Could a natural fungus compound fight fatigue and sharpen your mind? New research suggests cordycepin might hold the key to boosting endurance and protecting brain function when pushed to the limit.
Cordyceps parasitic fungus growing on an ant, also known as zombie-ant fungus, 3D illustration. Study: Cordycepin combined with antioxidant effects improves fatigue caused by excessive exercise. Image Credit: Kateryna Kon / Shutterstock
In a recent paper published in the journal Scientific Reports, researchers used a mouse model to examine the anti-fatigue effects of cordycepin, a compound found in Cordyceps militarist. (C. militarist) is a fungus species with applications in traditional Chinese medicine and modern pharmaceuticals.
Their results suggest that cordycepin has the potential to alleviate exercise-induced learning and memory deficits, reduce oxidative stress, and combat fatigue caused by excessive exercise. Further investigation is needed to explore its potential as an ingredient in functional foods and anti-fatigue supplements.
Background
Modern lifestyles seem to be making people more tired! Fatigue is increasingly common, and researchers classify it as peripheral fatigue, which affects the muscles, or central fatigue, which affects the brain and nervous system.
Recent studies link central fatigue to the buildup of chemicals in the brain, particularly the hippocampus, which is highly sensitive to oxidative damage. Oxidative stress occurs when harmful reactive oxygen species overwhelm the body’s antioxidant defenses, leading to neuron damage. It can also affect memory and impair learning.
Minimizing the impacts of fatigue is an important research focus. Scientists have found that the key defense mechanism is the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway. Nrf2 activates antioxidant proteins, while heme oxygenase-1 (HO-1), a downstream gene, helps reduce fatigue and oxidative damage. Cordycepin was shown to modulate the Keap1/Nrf2/HO-1 pathway, boosting antioxidant defenses by increasing Nrf2 and HO-1 levels and reducing Keap1.
One avenue of investigation is cordycepin, found in the insect-parasitizing fungus species Cordyceps militaris, commonly known as the caterpillar or zombie fungus. Cordycepin appears to confer neuroprotective, anti-inflammatory, and antioxidant benefits by protecting the hippocampal neurons. This delays muscle fatigue and improves brain functioning, even under low oxygen conditions.
About the Study
Researchers investigated how cordycepin protects brain function and reduces fatigue, hoping to establish a foundation for the development of anti-fatigue supplements. They used a mouse treadmill exercise model with electrical stimuli to mimic excessive exercise-induced fatigue and ensure mice met exhaustion criteria.
The experiments used male Kunming mice that were six weeks old. The mice were divided into five groups: a non-exercised control group receiving saline, an excessive exercise group (also given saline), and three treatment groups that received cordycepin (5 mg/kg, 10 mg/kg, and 25 mg/kg for 22 days) alongside exercise.
Over six days, the mice ran at increasing speeds, with exhaustion defined as failure to maintain a 30 m/min speed. Electrical stimulation was applied to prompt the mice to continue running, which may introduce additional stress affecting the results. The 10 mg/kg dose showed the most pronounced improvements in both biochemical and behavioral tests, while the higher dose (25 mg/kg) did not offer additional benefits and may have been less effective.
Findings
Researchers found that mice treated with cordycepin showed significantly higher exercise endurance and were able to keep running for longer compared to fatigued mice given saline.
They also showed reductions in markers of peripheral fatigue, such as higher levels of glycogen in the muscles and liver (indicating improved energy storage), and lower levels of creatine kinase, lactate dehydrogenase, blood urea nitrogen, and lactic acid. These indicated that cordycepin enhanced glycogen storage, improved energy metabolism, and decreased muscle damage.
Cordycepin also counteracted oxidative stress by increasing superoxide dismutase (SOD) activity and reducing malondialdehyde (MDA) levels. In in vitro muscle cell (C2C12) experiments, cordycepin improved cell viability under hydrogen peroxide-induced oxidative stress and reduced MDA and LDH levels while boosting SOD activity, supporting its antioxidant effects.
Cognitive Benefits
Cordycepin improved performance in the Y-maze test, reversing fatigue-induced declines in neurotransmitters like glutamate and acetylcholine while reducing stress-linked chemicals like serotonin and gamma-aminobutyric acid. Specifically, it increased levels of acetylcholine and glutamate—associated with learning and memory—and decreased gamma-aminobutyric acid (GABA) and serotonin (5-HT), which are linked to stress and fatigue.
This aligned with increased expression of brain-derived neurotrophic factor (BDNF), HO-1, and Nrf2 proteins, alongside reduced Keap1, which together protect against cognitive impairment and oxidative stress.
Conclusions
Cordycepin shows significant effects on anti-fatigue, metabolic regulation, oxidative stress reduction, neuroprotection, and alleviation of learning and memory deficits. However, these findings are limited by the use of only male mice and the application of electrical stimuli to encourage exercise, which introduces additional stress.
While further research is needed, this study indicates the potential of cordycepin in natural supplements for physically active individuals needing enhanced cognitive function and endurance despite fatigue. Future studies should explore the role of other pathways mentioned in the paper, such as AMPK, mitochondrial biogenesis, and FOXO3, to fully understand the mechanisms behind cordycepin’s effects.