Could creatine slow cognitive decline? Mouse study reveals promising effects on brain aging

A new study published in the journal Food Science & Nutrition suggests that creatine supplementation may help protect the brain from age-related memory and learning impairments. The researchers found that creatine increased the activity of a key brain enzyme involved in energy metabolism—called creatine kinase BB (CK-BB)—and reversed memory deficits and structural damage in the brains of aging mice. These results point to creatine as a potential nutritional intervention to help preserve brain function in later life.

The research, conducted by scientists at Nanjing University of Chinese Medicine, focused on understanding the biological mechanisms that underlie age-related declines in cognitive ability—and whether these could be influenced by creatine. Cognitive aging, which includes declines in memory, attention, and problem-solving, is a growing concern as the global population continues to age.

Brain aging contributes significantly to the risk of developing neurodegenerative conditions such as Alzheimer’s disease and other forms of dementia. As a result, researchers are increasingly focused on identifying strategies that could preserve brain function or slow the progression of age-related decline. One area of interest is how the brain maintains energy balance, particularly in regions like the hippocampus that are critical for learning and memory.

Creatine, a naturally occurring compound found in the body and in certain foods, plays a key role in this process. It helps the brain and other high-energy-demand tissues regenerate adenosine triphosphate (ATP), the molecule that powers most cellular activities. Inside the brain, creatine is converted to phosphocreatine through the action of CK-BB. This system acts like a backup battery, rapidly restoring energy during times of increased demand.

While creatine is widely used by athletes to enhance muscle performance, recent studies suggest that it may also support brain function by helping neurons maintain energy levels needed for communication and plasticity.

To explore these potential effects, the researchers used a common model of brain aging in mice. They repeatedly injected the animals with D-galactose, a sugar known to cause oxidative stress and mimic the effects of aging. Mice that received either moderate or high doses of D-galactose developed memory impairments, signs of oxidative damage, and reductions in CK-BB expression and activity. These animals also showed physical changes in brain structure, including fewer and shorter dendritic spines in the hippocampus—a brain area essential for memory.

In a second set of experiments, the researchers used a virus-based technique to reduce the expression of CK-BB specifically in the hippocampus, without using D-galactose. Mice with lower levels of this enzyme displayed many of the same impairments as the aging model, including memory deficits, signs of oxidative stress, and structural damage to brain cells. These findings suggested that lower CK-BB levels could directly contribute to cognitive problems by disrupting the brain’s energy balance and weakening synaptic connections.

Finally, the scientists tested whether creatine supplementation could reverse or prevent these negative effects. They added 3% creatine to the diet of aging-model mice and observed notable improvements. Mice that received creatine showed increased CK-BB expression and activity, restored dendritic structure in the hippocampus, and better performance on memory tests. These animals also had lower levels of oxidative stress markers, suggesting that creatine helped protect their brains from damage caused by aging.

The behavioral tests used in the study included two well-established tasks: the Morris water maze and the Y-maze. These tasks measure an animal’s ability to learn and remember spatial locations and recognize new environments. In both tests, creatine-fed mice performed significantly better than their counterparts who received D-galactose alone. Notably, creatine supplementation did not impair motor or visual abilities, which means the improvements in memory were not due to enhanced movement or perception.

At the cellular level, creatine-fed mice had higher levels of brain proteins associated with synaptic health, including PSD-95, BDNF, and NF-L. These proteins are critical for the formation and maintenance of synapses, the tiny junctions where neurons communicate. The researchers used staining techniques to visualize and measure these structural features and found that creatine restored spine density and dendritic length in the hippocampus to near-normal levels.

These findings build on previous research that has shown links between creatine and cognitive performance. For example, prior human studies have found that older adults may experience improved memory and reasoning abilities after taking creatine supplements. People with genetic disorders that impair creatine metabolism often suffer from intellectual disabilities, but early creatine supplementation can help reduce the severity of symptoms.

In this new mouse study, the researchers provide additional evidence that creatine’s benefits may stem from its effects on CK-BB, a brain-specific enzyme that helps maintain energy balance. CK-BB plays a key role in regenerating ATP, the molecule that powers nearly all cellular activities. In energy-demanding organs like the brain, this process is especially important for maintaining synaptic activity and supporting learning and memory.

Interestingly, the study also examined gene expression data from human brain tissue to confirm the relevance of CK-BB in age-related disorders. By analyzing publicly available datasets, the authors found that the gene encoding CK-BB (known as CKB) was significantly downregulated in people with Alzheimer’s disease compared to healthy controls. This supports the idea that reductions in CK-BB may be a shared feature of aging and neurodegenerative diseases.

Although the findings are promising, the researchers acknowledge some limitations. While the experiments showed a strong link between CK-BB levels and cognitive performance in mice, the exact pathways by which CK-BB affects synaptic plasticity are still unknown. The authors speculate that reduced CK-BB could disturb mitochondrial energy production or increase the brain’s vulnerability to oxidative stress. More work is needed to confirm whether these mechanisms are at play, and whether similar results would occur in humans.

Another limitation is the method used to reduce CK-BB expression in the brain. The researchers used a viral vector to knock down the CKB gene in a specific brain region, but more precise tools—such as genetically engineered knockout mice—could help clarify the role of this enzyme throughout development and aging. Future studies may also explore whether creatine can offer protective effects in models of other brain conditions, such as stroke or Parkinson’s disease.

The study, “Long-Term Creatine Supplementation Improves Cognitive and Hippocampal Structural Plasticity Impairments in a D-Gal-Induced Aging Model via Increasing CK-BB Activity in the Brain,” was authored by Zhu Zhu, Hantao Zhang, Qianlin Li, Xu Han, Tiantian Wang, Wenjing Zhang, Feiyan Chen, Ling Gu, Qi Yao, Lin Chen, and Yunan Zhao.