Latest Progress in NMN Research! It Doesn’t Directly Fight Aging—The Gut-Liver Cycle and Microbiota Are the Real “Masters Behind the Scene”!

In the pursuit of health and longevity, NMN, as a precursor of NAD+, has attracted great attention in the field of anti-aging. However, its mechanism of action and individual differences in efficacy have long remained uncertain.

In 2025, top journals such as Science Advances and Science published a series of groundbreaking studies that completely overturned the traditional view that NMN is “directly absorbed and converted into NAD+.” At the same time, these studies expanded the functional boundaries of NMN — revealing that it not only aids anti-infection by enhancing mitochondrial function, but also shows potential to extend lifespan and improve pathological indicators in progeria.

These discoveries have laid a scientific foundation for the shift from “blind supplementation” to “precision regulation” of NMN use, opening a new direction in aging-related research.

The Role of the Gut-Liver Cycle and Microbiota

For a long time, the scientific community believed that orally ingested NMN (β-nicotinamide mononucleotide) could be directly absorbed and converted into NAD+ (nicotinamide adenine dinucleotide).

However, a 2025 study published by Harvard Medical School in Science Advances completely redefined this framework, revealing that gut microbiota and the enterohepatic (gut-liver) circulation play a central regulatory role in NMN metabolism.

The study found that NMN and NR taken orally are not directly converted into NAD+, but must first undergo a “pre-processing” step by intestinal bacteria, transforming into niacin-related metabolites, which then enter the liver through the gut-liver cycle to complete the final “upgrade” into NAD+.

Using stable isotope labeling and tracking, researchers observed the entire metabolic process of NMN in the body and reached three revolutionary conclusions:

1. Extremely low absorption efficiency: Only a small portion of NMN is absorbed directly through the small intestine. About 90% passes into the colon.

2. Gut bacteria are indispensable: Bacteria in the colon remove NMN’s amide group and convert it into niacin (NA) and other key metabolites. This “pre-processing” step is essential for NMN’s effectiveness.

3. Final synthesis in the liver: The niacin produced is then converted into NAD+ in the liver through the Preiss–Handler pathway.

To validate this mechanism, researchers conducted experiments on germ-free mice. When germ-free mice (without gut bacteria) were given high doses of NMN, their NAD+ levels showed almost no increase. However, when these mice received fecal transplants from normal mice (restoring gut flora) and were given the same dose of NMN, their NAD+ levels rose significantly.

This discovery explains why NMN supplementation works for some people but not others. Individual differences in gut microbiota composition and the efficiency of the gut-liver cycle may be key factors influencing NMN’s effectiveness.

This insight offers a new direction for optimizing NAD+ supplements — moving from simply “supplying precursors” to regulating metabolic pathways, combining microbiome engineering and targeted delivery technologies for more efficient NAD+ enhancement strategies.

Therapeutic Potential for Progeria

A study published in The FASEB Journal in August 2025 explored NMN’s therapeutic potential for Hutchinson-Gilford Progeria Syndrome (HGPS), a rare disease caused by LMNA gene mutations that lead to the abnormal accumulation of progerin and accelerated aging.

In patient-derived induced pluripotent stem cell–mesenchymal stem cell models, NMN supplementation significantly increased NAD+ levels. It activated the longevity-related SIRT1 and PGC1α pathways, effectively repairing damaged mitochondrial function. Experimental data showed that this intervention reduced reactive oxygen species (ROS) levels and markedly decreased the accumulation of DNA damage marker γ-H2AX.

In transgenic mice carrying the G608G mutation, four months of NMN treatment resulted in comprehensive improvements:

• Gonadal function increased by 28%

• Cardiovascular parameters approached normal levels

• Skin pathological characteristics significantly improved

• Most importantly, the treatment group exhibited a statistically significant extension of lifespan

These findings provide new hope for progeria patients and valuable insight into interventions for general age-related diseases.

Mitochondrial Anti-Infection Function

A September 2025 study published in Science further clarified the role of mitochondria in infection resistance. The research showed that mitochondria can directly inhibit pathogen replication by regulating folate utilization.

When pathogens invade, mitochondria can “lock” intracellular folate, preventing pathogens from accessing it — a defense mechanism described as “starving out” pathogens.

In addition, mitochondria help regulate immune responses, reducing excessive inflammation that can cause secondary cellular damage. Chronic inflammation is a key driver of aging, and this discovery highlights the central role of mitochondria in infection resistance — suggesting that NMN may enhance this protective function through mitochondrial support.

Safety of NMN

Multiple studies have evaluated NMN’s safety profile. Most clinical trials testing its safety and efficacy in healthy adults used doses between 250 mg and 1 g per day.

A multicenter randomized, double-blind, placebo-controlled trial published in GeroScience (2022) confirmed NMN’s excellent safety record. Involving 80 healthy middle-aged adults, the study showed that daily oral NMN doses of 300 mg, 600 mg, or 900 mg for 60 days were well tolerated, with no NMN-related adverse events.

Even higher-dose studies found no significant side effects:

• 1200 mg/day for 6 weeks

• 900 mg/day for 8 weeks

• 2000 mg/day for 2 weeks

All demonstrated good tolerability.

Market Outlook

According to industry data, the global high-purity NMN market was valued at 4.95 billion yuan in 2024 and is projected to reach 10.01 billion yuan by 2031, representing a compound annual growth rate (CAGR) of 10.5%.

The U.S. anti-aging supplements market reached $1.39 billion in 2024 and is expected to grow at a CAGR of 7.2% from 2025 to 2030. This growth is driven by rising health awareness, longer life expectancy, and the proactive attitude of American consumers toward age-related health management.

Consumers are increasingly seeking targeted solutions for cognitive function, joint flexibility, and cellular regeneration, encouraging brands to invest in advanced R&D and precision health technologies.

Summary and Outlook

As a precursor to NAD+, NMN has shown broad potential in anti-aging and health maintenance. Scientific studies confirm that it promotes NAD+ synthesis, activates sirtuins (longevity proteins), enhances DNA repair, improves mitochondrial function, and strengthens the immune system.

However, we should approach NMN rationally — the best supplement is the one that fits your own biology.

In conclusion, NMN represents a science-based anti-aging strategy, targeting the core of cellular energy metabolism and providing a pathway toward healthy aging. As more clinical research unfolds and mechanisms become clearer, NMN is poised to play an increasingly important role in precision anti-aging medicine.

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Reference：

Yaku, K., et al. (2025). Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD+ synthesis via enterohepatic circulation. Science Advances, 11(12), eadr1538.

Treebak, J., et al. (2025). NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging. Cell Metabolism. Advance online publication.

Zhou, Y., et al. (2025). Cellular catalysis of NMN synthesis via ATP-regenerating yeast surface display enzyme systems. Food Bioscience, 73, 107677.

Chen, L., et al. (2025). Epitranscriptomic analysis reveals features of NAD-capped RNAs upon supplementation of nicotinamide mononucleotide in human. Experimental Cell Research, 114780.