NAD+ Precursors & Longevity: Science vs. Speculation

Longevity, healthspan, and lifespan strategies are all the rage right now. Many people who are health-conscious dream of a “magic pill” that extends life and improves health - without the hassle of training, sleeping, or eating consciously. NAD+ precursors like NMN are particularly coming into the spotlight. These are being marketed – at a purely speculative level – sometimes very aggressively as powerful molecules to slow down your aging process at the cellular level.

In addition to dietary supplements, some people are even taking NAD+ infusions, in which the molecule is introduced directly into the bloodstream. This takes up to two hours and is not only costly but also time-consuming.

But is it worth it? As with any significant investment in life, it comes down to carefully weighing the potential benefits and risks. What is actually behind the scientific hypothesis on NAD+ precursors and NMN? Should these substances become an integral part of your longevity approach? Let's look at it from the perspective of an investment manager who keeps an eye on the opportunities and risks.

The hypothesis of declining NAD+ levels

NAD+ (nicotinamide adenine dinucleotide) is a molecule that plays a key role in energy production, DNA repair and maintaining cell health. Preclinical studies, primarily in rodents, have shown that NAD+ levels decline with age – by 10 to 50%, depending on the tissue.

This decline seems to affect important processes such as DNA repair and mitochondrial function, which are associated with the aging process. However, these findings are based on preclinical research and need to be confirmed by clinical studies in humans. Until we have that data, we can't say for sure how decreasing NAD+ affects the aging process in humans, or whether increasing NAD+ levels can make a difference.

Hypothetical Approaches to Boosting NAD+

If the hypothesis that NAD+ is important for healthy aging is correct, how can we replenish it? There are two main approaches: NAD+ drops and precursors like NMN.

NAD+ drops bypass the digestive tract and introduce NAD+ directly into the bloodstream. However, because NAD+ molecules can only be taken up into cells to a limited extent, the practical benefit of this method remains scientifically unclear. This method is also expensive and time-consuming, and its practical benefit is more theoretical than scientifically proven.

NAD+ precursors such as NMN and NR (nicotinamide riboside) are taken up into cells in small amounts and converted into NAD+. Short-term studies in humans show that these dietary supplements can slightly increase NAD+ levels in the blood and in tissues such as the liver. Short-term studies in humans show that NAD+ precursors can slightly increase NAD+ levels in certain tissues such as the liver, while only limited effects have been observed in muscles and the brain. It is currently completely unclear whether these increases offer clinically relevant benefits.

Possible benefits of exogenous NAD+ precursors

In rodents, NAD+ precursors such as NMN have shown the potential to counteract age-related functional disorders and, among other things, to improve metabolism, boost cognitive function and increase physical performance. These results suggest that restoring NAD+ could have a positive effect on cell health.

However, in the scientifically very rigorous animal studies of the NIH's Intervention Testing Program (ITP), NMN hasshown no clear benefits in terms of lifespan or aging. In one study, mice treated with nicotinamide riboside (NR) from mid-life showed no improvement in median or maximum lifespan compared to control animals. While a slight increase in lifespan was observed in females at one site, this was offset by a shortening of lifespan at other sites, indicating that there is no conclusive evidence for anti-ageing effects of NR. NMN has not yet been tested in ITP protocols, adding to the uncertainty surrounding its potential.

NMN is often advertised with claims such as potentially slowing the aging process, increasing energy, or improving vitality. However, these statements are based on insufficient scientific evidence and are currently speculative. However,the evidence for these claims is extremely weak. Without robust human clinical trials demonstrating the effects of NMN, these marketing claims remain speculative—like trying to predict an entire rugby season based on a single training match.

Potential risks of exogenous NAD+ precursors

The risks of NAD+ precursors such as NMN or NR depend on the dosage and frequency of use. Occasional use of low doses appears to be safe based on preliminary findings, but the long-term effects of daily use are unclear in the absence of comprehensive clinical trials in humans.

In rodent studies, high doses of NMN have been associated with kidney inflammation and other possible side effects, although these results have not been confirmed in humans. It should be noted that the doses used in these studies are often higher than those in dietary supplements for humans, making a direct comparison difficult.

Another concern is the possible role of NAD+ in cancer development. Preclinical studies in rodents have investigated whether increased availability of NAD+ could affect cell growth to such an extent that it could theoretically promote the development of cancer. However, this hypothesis is based on early research results that cannot be applied to humans and require further investigation. While speculative and untested in humans, these findings underscore the need for caution, particularly in individuals at increased risk for cancer.

To fully understand the safety and efficacy of NAD+ supplementation, robust long-term clinical trials are urgently needed. These studies would not only confirm the potential health benefits, but also the safety profile of these compounds under various conditions of use.

Our recommendation

For us at ASPRIVA, scientific evidence is the basis for all our decisions. We know that health does not tolerate experiments, but requires clear, well-founded approaches. When evaluating new substances such as NAD+ precursors, a fundamental criterion for us is to carefully weigh up the possible health benefits against the possible risks.

This consideration follows the same principle as for prescription drugs: if the expected benefits – for example in the treatment of diseases – outweigh the known risks and side effects, then it makes sense to take them.

For NAD+ precursors such as NMN and NR, there is insufficient clinical evidence to date to support their potential benefits in slowing down age-related processes. Without further long-term studies, it is not possible to make a well-founded assessment of the risks and benefits.

Our recommendation is therefore clear: rely on scientifically proven and tested strategies such as regular zone 2 training, strength training, exercise, good sleep, stress management and a balanced diet. These approaches will significantly advance your longevity journey – without speculative risks. So don't be lazy and put your mitochondria under positive stress by putting on your sneakers for a workout. Your future self will thank you from the bottom of their heart.

Want to learn more?

• The Latest Data from the Interventions Testing Program: Nicotinamide Riboside has No Effect on Mouse Life Span (April 9th, 2021)
• Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner | preprint (June 27, 2024)
• Separating substance from nonsense in a study on NMN supplements (Angela Misic, Kathryn Birkenbach, Peter Attia, June 3, 2023)
• Prof. Matt Kaeberlein on X: ( Nov. 20, 2022)
  
• Andrew Huberman with Dr. Peter Attia: Supplements for Longevity & Their Efficacy (July 29, 2024)
• Evaluating NAD and NAD precursors for health and longevity
• Does NMN improve metabolic health in humans? - Peter Attia May 9, 2021
• Does NAD+ Actually boost longevity? | Dr. Matt Kaeberlein
  
• #148 - Richard Miller, M.D., Ph.D.: The gold standard for testing longevity drugs: the Interventions Testing Program - Peter Attia