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Do NAD Precursors Slow Aging?
Few ideas in longevity science have generated as much excitement as the suggestion that increasing NAD will help to slow down aging.
The case is quite compelling. NAD is associated with many different biological functions including the generation of energy, repair of DNA and signaling between cells. It appears to be connected to the biochemical pathways that underlie caloric restriction and there have been preliminary animal studies that indicated raising NAD levels could potentially restore more youthful cellular function.
It was this combination of biological plausibility, and the apparent positive outcomes in animal studies that contributed to the large interest in NAD precursors (such as nicotinamide riboside, or NR, and nicotinamide mononucleotide, or NMN) being developed as supplements. However, the human evidence is nowhere near as exciting.
Why this matters
NAD precursors are currently sold as anti-aging supplements. As such, many individuals take them hoping to improve their energy, metabolic health, and/or decrease their rate of decline as we age. While this broader enthusiasm for supplements is part of why articles such as 5 supplements that could be hurting your health matter, the fact remains that raising a blood marker is not the same as improving function; and an appealing mechanism of action is not the same as a proven intervention. Thus, if our goal is to promote healthy aging, the ultimate measure of the effectiveness of these supplements is whether they affect real world outcomes, not merely whether they meet our expectations based on a hypothetical model.
How the NAD theory of aging got started
The modern NAD theory of aging was stimulated by the investigation into the effects of caloric restriction on longevity.
For decades, scientists had demonstrated that caloric restriction could extend lifespan in various animal models. By the end of the 1990's, investigators were attempting to identify the molecular mechanisms that mediated the longevity promoting effects of caloric restriction. One clue that emerged from yeast studies was the critical role of a protein called Sir2 in mediating some of the longevity enhancing effects of caloric restriction. To learn more about this area, see the Science of Fasting.
Sir2 activity required NAD. Without NAD, the Sir2 pathway did not appear to be functioning appropriately. This discovery provided further evidence that NAD might be a key regulator of the aging process.
A second body of evidence provided further credibility to the notion that NAD might be a key player in regulating the aging process. Studies conducted in rodents and in human tissue samples reported that NAD levels decreased with age, while the levels of markers of DNA damage increased. Based upon this finding, it was hypothesized that declining NAD might contribute to impaired DNA repair and/or other protective processes during aging.
If this were the case, then increasing NAD levels should theoretically counteract some of the biology of aging.
Why NR and NMN became so well-known
Once researchers identified compounds that could elevate NAD levels, the logical next step was to ask if elevating NAD levels via NAD precursors (such as NR or NMN) could counteract some of the biological manifestations of aging.
One influential mouse study published in 2016 significantly advanced this concept. This study found that increasing NAD levels restored more youthful stem cell function in muscle and extended lifespan.
Together, this mouse study and the larger theoretical framework created a powerful narrative:
- NAD is essential to cellular health
- NAD levels decline with age
- Increasing NAD levels increases NAD
- Thus, increasing NAD levels could potentially slow aging
As this idea gained popularity, it rapidly disseminated throughout the longevity community, particularly among prominent longevity advocates and researchers, who began to discuss and utilize these substances publicly.
The flaws with initial breakthrough studies
Biomedical science frequently follows a predictable path. An early study identifies a novel association. The press covers the findings extensively. Products and supplements begin to generate interest. Subsequent studies ultimately fail to reproduce the original findings, and/or demonstrate that the impact of the compound was much smaller than originally stated.
This represents part of a broader issue in biomedical science, namely the "reproducibility" problem. Initial exciting discoveries rarely withstand more rigorous or repetitive testing.
Therefore, it is particularly significant when an intervention is evaluated using more robust testing methods that are designed to minimize the likelihood of false positives.
What the Interventions Testing Program found
One of the more rigorous preclinical evaluations of potential anti-aging treatments in aging research is the Interventions Testing Program, which evaluates multiple compounds simultaneously across three independent laboratories.
When the Interventions Testing Program evaluated NR, the results were unimpressive.
NR raised blood NAD levels in mice. However, it did not extend lifespan. It also failed to provide evidence of significant functional enhancements.
This is a major blow to the simplistic anti-aging premise. If raising NAD levels sufficiently could delay aging in mammals, this would likely be the type of evaluation where that is seen.
Furthermore, this also calls into question the assumption that a different precursor (such as NMN), that also increases NAD, would necessarily be more effective.
Are declining NAD levels really a hallmark of aging?
While the basic premise of the age-related NAD decline story has received widespread attention, it may not be as universal as initially assumed.
Some human tissue studies have demonstrated that many older adults (particularly those that are physically active) maintain NAD levels similar to younger adults. Therefore, while NAD biology is certainly relevant, it is possible that the aging narrative may be more context-dependent than the marketing of NAD precursors typically suggests.
In other words, the premise that aging is simply a consequence of NAD depletion may be overly simplistic.
What do human trials indicate?
Ultimately, this is the most important question.
Have NR or NMN resulted in meaningful functional enhancements in humans?
To date, the majority of human studies have consistently demonstrated that these supplements can raise blood NAD levels, but none have conclusively demonstrated meaningful improvements in measurable outcomes.
A recent long COVID trial exemplifies this.
Researchers randomly assigned approximately sixty participants diagnosed with long COVID to either receive NR or a placebo. The rationale for the study was reasonable. Long COVID encompasses symptoms such as fatigue, brain fog, immune dysfunction, and mitochondrial dysfunction, each of which could logically relate to stressed NAD metabolism.
During the six-week treatment period, NAD levels increased dramatically, as expected.
However, clinically, nothing meaningful occurred.
There were no meaningful differences between the two groups regarding the symptoms and metrics assessed.
This is important because long COVID is the type of condition where, if NAD metabolism had a demonstrable functional value, it is reasonable to expect to observe a signal. Conversely, the study found elevated NAD without observable improvement in function or quality of life.
Why are anecdotal experiences not sufficient?
Some individuals continue to experience subjective improvements when taking NR or NMN.
Subjective improvements may be genuine for the individual experiencing them. However, anecdotal experiences have limitations.
Possible reasons include:
- The placebo effect
- Other changes in behavior occurring simultaneously.
- Use of other supplements that are the actual agents of change.
Trimethylglycine (TMG)
Many individuals who take NAD precursors also concurrently take TMG. TMG is a substance that has some human evidence supporting its effectiveness in improving certain areas such as exercise performance, particularly when used in conjunction with training. TMG also has some evidence suggesting potential impacts on testosterone.
This does not prove that TMG is responsible for subjective improvements. However, TMG is a more plausible explanation for subjective improvements than assuming that NR or NMN are the cause of subjective improvements solely because the two were taken in combination.
What this means for anti-aging claims
Currently, the general pattern is evident.
NR and NMN can elevate blood NAD levels. They have not demonstrated a consistent or reliable enhancement in measurable clinical outcomes.
Thus, this is the primary distinction.
Elevating a blood marker is not the same as enhancing function. A theoretical mechanism of action is not equivalent to a proven intervention.
Therefore, to-date, the evidence does not support the claim that NAD precursors effectively fight aging or age-related disease in humans.
Practical Takeaways
- Interesting, the biological theory of NAD exists. Theory alone is not sufficient.
- NR and NMN can raise blood NAD levels.
- More rigorous mouse testing has not demonstrated lifespan extension with NR.
- No human studies have demonstrated convincingly improved functional benefits.
- A recent long COVID study demonstrated elevated NAD levels without symptom improvement.
- Anecdotal benefits may be due to the placebo effect and/or other supplements being taken at the same time.
- Current evidence does not support NAD precursors as established anti-aging interventions.
Summary
The NAD story began with a strong concept. Caloric restriction extends lifespan. NAD is tied to the key pathways of caloric restriction. Early mouse studies were encouraging. This was enough to create considerable enthusiasm for NR and NMN.
However, the more rigorous evidence has been unimpressive.
Clearly, NAD levels can be elevated. However, what has not been demonstrated is that increasing NAD levels results in measurable improvements related to aging in humans. At present, NAD precursors represent an intriguing hypothesis rather than an established tool for longevity.