With over 5 million Americans living with cognitive loss disorders and many more with pre-clinical symptoms of memory loss, researchers are hopeful to discover therapies to prevent this increasingly prevalent condition. 

Recently, researchers have given more attention to the link between brain health and blood sugar control. As excess sugar in the bloodstream is the leading cause of metabolic conditions, it’s hypothesized that excess sugar in the brain is also a cause of cognitive loss. High blood sugar in the brain is linked to inflammation, neurodegeneration, and an increase in amyloid-beta plaque buildup, a hallmark of certain cognitive disorders.

Due to the growing evidence linking brain health and blood sugar, a recent study aimed to determine the molecule nicotinamide mononucleotide, or NMN, can support both of these health outcomes. 

What Is NMN? A Recap

Nicotinamide mononucleotide is a precursor to the coenzyme NAD+ (nicotinamide adenine dinucleotide), which is necessary for the survival and function of all human cells. 

With age, NAD+ levels naturally decline; this decline is implicated in chronic disease development and premature aging. Maintaining elevated levels of NAD+ is linked to healthier cells, and an increase in both lifespan and healthspan — the years lived healthfully and disease-free.

Although NAD+ can be taken supplementally, it is not the most efficient way to raise NAD+ levels. Instead, the precursor NMN directly enters cells and converts into NAD+, effectively boosting levels of this crucial coenzyme. 

In addition to potentially increasing longevity, NMN is linked to cardiovascular, metabolic, and cognitive support. 

NMN and Cognitive Support

Published in the International Journal of Molecular Sciences in June 2020, this study used an animal model to assess NMN’s effects on blood sugar and brain health. Researchers analyzed several biomarkers and cognitive tests before and after inducing rats with a metabolic disorder, finding that these rats had significantly higher hippocampal glucose and glutamate levels, with reduced levels of the antioxidant glutathione. 

The rats also experienced memory deficits and significant decreases in hippocampal CA1 neurons, which are necessary for the formation, consolidation, and retrieval of memories. 

After the initial measurements and tests, 100 mg/kg of NMN was given to some of the rats subcutaneously on alternating days for three months. To assess brain biochemistry changes, the researchers used localized high-resolution proton magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) on the hippocampi of the rats.

What Did the Researchers Find? 

After administering NMN to the metabolically and cognitively impaired rats, the results were encouraging. The researchers found that:

1. NMN Normalized Brain Chemicals

The treatment group experienced significant decreases in glutamate, an excitatory neurotransmitter implicated in cognitive loss disorders when found in excess. 

Also, NMN increased glutathione levels, the body’s master antioxidant that reduces free radicals and oxidative damage. Brain glutathione levels tend to be significantly lower in patients with cognitive loss disorders.

2. NMN Prevented Hippocampal Neuron Loss

In the metabolically disordered rats who did not get NMN, there was a 40% reduction in the CA1 neurons in the hippocampus. In rats with NMN supplementation, both the volume and number of hippocampal CA1 neurons were increased significantly, thereby reversing the metabolic-related decline in neuronal health. 

The CA1 region of the brain is involved in learning, cognition, and memory; the neurons in this area are especially vulnerable to damage from injury, excess glutamate, or hyperglycemia. Loss of hippocampal CA1 neurons is a cause of memory impairment in cognitive loss disorders.

3. NMN Prevented Memory Loss 

The researchers analyzed memory loss using cognitive tests, including a maze that assessed short-term spatial memory. The treatment group experienced significantly improved scores on these tests. 

Spatial memory is highly dependent on hippocampal function. The increase in hippocampal neuron count and volume after NMN supplementation likely played a large role in improving these memory scores. 

4. NMN Improved Mitochondrial Respiration 

In those with blood sugar dysregulation, the high glucose environment inhibits mitochondrial function, which increases oxidative stress and cellular workload. This increase in workload decreases maximal oxygen consumption rate and spare respiratory capacity to the brain, leading to cognitive loss disorders. 

The researchers measured respiration in the hippocampal mitochondria and found that maximal oxygen consumption and mitochondrial spare reserve capacity significantly increased after NMN supplementation. 

These results indicate that NMN protected the mitochondria against the high energy demands of the metabolically impaired brain. The spare reserve capacity is a backup of extra ATP to be used in cases of sudden energy demands; a decrease in this function would lead to increased mitochondrial stress and damage to neurons. 

5. NMN Upregulated Sirtuin Expression  

Sirtuins are a family of proteins linked to increased longevity; their function depends on NAD+. One of the sirtuins, SIRT1, is highly expressed in the hippocampal neurons; low levels of SIRT1 are linked to cognitive loss. 

In this study, NMN supplementation enhanced levels of SIRT1 and the protein PGC-1α, both of which protect against cognitive loss. NMN also activated levels of SIRT3 within the mitochondria and promoted deacetylation of proteins, which increases DNA repair and regulates cellular death and metabolism.  

In summary, this study produced highly encouraging results for the use of supplemental NMN with blood sugar-related cognitive impairment. As the research was done only with rats, we do not yet know if results can be extrapolated to humans. 

NMN has been shown to be safe for human consumption; however, more research is still needed on whether or not NMN can be used as a therapeutic strategy for supporting cognitive health. 

References: 

Chandrasekaran K, Choi J, Arvas MI, et al. Nicotinamide Mononucleotide Administration Prevents Experimental Cognitive Impairment and Loss of Hippocampal Neurons. Int J Mol Sci. 2020;21(11):3756. Published 2020 May 26. doi:10.3390/ijms21113756

Irie J, Inagaki E, Fujita M, et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocr J. 2020;67(2):153-160. doi:10.1507/endocrj.EJ19-0313

Lee HJ, Seo HI, Cha HY, Yang YJ, Kwon SH, Yang SJ. Clin Nutr Res. 2018;7(4):229-240. doi:10.7762/cnr.2018.7.4.229