There’s been a lot of talk lately about longevity, i.e., extending lifespan and perhaps “healthspan,” based on preliminary science emerging from observations in worms, mice, and other non-human species. Basic science researchers, most notably Dr. David Sinclair, have argued, for instance, that restoration of youthful levels of nicotinamide mononucleotide, NMN, increases intracellular nicotinamide adenine dinucleotide, NAD+, levels that thereby increase expression of various sirtuin proteins that increase energy production and cellular repair and reduce insulin resistance. While it plays out in experimental animals, it has not yet been corroborated in humans. The hype surrounding this idea has been fueled by Sinclair’s claims such as “One hundred years from now, people will be taking these molecules on a daily basis to prevent heart disease, stroke, and cancer,” a bold statement for something that has never been shown to be beneficial in living humans. Statements like this are also part of the reason that the FDA banned sale of NMN in 2022.

Imagine: In order to prove whether a strategy such as NMN supplementation prolongs life, we would have to enroll a large number of people at, say, age 40 or 50 years, randomize them blindly to either a dose (or escalating doses to assess “dose-response”) of NMN versus placebo, then track the lives of these people for 30, 40, or more years to see whether diseases are reduced and life is extended. Over that time period, some of the original researchers will die and the world has undergone changes, including emergence of additional research findings that confirm or refute some of the initial experimental observations. In short, it is a logistical nightmare, one that makes it highly unlikely such a human clinical trial will ever be conducted.

If you embrace the findings of this basic research, you supplement a dose of NMN (or nicotinamide riboside to circumvent the FDA ban), perhaps engage in other sirtuin-active compounds such as resveratrol, for the next several decades in the hopes that you add several months to your lifespan. It is worth nothing that research into resveratrol and its derivatives was abandoned by GlaxoSmithKline after acquiring Sinclair’s company, Sirtris, for $720 million, abandoned due to lack of efficacy and undesirable side-effects, coupled with negative findings in related research conducted by Amgen and Pfizer. So go ahead and supplement NMN. Will you see changes in the mirror? Loss of skin wrinkles, restoration of youthful muscle, broader shoulders, firmer thighs, buttocks, chest, and arms? Will you experience a return of youthful libido, restoration of vaginal moisture, an increase in testosterone in males? Will you heal faster, be able to mount a youthful immune response, and reduce the endotoxemia of gastrointestinal dysbiosis and small intestinal bacterial overgrowth (SIBO)? Will blood levels of growth hormone and oxytocin increase while cortisol levels decrease? Will sleep be deeper and filled with vivid child-like dreams?

Here is my concern with this line of thinking, having witnessed numerous other instances in which broad and ambitious pronouncements have been made based on experimental and biochemical evidence: they rarely play out to yield meaningful effects in humans. Another reservation I have is that a strategy such as addressing the sirtuin pathway with agents such as NMN ignore the numerous other aspects of health that impact health, youthfulness, and longevity. Can we hope, for instance, that boosting intracellular NAD+ levels overcomes the adverse effects of vitamin D deficiency, lack of magnesium in water and food, iodine deficiency, consumption of wheat and sugar, and consumption of hydrogenated oils? Can it correct gastrointestinal microbiome disruption, small intestinal bacterial colonization and endotoxemia? I doubt it. It is highly unlikely that addressing this single biochemical pathway can overcome the broad landscape of detrimental effects of these and other factors.

Let me contrast that with what we have been experiencing on a large scale by engaging in another menu of strategies, but mostly restoration of the gastrointestinal microbe lost by nearly all modern humans, Lactobacillus reuteri, that yields two important effects with implications for youthfulness: 1) provocation of oxytocin release from the brain, and 2) colonization of the small intestine and colon where it takes up residence and produces bacteriocins, antibiotics effective in killing and thereby reducing numbers of Proteobacteria, i.e., fecal microbes. There are other effects that hold additional potential for restoring youthfulness but not yet corroborated in humans, effects that include suppression of cortisol, increased growth hormone, increased testosterone in males, amplification of the immune response via reversal of thymic involution (atrophy), and restoration of youthful muscle. And you achieve this with only a minor investment in, for instance, organic half-and-half, a source of the microbe, some prebiotic fiber, and a device to make yogurt.

Restoring L. reuteri, lost from the microbiomes of nearly all modern humans, has indeed been yielding effects such as increased muscle and strength, increased libido, deeper sleep, smoother skin with reduced wrinkles, increased testosterone, and it is the first step you can take to eradicate SIBO, thereby reducing insulin resistance and inflammation.

There is likely no harm in supplementing NMN or derivatives to obtain its presumptive benefits. But I would be skeptical that this serves as a standalone strategy for restoring youthful or extending lifespan. And you already have access to a key strategy that restores youthful characteristics in the here-and-now in the form of restoring L. reuteri.