Science Corner 19 | The (Actual) Science Behind NAD+
SuppCo recently launched our comprehensive NAD⁺ testing report, recognizing that NAD⁺ and its precursors have become some of the most popular supplements among our community. With this popularity, however, comes significant confusion around the science; specifically, the differences in efficacy between NAD⁺ itself and its precursor compounds.
This edition of Science Corner is unique.
It is longer, more in-depth, and aims to demystify this complex topic, clearly outlining what current research tells us and highlighting the gaps that remain.
This one is for those of you that enjoy getting into the more sciencey “weeds.”
NAD⁺: Promising Pathways, Lingering Questions
As we age, a critical molecule within our cells, nicotinamide adenine dinucleotide (NAD⁺), significantly declines. This molecule plays essential roles in energy metabolism, DNA repair, and cellular stress responses, positioning it at the forefront of longevity research.
The most central issue plaguing supplementation of traditional NAD⁺ is bioavailability, the body’s ability to absorb and utilize the compound effectively. When taken orally, NAD⁺ is largely degraded in the digestive tract before it can be used, which is why precursors like nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) have gained prominence. These compounds are converted into NAD⁺ inside cells, bypassing the breakdown issue.
These NAD+ precursors have emerged as more viable options, supported by increasingly robust scientific data.
A pivotal 2022 meta-analysis published in Nutrition & Metabolism evaluated the effects of NAD⁺ precursor supplementation across multiple clinical trials. Notably, the data revealed a crucial distinction:
NAD⁺ precursors demonstrated only minimal improvements in healthy individuals, but yielded significant metabolic benefits in those diagnosed with cardiovascular disease and dyslipidemia.
These patient groups experienced reductions in fasting glucose levels and improved lipid profiles, including lowered LDL cholesterol and increased adiponectin, a hormone essential for insulin sensitivity and metabolic regulation.
This underscores an important nuance often missed in longevity conversations.
Supplements frequently exert measurable effects only when there is physiological room for improvement. Individuals already within optimal metabolic ranges may derive little immediate benefit from NAD⁺ or its precursors, at least in terms of short-term biomarker shifts.
Precursors: NR and NMN, What's the Difference?
As discussed, NAD+ supplements have poor bioavailability, thus precursor supplementation remains the more efficacious route for elevating cellular NAD⁺ levels.
Among these, NR is the most extensively studied. Clinical trials have shown that daily doses of 300-500 mg effectively raise NAD⁺ levels in human blood cells. One study in older adults found that 500 mg/day of NR elevated NAD⁺ within weeks, improved mitochondrial function, and reduced markers of inflammation. Additional studies have shown NR may also enhance metabolic health by improving glucose tolerance and reducing liver fat in overweight individuals.
NMN is another promising precursor, often compared with NR. While both ultimately convert to NAD⁺, they enter the salvage pathway at slightly different points. NMN is a direct precursor to NAD⁺ and may be transported into cells via specific NMN transporters, while NR must be converted into NMN first. Some preclinical studies suggest NMN may be more rapidly utilized in certain tissues, such as muscle, although human evidence remains limited and mixed. In practice, both NR and NMN have been shown to raise NAD⁺ levels, but no clear clinical superiority has emerged yet.
Bioavailability Challenges and the Rise of Liposomal Delivery
While the bioavailability of NAD+ is a clear and present issue, scientific advancements in delivery may help improve efficacy for use.
Responding to this challenge, supplement manufacturers have begun exploring liposomal delivery systems. This method encapsulates active ingredients within tiny lipid vesicles (liposomes) that mimic cell membranes, potentially allowing compounds like NAD⁺ to bypass degradation in the gut and enter the bloodstream more efficiently.
Several companies now market liposomal NAD⁺ products, suggesting superior absorption and efficacy. One such product, Rho, passed our internal testing and is currently the most popular NAD⁺ supplement on SuppCo. However, despite these innovations, the scientific consensus on liposomal NAD⁺ remains unsettled. While preliminary data and marketing claims are encouraging, independent research is limited.
Furthermore, there are multiple "liposomal" products that failed our third-party testing for potency and consistency (Maripolio, Wellness LabsRX), underscoring the ongoing need for rigorous verification and adding to the mystique of the method.
Bonus: Regulatory Uncertainty Around NMN
While scientific interest in NMN has surged, its availability in the U.S. faces ongoing regulatory challenges. In late 2022, the U.S. FDA ruled that NMN does not qualify as a dietary supplement due to its parallel development as a pharmaceutical ingredient. Specifically, the FDA determined that NMN was first investigated as a drug before being marketed as a supplement, making it ineligible under the Dietary Supplement Health and Education Act (DSHEA).
As a result, NMN’s status as a direct-to-consumer supplement remains under threat. Several major retailers, including Amazon, have delisted NMN products. While many NMN brands still operate in legal gray zones or are distributed internationally, consumers should be aware of this shifting landscape and stay attuned to updates from regulatory bodies.
A Note on Safety
Despite these uncertainties, NAD⁺ precursors have shown strong safety profiles across multiple trials. NR has been studied in both short-term and long-term contexts, with doses up to 2000 mg/day deemed well-tolerated in humans. Common side effects, when present, tend to be mild (e.g., flushing, nausea).
NMN studies in humans are more limited but thus far report no serious adverse events in doses ranging from 250-500 mg/day for up to 12 weeks. As always, more data from longer and larger trials is needed, but current evidence suggests that these compounds are generally safe for healthy adults when used within studied ranges.
When taken together, all of this information becomes… confusing.
NAD⁺ has poor bioavailability, but…
liposomal delivery might be the answer
To enhance bioavailability we take NAD⁺ precursors like NR and NMN but…
the long-term science on efficacy isn’t there yet
Precursors may work in the short term, but…
only if we already have unhealthy biomarkers to change
We can buy NMN as a precursor, but…
there are legal complications
All of this tells a very complicated story. But perhaps that is what makes NAD⁺ exciting.
We are in the 3rd mile of a marathon right now. We have some early indicators, we feel pretty good, but there is a long way to go.
Therefore, this is a call to action for researchers, scientists, biohackers, and innovators: robust, well-designed long-term studies are urgently needed. Only through rigorous scientific exploration will we fully understand the potential, and limitations, of NAD⁺ and its associated precursors as effective longevity supplements. There remains far more unknown than known, and the true promise of NAD⁺ and its associated precursors awaits careful scientific validation.
In the meantime, enjoy the ride! This is an incredibly exciting time to be following (and using) NAD⁺ as a supplement.
As science evolves, SuppCo will be here keeping you up to date.
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Personal note from Jordan
I find the science and the hype around NAD⁺ uniquely fascinating. Supplements regularly surge into the public consciousness, often fading as quickly as they arrive, but NAD⁺ feels different. Between the emerging scientific data, ongoing confusion around optimal delivery methods, and a base of passionately engaged consumers, NAD⁺ has developed something of a unique aura, even a lore, around its use.
It is genuinely enjoyable for me to observe and interact with this evolving space. Still, I encourage us all to approach supplementation thoughtfully. Let us remain mindful of our personal health goals, carefully consider the reasons behind the supplements we choose, and ensure we truly understand what we are taking, and why.
Citations from this article
Zhong, O., et al. Effects of NAD+ precursor supplementation on glucose and lipid metabolism in humans: a meta-analysis. https://doi.org/10.1186/s12986-022-00653-9
Elhassan YS, et al. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. https://pmc.ncbi.nlm.nih.gov/articles/PMC6702140/