieties, may offer a natural way to incorporate TG into one’s diet.

Model and Dosage

Model: Senescence-accelerated mouse prone 8 (SAMP8) mice

Dosage: 5 mg/kg per day of oral trigonelline


Aktar S, Ferdousi F, Kondo S, Kagawa T, Isoda H. Transcriptomics and biochemical evidence of trigonelline ameliorating learning and memory decline in the senescence-accelerated mouse prone 8 (SAMP8) model by suppressing proinflammatory cytokines and elevating neurotransmitter release. Geroscience. 2023 Sep 18. doi: 10.1007/s11357-023-00919-x. Epub ahead of print. PMID: 37721682.

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