Why This Matters to Us
As longevity enthusiasts, sustaining and improving health through ageing is paramount. This study demonstrates that nicotinamide mononucleotide (NMN) holds promise in combating age-related biological decline by activating sirtuins, a family of enzymes responsible for promoting cellular repair, reducing inflammation, and maintaining energy balance. Given the decline of NAD+ and sirtuin activity with age, these findings show that restoring NAD+ levels could be crucial for sharper cognition, gut health, and overall resilience against ageing.
These results align with the broader goal of promoting interventions that enhance lifespan and healthspan, while also addressing fundamental causes of ageing such as inflammation and mitochondrial dysfunction.
The Detail
A recent study has provided compelling evidence on how NMN can counteract ageing in both the brain and the gut. Sirtuins, proteins dependent on the coenzyme NAD+ (nicotinamide adenine dinucleotide), are vital regulators of cellular processes like DNA repair, inflammation reduction, and energy metabolism. However, as we age, NAD+ levels drop significantly—up to 50%—leading to reduced sirtuin activity and contributing to cognitive decline, inflammation, and gut barrier dysfunction.
What Did the Study Show?
Conducted by researchers in China, the study investigated the effects of NMN in a model of accelerated ageing using D-galactose (D-gal) in mice. The ageing mice developed human-like symptoms, such as cognitive decline and gut dysfunction. Supplementation with NMN was found to reverse these symptoms through sirtuin activation:
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Reduction in Brain Inflammation and Oxidative Stress
NMN reduced inflammation and damage caused by reactive oxygen species (ROS) in the brain. This improvement correlated with better cognitive performance in tasks like the Morris Water Maze, used to test memory and spatial navigation. -
Improved Gut Barrier Integrity
Ageing compromises the gut lining, often leading to a “leaky gut,” where harmful substances enter the bloodstream and accelerate systemic inflammation. NMN preserved the gut's structural integrity by maintaining goblet cells (which produce protective mucus) and preventing the infiltration of inflammatory cells. -
Mechanism of Action: Sirt1 Signalling Pathway
Researchers uncovered the Sirt1/AMPK/PGC-1α molecular pathway as the key mechanism. Sirt1 activation triggered a cascade of events: it activated AMPK (an energy-regulating enzyme), which then enhanced PGC-1α, responsible for promoting mitochondrial health and suppressing free radicals and cellular damage.
However, these benefits disappeared when Sirt1, the primary enzyme involved, was inhibited, confirming its central role in NMN’s effects.
Context from NAD+ Biology and Ageing
The study aligns with findings from NAD+-related research discussed in this article. The article emphasises:
- NAD+ Decline with Age: Evidence robustly shows that NAD+ concentration decreases with age in humans and animals, resulting in impaired energy metabolism and increased activity of NAD+-dependent enzymes like sirtuins. Significant reductions in NAD+ have been documented in tissues such as the brain, liver, and muscle.
- Drivers of NAD+ Decline: Increased use of NAD+ by enzymes such as CD38 (active in immune cells) and PARPs (stimulated by DNA damage) contribute to the depletion. Similarly, decreased synthesis of NAD+ via precursors like NMN may play a role.
- Benefits of NAD+ Restoration: In rodents, strategies to elevate NAD+, such as NMN supplementation, have reversed many signs of ageing, including mitochondrial dysfunction and inflammation. The findings suggest supplementation could serve as a therapeutic strategy in humans to maintain NAD+ homeostasis and enhance lifespan.
Implications and Future Directions
The gut-brain connection, central to this study, sheds light on how interventions like NMN might have widespread effects on ageing-related diseases. A stronger gut barrier not only reduces systemic inflammation but also protects the brain from inflammatory damage, potentially slowing conditions like Alzheimer’s disease.
Additionally, combining NMN with other interventions may enhance its effects. For instance, antioxidants like lycopene can improve NMN’s memory-boosting ability, while prebiotics targeting the gut microbiome may provide complementary benefits. The insights also suggest other NAD+ precursors, like nicotinamide riboside (NR), could work synergistically with NMN to expand their application to tissues like the heart, liver, and skeletal muscle.
The PMC study referenced explains that while NAD+ supplementation benefits rodents, clinical trials in humans are essential for translating findings into treatments. Future NAD+-targeted strategies might include targeted supplementation for tissues with the greatest deficiencies or inhibition of NAD+-consuming enzymes like CD38.
Conclusion
This study confirms NMN’s ability to elevate NAD+ levels, reactivate sirtuins, and combat ageing-associated dysfunction in both the brain and gut. By fuelling critical cellular repair pathways like Sirt1/AMPK/PGC-1α, NMN could offer a promising approach to slow ageing and alleviate diseases linked to inflammation, oxidative stress, and mitochondrial damage. These findings, combined with existing evidence, present NMN as a key tool in advancing longevity science.
However, further human trials are needed to determine how NAD+ precursors like NMN can benefit ageing individuals and whether combining them with other interventions enhances their efficacy.
For longevity enthusiasts, this research links the science of NAD+ restoration to practical, therapeutic possibilities—and a step closer to healthier, longer lives.