“I have trouble remembering people’s names.” “I feel as though I am becoming more forgetful.” Many people notice changes like these as they age. Research suggests that age-related cognitive decline may involve the accumulation of oxidative stress and chronic inflammation in the brain.
Another molecule relevant to age-related cognitive function is NAD+, a coenzyme whose levels decline with aging. NAD+ supports energy metabolism and DNA repair and contributes to cellular defenses against oxidative stress and inflammation. This has prompted interest in NMN, or nicotinamide mononucleotide, a precursor that can be converted into NAD+ in the body.
Previous articles on this site have explained how NMN may increase NAD+. The 2026 study examined here asked whether NMN could influence the brain in an aging-model mouse. Published in Metabolites, the preclinical study investigated cognitive outcomes and proposed two mechanistic perspectives: the gut–brain axis and the Nrf2/HO-1 pathway.
What You Will Learn
- How oxidative stress and NAD+ are related to age-associated cognitive decline
- What the gut–brain axis is and why it may influence brain health
- Five changes reported after NMN treatment in aging-model mice: spatial memory, antioxidant defenses, inflammation, the gut microbiome, and Nrf2/HO-1 signaling
Why Cognitive Function Declines With Aging: Oxidative Stress and NAD+
Cells generate reactive oxygen species while producing energy. Small amounts are part of normal biology, but when production exceeds the capacity of cellular defenses, reactive oxygen species can damage cells and DNA. This state is known as oxidative stress.
- Reactive oxygen species
- Highly reactive molecules produced naturally during energy metabolism. In excess, they can damage cells and DNA.
The brain consumes large amounts of oxygen and is particularly vulnerable to oxidative stress. Persistent oxidative stress may overactivate microglia, the brain’s resident immune cells, contributing to chronic neuroinflammation. This sequence from oxidative stress to neuroinflammation has been implicated in age-related memory decline1.
- Neuroinflammation
- Inflammation within the brain. When persistent, it may disrupt neuronal function.
NAD+ supports cellular defenses against oxidative stress and inflammation. NAD+ levels decline with aging2, and NMN is being studied as a precursor that may replenish them3. NAD+ metabolism is also associated with the Nrf2/HO-1 antioxidant pathway discussed below.
- Coenzyme
- A substance that assists an enzyme in carrying out a biochemical reaction.
The Gut–Brain Axis: How the Gut Communicates With the Brain
Oxidative stress and neuroinflammation were once studied mainly as processes occurring within the brain. The gut has now become another important focus.
The gut and brain communicate bidirectionally through neural, hormonal, and immune pathways. This network is known as the gut–brain axis. Among its important mediators are short-chain fatty acids, compounds produced when gut bacteria break down dietary fiber and other substrates. Butyrate, a major short-chain fatty acid, supports the intestinal barrier and has reported anti-inflammatory effects45.
- Butyrate
- A short-chain fatty acid produced by gut bacteria. It supports intestinal-barrier function and may modulate inflammatory responses.
When the gut microbiome becomes disrupted, intestinal-barrier function may weaken, allowing inflammatory signals to spread more readily through the body and potentially influence the brain. Conversely, an increase in butyrate-producing bacteria may create a less inflammatory intestinal environment. This is one proposed component of gut–brain-axis signaling6. The study discussed here examined NMN from this perspective.
Study Overview: NMN in D-Galactose-Induced Aging-Model Mice
The 2026 study in Metabolites used an aging-model mouse to examine the effects of NMN on cognition, oxidative stress, neuroinflammation, and the gut microbiome.
Study Design
- Model: Mice received subcutaneous D-galactose injections for six weeks to induce aging-like changes.
- Intervention: Oral NMN at 300 mg/kg or 500 mg/kg was administered in parallel with D-galactose.
- Cognitive and behavioral tests: Y-maze for spatial memory and elevated plus maze for anxiety-like behavior
- Biological measures: Oxidative-stress markers, inflammatory cytokines, and components of the Nrf2/HO-1 pathway were measured using ELISA, western blotting, and immunohistochemistry.
- Gut-microbiome analysis: Bacterial composition was assessed using 16S rRNA gene sequencing.
- D-galactose
- A sugar naturally present in the body. At high experimental doses, chronic administration produces oxidative stress and aging-like changes and is therefore used to create animal models for aging research.
Chronic D-galactose administration is widely used to model some aspects of age-related cognitive decline mediated by oxidative stress7. It does not reproduce every feature of natural human aging.
Study Results
1. Spatial Memory Improved, With No Change in Anxiety-Like Behavior
Mice treated with NMN performed better in the Y-maze measure of spatial memory. No change was observed in anxiety-like behavior measured with the elevated plus maze. The findings suggest that the reported behavioral effect was specific to the memory outcome tested rather than a general change in anxiety-like behavior.
2. Antioxidant Enzymes Increased and Oxidative-Stress Markers Declined
NMN increased measures of the endogenous antioxidant systems SOD, GSH, and CAT and reduced malondialdehyde (MDA), a marker of oxidative stress. The findings indicate a shift in the oxidative–antioxidant balance toward greater antioxidant capacity in this model.
3. Neuroinflammation Was Reduced
NMN lowered concentrations of pro-inflammatory cytokines and reduced microglial activation in the hippocampus. Because the hippocampus is central to memory, the researchers proposed that lower inflammation in this region may have contributed to improved spatial-memory performance.
4. Gut-Microbiome Composition Changed, Including More Butyrate-Producing Bacteria
16S rRNA analysis showed changes in the gut microbiome after NMN administration, including increases in butyrate-producing bacteria such as Butyrivibrio_A and Clostridium_T. From the gut–brain-axis perspective, the researchers interpreted this as a shift toward a potentially less inflammatory intestinal environment.
5. The Nrf2/HO-1 Pathway Was Activated
NMN increased activity in the Nrf2/HO-1 pathway. Nrf2 coordinates the expression of genes involved in antioxidant, detoxification, and anti-inflammatory defenses, while HO-1, or heme oxygenase-1, is one of its downstream antioxidant enzymes8. For more detail, see this explanation of Nrf2.
Activation of this pathway was consistent with the antioxidant and anti-inflammatory findings reported above.
Discussion: What the Gut–Brain Axis and Nrf2/HO-1 Findings May Mean
Two Proposed Routes
Taken together, the results suggest two possible routes through which NMN affected the brains of these mice.
The first route involves NAD+ metabolism and Nrf2/HO-1 signaling, which may reduce oxidative stress and inflammation in the brain. The second involves changes in the gut microbiome, including increases in butyrate-producing bacteria, which may influence the inflammatory environment through the gut–brain axis.
This possibility of effects through both systemic metabolism and the intestinal environment is consistent with previous findings that NMN interacts with the gut microbiome during NAD+ metabolism. The role of the gut in NMN biology remains a subject for future investigation.
Limitations of the Mouse Model
This was preclinical research in mice. The D-galactose model reproduces some aspects of aging but does not represent every feature of natural human aging or dementia. The doses used in mice—300 mg/kg and 500 mg/kg—cannot be transferred directly to humans.
The appropriate conclusion is therefore limited: NMN was reported to produce neuroprotective changes in a D-galactose-induced aging mouse model, with findings implicating the gut–brain axis and Nrf2/HO-1 signaling. Whether similar effects occur in humans requires clinical investigation910.
Summary
- Oxidative stress and chronic neuroinflammation are thought to contribute to age-related cognitive decline.
- The gut–brain axis is increasingly studied as a pathway through which gut bacteria may influence the inflammatory environment of the brain.
- In this study, six weeks of oral NMN in aging-model mice improved spatial-memory performance, increased antioxidant enzymes, reduced neuroinflammation, increased butyrate-producing bacteria, and activated Nrf2/HO-1 signaling.
- The findings suggest possible effects through both systemic metabolism and the gut microbiome.
- These results were obtained in a mouse model and do not establish cognitive or neuroprotective benefits in humans.
What Can Be Done Now?
Butyrate-producing gut bacteria are supported by dietary patterns that include fiber-rich foods and fermented foods. A balanced diet that supports gut-microbiome diversity is one practical approach to general health, although this study did not test dietary interventions in humans.
For more information on NMN and NAD+ metabolism, see this article.
Important Considerations
This article explains recent research and does not recommend the use of any specific supplement or claim that a product is effective. The study was conducted in mice and does not establish efficacy or safety in humans.
References
- Neuroinflammation in the Normal Aging Hippocampus. Neuroscience. ↩
- NAD+ in Aging: Molecular Mechanisms and Translational Implications. ↩
- The Science Behind NMN — A Stable, Reliable NAD+ Activator and Anti-Aging Molecule. ↩
- The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Frontiers in Endocrinology. 2020. ↩
- Short-chain fatty acids: Important components of the gut-brain axis against AD. Pharmacological Research. ↩
- Elucidating the specific mechanisms of the gut-brain axis: the short-chain fatty acids–microglia pathway. Journal of Neuroinflammation. 2025. ↩
- Geraniol attenuates oxidative stress and neuroinflammation-mediated cognitive impairment in D-galactose-induced mouse aging model. Aging. 2024. ↩
- A Perspective on Nrf2 Signaling Pathway for Neuroinflammation: A Potential Therapeutic Target in Alzheimer's and Parkinson's Diseases. Frontiers in Cellular Neuroscience. 2021. ↩
- The Safety and Antiaging Effects of Nicotinamide Mononucleotide in Human Clinical Trials: an Update. Advances in Nutrition. ↩
- Chronic nicotinamide mononucleotide supplementation elevates blood NAD levels and alters muscle function in healthy older men. npj Aging. 2022. ↩
