- by Nils Osmar. August 21, 2023
- This post is not intended as, and should not be taken as, medical advice.
- See full Medical Disclaimer
Dr. Brad Stanfield posted a video this morning looking at the human studies to date using NMN. In the video, he says that there’s no direct evidence that NMN increases lifespan.
He’s right on this point; taking NMN has not been shown to directly increase lifespan. But that doesn’t mean it has no anti-aging benefits. Most people taking NMN are doing so because the sirtuin genes — which do increase lifespan in lab animals — are NAD+ dependent (See study: The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling) And taking NMN raises NAD+ levels in the body, which makes it possible for the sirtuins to do their work. This matters because…
Evidence from animal studies
We can’t prove life extension directly in human beings, because it would take longer than a human lifespan to do so. But in lab animals, activation of the sirtuins, in particular SIRT6, is associated with a significant increase in lifespan. Here’e a quote from a 2019 study, Sirtuin signaling in cellular senescence and aging:
In addition to the roles in cellular senescence, it is well established that Sirtuin regulates the organismal lifespan in several animal models. Increased expression levels of Sirtuin, especially yeast SIR2 and its homologues, extends the lifespan of budding yeast S. cereviseasae, worms C. elegans, fruit flies D. melanogaster, and mice (4, 10, 50, 51).
The first investigation for the prolongevity effect of SIR2 was established using the yeast model system almost 20 years ago, in which the complex of SIR2/3/4 extended the replicative lifespan of S. cerevisiae by silencing the HM loci and preventing a/α co-expression; SIR2 alone also extended the lifespan by repressing the recombination and generation of toxic rDNA circles (4).
The prolongevity effect of SIR2 has been confirmed in higher organisms, while there are different mechanisms of exerting prolongevity effects in yeast, including changes in mitochondrial function and biogenesis, suppression of inflammation, and regulation of genomic stability (52). A 7-fold overexpression of sir-2.1 extended the mean lifespan of worms by 14.8–50.5% (50), whereas a low-copy overexpression of sir-2.1 extended the lifespan by 26.2% (53). In addition, sir-2.1 mutation resulted in decreased lifespan of C. elegans (4, 54, 55).
In Drosophila, overexpression of dSir2 using a P-element mediated insertion of the UAS sequence upstream of dSir2 extended the lifespan (10), whereas dSir2 null mutants showed a shortened lifespan (31). Of note, the overexpression of dSir2 in the pan-neuronal cells or fat body extended the lifespan up to 52% and 32.2%, respectively, but the dSir2 induction in motoneuron or muscles had no effect on the lifespan (10, 56).
These results indicate that the prolongevity effect of Sirtuin is tissue-specific. Similarly, mice overexpressing SIRT1 specifically in the hypothalamus had increased median lifespan by 16% in females and 9% in males (57).Sirtuins other than SIRT1 are also reported to exert a prolongevity effect. The transgenic male mice overexpressing SIRT6 showed a significantly longer lifespan than wild-type mice by 16% (51), whereas the SIRT6- and SIRT7-deficient mice lived shorter than controls (43, 58).
Re: NMN raising NAD+, and high levels of NAD+ supporting the sirtuins, this is not generally disputed. As stated in an article called Sirtuins and NAD+ in the Development and Treatment of Metabolic and Cardiovascular Diseases:
Mammalian sirtuins are NAD+-dependent deacylases with a huge range of roles in transcription regulation, energy metabolism modulation, cell survival, DNA repair, inflammation, and circadian rhythm regulation.
So in short:
- NMN does not, as far as we know, extend lifespan directly.
- It does, though, raise NAD+ levels.
- NAD+ fuels the operation of the sirtuins.
- The sirtuins do extend lifespan.
- When we’re young, we have high levels of NAD+, which helps with key metabolic functions such as DNA repair. When we’re older, levels drop. That’s the real reason people are taking NMN.
Re: Brad’s other statements:
- He points out that NMN doesn’t lower A1C or lower cholesterol. This is true, but I’m not sure why he’d be talking about this, because I haven’t heard anyone claiming that it does. Lipids and blood sugar levels are important, but they’re not all there is to the aging process. Saying NMN has no benefits because it doesn’t lower cholesterol is a bit like saying penicillin has no benefits because it doesn’t cure blindness.
- He states that NMN raises NAD+ in the blood but doesn’t raise it in the muscles. I’m not sure this is accurate, because it’s usually only measured in the blood. Muscle biopsies are expensive and invasive, so most studies have not attempted to measure its level in the muscles.
- I do agree with Brad’s point that exercise is essential, but not everyone who is experiencing lower NAD+ as a result of the aging process is able to exercise as vigorously as they could when they were young. This study is a good summary of the benefits of exercise in maintaining high NAD+ levels, for those able to do it.
- He suggests in the video that people taking NMN felt better because they also started exercising, getting more sleep and eating better meals when they started taking it — i.e., that the perceived benefits are a placebo effect. They may be in some cases; the placebo effect is very real, and applicable to all drugs and supplements. But where is the evidence that anyone taking NMN did any of these things? When I started taking it, I didn’t make any changes in my diet or exercise or sleep schedule. I noticed an energy-boosting effect almost immediately. In fact, it was a little jarring and I had to cut my dose for a while till I got used to taking it.
- Re: the studies he cites, in many of them, tiny amounts of NMN were used. In the first study he talks about, for example, people were given only 250 mg. In another, people were given 300, 600 or 900 mg. Most people I know are taking at least a full gram; I routinely take 1,500 mg. Even at those very low doses, NMN has been found to increase blood levels of NAD+, which is what should be needed to activate the sirtuin genes.
- Re: the study showing that people with poor gait speed experienced improvement, it did show exactly that. He’s right that they were elderly and could barely move around, but this doesn’t negate the study. Their results, of course, don’t prove that young athletic people will benefit from taking NMN — at least, their athleticism. may not improve — but it does suggest that the elderly could benefit, which is the whole point.
- Re: his statement that exercise increases NAD+ levels, this is true, and is why so many people in our community have added exercise to their protocol. Cold showers also increase NAD+. I do all three: I take supplements, take cold showers, do some fasting, and exercise. At the age of 70, as a result, I have the NAD+ levels of a young adult.
- He states that supplements like creatine have well-established anti-aging benefits. I agree with him on this point. Creatine is a key supplement in my anti-aging protocol, right up there with taking NMN. But this doesn’t mean NMN has no value.
- The point is that many compounds that are high when we’re young tend to decrease as we age. If we want to tackle aging, in my opinion, it’s good to tackle it on all fronts. For me, this means taking creatine – and taking taurine – and taking NAC plus glycine – and taking NMN – and taking fucoidan in the form of SIRT6 Activator. (See this video for why I consider SIRT6 Activator a key anti-aging supplement, and why I always take it along with NMN):
Benefits of NMN in animal studies
There are well established benefits to taking NMN in both human and animal studies. Here’s a summary of some of the effects found when giving NMN to animals:
In numerous mouse models of disease and aging, NMN has demonstrated a wide array of remarkable effects, benefitting conditions ranging from diabetes to Alzheimer’s disease to ischemia.27
Orally administered NMN is quickly synthesized into NAD+ in tissues in mice. NMN has been able to suppress age-associated weight gain, enhance energy metabolism and physical activity, improve insulin sensitivity, improve eye function, improve mitochondrial metabolism and prevent age-linked changes in gene expression.28
In mice bred to be diabetic or obese, NMN improved both the action and secretion of insulin.29 NMN also protected the mouse heart from ischemia and/or reperfusion injury.30 It has restored skeletal muscle in aged mice31, and slowed cognitive decline in a mouse model of Alzheimer’s disease, by improving the survival of neurons, improving energy metabolism, and reducing reactive oxygen species.32 It may help maintain the integrity of the blood brain barrier.33
NMN is likely a good candidate to suppress inflammaging—the increase in inflammation associated with aging—since studies show it lowers adipose tissue inflammation associated with age. In fact, older mice appear to be more responsive to NMN, in comparison with young mice.
Benefits of NMN in human studies
Benefits have also been found in human studies. The authors of a recent human study wrote:
Blood NAD concentrations were statistically significantly increased among all NMN-treated groups at day 30 and day 60 when compared to both placebo and baseline (all p ≤ 0.001).
Blood NAD concentrations were highest in the groups taking 600 mg and 900 mg NMN. No safety issues, based on monitoring adverse events (AEs), laboratory and clinical measures, were found, and NMN supplementation was well tolerated.
Walking distance increase during the six-minute walking test was statistically significantly higher in the 300 mg, 600 mg, and 900 mg groups compared to placebo at both days 30 and 60 (all p < 0.01), with longest walking distances measured in the 600 mg and 900 mg groups.
The blood biological age increased significantly in the placebo group and stayed unchanged in all NMN-treated groups at day 60, which resulted in a significant difference between the treated groups and placebo (all p < 0.05)…
The change of SF-36 scores at day 30 and day 60 indicated statistically significantly better health of all three treated groups when compared to the placebo group (p < 0.05), except for the SF-36 score change in the 300 mg group at day 30.
NMN supplementation increases blood NAD concentrations and is safe and well tolerated with oral dosing up to 900 mg NMN daily. Clinical efficacy expressed by blood NAD concentration and physical performance reaches highest at a dose of 600 mg daily oral intake.
Not medical advice
This article is not intended as, and should not be taken as, medical advice. I’m not advising that people eat any particular diet or take any particular supplement(s), just reporting on what I’m doing. Supplements, like medications and other interventions, can have side effects; I would encourage people to research both possible benefits and side effects before starting on any supplementation regimen, and consult with a medical professional about any issues which might have a medical component. See full Medical Disclaimer
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