Creatine has been the go-to gym and sports supplement for over three decades, well known for supporting muscle size, physical performance and energy production. But its benefits may extend well beyond training.
In the longevity space, creatine has been associated with lower inflammation and cortisol levels, and it plays a direct role in the methylation cycle, one of the body's most fundamental biochemical processes.
DNA methylation involves tiny chemical tags (methyl groups) attaching to specific points on your DNA. These tags act like switches, either turning gene activity up or down (hyper- or hypo-methylation), and they influence how genes and biological processes function throughout the body. Most of this methylation activity happens in the liver, which is one reason evening wine with dinner isn't doing your long-term methylation status any favours.
Around 80% of the methyl groups your body produces go towards making two things:
1. Phosphatidylcholine
2. Creatine
Supplementing with either can help take pressure off the methylation cycle, allowing it to run more efficiently. Conversely, if something is disrupting methylation (MTHFR or MTR variants, poor liver health, chronic stress, or poor sleep), your body's own creatine production can drop significantly.
This matters for brain health specifically. Creatine supports ATP production, the primary energy currency of cells, and the brain is one of the most energy-hungry organs in the body. This is thought to be the main mechanism behind creatine's links to cognitive function and neuroprotection, an area with a growing body of research behind it.
The New Longevity Supplement for Your Brain: Testing the theory?
We looked at this using our own dataset: creatine monohydrate users aged 30-60 (n=298) compared against a non-supplement-using cohort in the same age bracket (n=761), assessed using our Memory Age DNA methylation clock.
Two genes central to the algorithm, SLC25A43 and TMLHE, showed significant hypomethylation in the creatine group (p=1.65 × 10⁻³⁴), a pattern we associate with more favourable cognitive ageing.
Based on this data, consistent creatine monohydrate use for a year or more was associated with an average reduction in Memory Age of 6.2 years. Since accelerated Memory Age has been linked to cognitive decline and subjective memory loss, this positions creatine as a supplement worth serious consideration in a longevity stack.
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Supporting evidence: Performance genes tell a similar story🧬
Interestingly, our findings echo a separate study by Chris Collins, which compared saliva DNA methylation in resistance-trained adults using creatine long-term (average 6.2 years, n=107) against non-users (n=243) using the Illumina EPIC850k array. The researchers identified 64 differentially methylated CpG sites mapping to 34 genes, enriched in pathways covering energy metabolism, muscle development, neuromuscular function and recovery.
Notably, long-term creatine users showed hypomethylation (associated with upregulation) at genes linked to muscle fibre differentiation, vascularisation and fatty acid metabolism, alongside hypermethylation (associated with suppression) at genes linked to growth inhibition.
One standout finding: lower methylation at NOS3, a gene tied to nitric oxide production and previously linked to elite endurance and power athlete status, suggesting creatine users may show an epigenetic profile that mirrors the adaptations seen with exercise training itself.
Taken together, our cognitive ageing data and performance-focused study point in a consistent direction: long-term creatine use is associated with methylation patterns that favour both brain and muscle function, though as with any observational epigenetic research, more work is needed to establish direction of causality.
Creatine vs Non-Creatine: The wider data picture
New data from Muhdo Health, from our Head of Data Science, Christopher Collins.
· Men were 72% more likely to use creatine than women ♂️
· 89% of creatine users also weight trained
· 98.3% of creatine users engaged in some form of regular exercise
· 71% of creatine users also took Omega-3 supplements
· 210 CpG sites (gene methylation locations) showed a significant difference (p<0.0001) between creatine users and non-supplement users, several of which have prior links in the literature to cognitive disease, ageing and cancer risk
Creatine users (n=964)
Average chronological age: 40.1 years
26% rated their health as excellent, 66% as very good
76% reported no diagnosed disease across a list of 101 conditions
75% reported no general aches and pains
Non-supplement/vitamin users (n=3,609)
Average chronological age: 45.1 years
11% rated their health as excellent, 44% as very good
59% reported no diagnosed disease
62% reported no general aches and pains
A note on interpretation
This is not a verdict for or against creatine supplementation. Multiple confounding factors are likely at play: creatine users in this sample were younger on average, more likely to exercise regularly, and more likely to also take Omega-3, any of which could independently influence methylation patterns and self-reported health. The association is compelling, but it doesn't establish causation.
Source: Collins, C. & Puras, A. (2025). Creatine Monohydrate Use Is Associated with Performance-Enhancing DNA Methylation Patterns. SportRxiv.
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