New Study Shows Trigonelline, a Coffee-Derived Molecule, Defends Against Cognitive Decline

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(University of Tsukuba |

Japanese researchers show that trigonelline wards off learning and memory impairment, suppresses neuroinflammation, and restores neurotransmitter levels in an accelerated aging mouse model.


  • Trigonelline (TG) improves spatial cue-based learning and memory as shown with water maze performance in mice that exhibit accelerated cognitive aging — SAMP8 mice.
  • TG suppresses neuroinflammation in a key brain region for learning and memory, the hippocampus, as shown with lower levels of inflammatory molecules — TNFɑ and IL6.
  • TG boosts neuronal messenger molecules — neurotransmitters dopamine, noradrenaline, and serotonin — in the hippocampus, to defend against cognitive decline.

Age-related cognitive decline that includes slower problem solving, reduced perceptual speed, and impaired memory affects ~11.7% of adults over age 65 and up to ~40% of adults over 80. Intriguingly, naturally occurring molecules and compounds found in foods and beverages have garnered attention as accumulating evidence suggests they can effectively slow brain aging and potentially ward off aging-associated cognitive impairments. Along those lines, trigonelline (TG), an alkaloid found in plants like coffee beans and Japanese radishes, has been shown to promote learning and memory in a mouse model for Alzheimer’s disease. However, whether TG helps to thwart general age-related cognitive decline hadn’t been tested until the release of a new study.

Published in GeroScience, Isoda and colleagues from the University of Tsukuba in Japan show that TG supplementation restores environmental cue-based learning and memory in a mouse model for accelerated cognitive aging — SAMP8 mice. The researchers also show that TG lowers hippocampal concentrations of molecules with key roles in neuroinflammation — TNFɑ and IL6. Furthermore, Isoda and colleagues show that TG restores hippocampal concentrations of essential neurotransmitters for neuronal signaling along with learning and memory — dopamine, noradrenaline, and serotonin — in SAMP8 mice. These findings suggest that TG alleviates neuroinflammation and restores essential neurotransmitter levels to promote learning and memory and defend against cognitive decline.

“TG might be considered a potential supplementary medicinal compound for ameliorating cognitive aging and neuroinflammation-related [central nervous system] dysfunctions,” say Isoda and colleagues.

Trigonelline Improves Learning and Memory, Reduces Neuroinflammation, and Restores Neuronal Signaling

To find whether supplementing with TG restores environmental cue-based learning and memory in accelerated cognitive aging SAMP8 mice, the Japan-based researchers supplemented with 5 mg/kg per day of oral TG for 30 days. After the TG supplementation regimen, the researchers then subjected the SAMP8 mice to a Morris water maze to test their learning and memory formation capabilities.

In the Morris water maze, the mice swam in a cylindrical pool of water with a hidden, submerged platform on which the mice could stand once they located it. After swimming in the pool of water for seven days and forming memories of the location of the submerged platform based on environmental cues around the pool, the platform was removed. Non-TG-treated SAMP8 mice with accelerated cognitive aging exhibited reduced time swimming in the area where the platform had been and showed a reduced number of times crossing where it had been located. Interestingly, TG supplemented SAMP8 mice exhibited restoration for both of these behavioral measurements of spatial cue-based learning and memory. These data support that TG supplementation defends against age-related spatial learning and memory impairments.

(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.

Since neuroinflammation significantly contributes to age-related cognitive deterioration, Isoda and colleagues measured TG’s effects on two molecules in the hippocampus with key roles in driving inflammation — TNFɑ and IL6. Compared to healthy, normally aged mice, SAMP8 mice exhibited significant elevations for these two inflammatory molecules in the hippocampus. However, supplementing SAMP8 mice with TG cut the TNFɑ and IL6 levels by ~30%. These results suggest that TG reduces neuroinflammation to ward off brain aging and defend against age-related cognitive decline.

(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.

Molecules that relay chemical signals between neurons to modulate their activation — the neurotransmitters dopamine, noradrenaline, and serotonin — play essential roles in cognition. As such, Isoda and colleagues sought to find whether TG supplementation increases their concentrations in the brain’s hippocampus. As expected, SAMP8 mice with accelerated cognitive aging exhibited significantly reduced levels of these neurotransmitters, but TG significantly restored their concentrations in the hippocampus. These findings suggest that TG restores key neurotransmitter levels necessary for memory formation and learning.

(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.

Arabica Coffee and Fenugreek Extract Supplements Contain Trigonelline

The study shows that TG blunts neuroinflammation and restores neurotransmitter levels to revitalize spatial learning and memory in a mouse model for accelerated cognitive aging. Since, TG is found in coffee, the study’s data lend support for the notion that consuming coffee enhances cognition. To reach a better understanding of TG’s effects against age-related cognitive impairments, research should seek to find whether coffee drinkers have a reduced incidence of aging-associated cognitive deterioration. So far, research in this area has shown mixed results, with some studies suggesting moderate coffee consumption can ward off age-related cognitive decline.

For those interested in supplementing with TG, a month’s supply of fenugreek extract, known to contain TG, can be purchased for ~$10. It’s unclear, though, how much TG is included in fenugreek extract capsules. Alternatively, the most popular way to consume TG is through coffee consumption, with arabica coffee beans in particular having the highest TG content.

Story Source

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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