If I told you there was an expensive, over-the-counter drug which some believe might increase lifespan but for which we have virtually no evidence indicating efficacy, would you take it? This question was part of the inspiration for my “Ask Me Anything” podcast conversation earlier this year with Dr. Matt Kaeberlein on the use of nicotinamide adenine dinucleotide (NAD) – and its more bioavailable oral precursor, nicotinamide riboside (NR) – as “anti-aging” supplements. In that discussion, Dr. Kaeberlein and I pointed out the paucity of evidence that NAD/NR supplementation has any effect on lifespan, as well as the lack of clarity on whether treatment with the NR precursor even produces the desired increase in intracellular NAD levels.
Still, NR supplements are safe from an acute toxicity standpoint, so to many consumers, perhaps the potential risk of wasting money if these drugs eventually prove ineffective is worth the enormous potential benefits if they eventually prove to extend lifespan. It’s an asymmetric bet, even with a small change of life-extension. But what if wasted money isn’t the only risk?
NR and Cancer
In a previous podcast episode, Dr. Iñigo San Millan explained some very preliminary data suggesting that, in a very small cohort of mice with an aggressive form of cancer, NR supplementation increased tumor growth by 15% relative to controls. This makes sense on a biological level, as cancer cells are highly glycolytically active, and NAD+ is an essential cofactor in glycolysis. However, with only four animals per group, Dr. San Millan’s pilot experiment could only hint at possible effects – more extensive and controlled experiments would be needed before we can make any educated conclusions about the impact of NR on cancer progression. But according to a study published just last month, authors Maric et al. have taken up the mantle of additional testing, revealing data which both corroborate the pilot observations and provide further mechanistic insights into the impact of NR supplementation on cancer.
About the Study
As part of their work, Maric et al. developed and validated a novel experimental system for monitoring NR uptake into cells, which they then applied in vivo to investigate the role of NR in cancer. A cohort of mice was divided into two groups: the NR group received a diet enriched with NR at a level of 400 mg/kg/day (approximately 10-15 mg per mouse per day, n = 10) throughout the study, while the control group received a standard diet (n = 9). (Note: this might be comparable to a human ingesting 30 grams of NR per day, far more than any nutritional supplement provides by a factor of 100.) After two weeks on their respective diets, the animals were injected with breast cancer cells to initiate tumor development. The investigators monitored the progression of tumors visually and through palpation as animals continued on their respective diets over the subsequent weeks, finding that, by 10 weeks post-injection, 7 animals on the NR-enriched diet had detectable tumors (70%), compared to 5 animals on the control diet (55%), corresponding to a hazard ratio of 1.27. (It’s worth noting that the authors did not report statistics for these binary data. Given that the difference between groups is modest and comes from a fairly small number of animals, it likely did not achieve significance, so take this set of results with a grain of salt.)
In a second mouse cohort (n = 23), Maric et al. then sought to determine the effect of NR supplementation on tumor metastases in the brain. Using the same test and control diets as in the previous experiment, the authors injected breast cancer cells into circulation. These cells had been modified in such a way that they would emit light (as would all cells resulting from division and proliferation of these modified cells), and this light could then be imaged and quantified to monitor tumor progression and location. By the end of the 6-week post-injection period, 9 out of 11 mice in the NR group were found to have brain metastases, compared to only 3 out of 12 mice in the control group (HR = 3.3). Correspondingly, the average head-localized light emission signal from the NR group was 3.8x higher than the average signal among controls.
Importantly, these data also provide clear evidence that orally-administered NR can indeed be effectively taken up by cells, as the bioluminescence-based test system was designed such that the light signal would only reflect intracellular NR levels. The authors had further demonstrated through in vitro experiments that increased NR uptake resulted in increased intracellular NAD+ (at least in the various cell types under study), a question which has to date been the subject of significant controversy. Taken together, Maric et al.’s in vivo and in vitro results provide compelling evidence that NR supplementation may accelerate cancer progression and metastasis of certain types of cancer.
Is NR only a problem for cancer patients?
Importantly, both the study described above and Dr. San Millan’s pilot experiment demonstrate that NR can accelerate tumor growth in animals with pre-existing cancer. Despite claims by Maric et al. that “NR supplementation results in a significant increase in cancer prevalence,” these data do not suggest that NR can initiate or cause cancer. When an intervention involves both supplementation with NR and injection with aggressive cancer cells, it seems fairly obvious that the latter is the more likely cancer-causing culprit. The differences between groups showed only that NR speeds cancer progression – at least when given at the extremely high doses used in this study. It’s worth reiterating that these doses were approximately 100x the dosages of most human supplements, and the results may or may not translate when NR is given at more typical therapeutic levels. But even if they do, does that mean NR is only dangerous if you already have cancer?
Possibly, though not necessarily. While there’s no evidence to indicate that NR supplementation can cause cancer – indeed, there’s even some evidence to suggest that it might help to prevent certain skin cancers – the evidence that it doesn’t cause some forms of cancer is scant at best. Still, even if we assume that NR is completely safe for those who do not have pre-existing cancer, the question remains: how can we be absolutely sure who does or does not have pre-existing cancer?
Tumors develop slowly over the course of years before they reach a level that can be detected by screening tests, let alone before they result in noticeable symptoms which might prompt a visit to the doctor’s office. I have no doubt that the current number of individuals with undiagnosed or pre-diagnosed cancer exceeds the current number living with cancer diagnoses (though of course, we have no statistics on the former group). Since the likelihood of catching cancer at an early stage – which is associated with better prognoses – depends on both screening frequency and on the rate of tumor progression, agents which accelerate the growth and metastasis of tumors can have a significant negative impact on clinical outcomes.
Do NR supplements have any therapeutic value?
In spite of the risks described above and the lack of evidence for anti-aging efficacy, I’d be remiss not to note that NR supplements may nevertheless have therapeutic value in treating certain diseases. As discussed with Dr. Kaeberlein, treatment with NAD+ precursors has been found to improve function and survival in a mouse model of a rare disorder in DNA repair and mitochondrial function, as a high level of DNA damage is associated with NAD+ depletion. DNA damage and repair deficiency are also common features of Alzheimer’s disease (AD), and NR supplementation has also been shown to improve cognition in AD mouse models.
Further investigation and clinical trials are certainly necessary before we can draw reliable conclusions about these potential therapeutic applications of NR, but already, results from these research avenues have proven more consistent and shown more promise than any existing data from investigations into NAD and aging. Our best, most reliable data to date on NR and longevity comes from a series of studies by the Interventions Testing Program at the National Institute on Aging, which showed that NR supplementation did not extend lifespan in treated mice relative to controls.
Risks vs. Benefits?
So in summary, I’ll again pose the question: if there were an expensive, over-the-counter drug which some believe might increase lifespan but for which we have virtually no evidence indicating efficacy, would you take it? What if taking that same drug provided a small, but plausible increase in your likelihood of dying from cancer?
Many patients have come into my practice believing that the potential longevity benefits outweighed the financial risk, and even just a couple of years ago, my thinking had been to accept their decisions to use NAD-boosting supplements in the face of this trade-off. But in part due to the results by Dr. San Millan and Maric et al., I now urge my patients to avoid these products, pending further investigation. Unless the upside can be shown to be significantly greater, or the downside can be more convincingly neutralized (e.g., showing these cancer effects do not persist at lower doses), I believe the small, possible benefits do not outweigh the small, possible risks. Someday, they may prove useful for treating very specific diseases, but when it comes to general use for longevity, the evidence supporting their anti-aging benefits is too unconvincing to overcome the risks of cancer acceleration.