NAD+ is a key molecule in the biology of ageing, but likely one that has been misunderstood as due to low availability and ubiquitous presence all around our cells, it’s not clear who really needs supplementation. In this article, we lay out some facts of NAD+ decline science, examine the intersection with mesenchymal stem cell therapy and cellular energy metabolism for perspective on why together they make an exciting case serous attention from those innovating at the cutting edge of regenerative medicine.
Some molecules are promoted in the supplement market years before they find their way to clinical guidelines for either treatment or prevention; currently, NAD+ is perhaps our best example of this. We have seen it all already the obscure kajal jelly research finding, enthusiastic popular science coverage of a supplement boom with excessive claims made for its benefits and then finally the correction where rigorous scientific criticism intervenes. What transpired after that correction is a story for the ages basic biology relating NAD+ decline to ageing actually exists, it has been well documented and better understood. Still a Work in Progress for Clinical Practice
An unexpected but biologically logical nexus into this ongoing picture is the relationship between cellular NAD+ metabolism and MSC therapeutic effects. These two fields developed largely in parallel, but the biological logic linking them is increasingly undeniable.
NAD+: What It Does & Why You Need More of It
This coenzyme has the acronym NAD+ and is nicotinamide adenine dinucleotide that exists in all living cells. It is at the crossroads of energy metabolism and cellular repair, serving two different but complementary functions. As a metabolic cofactor, it is an electron acceptor and donor in the mitochondrial reactions that generate ATP always needed for cellular energy production. It acts as a signalling substrate which activates the class of enzymes sirtuins and PARPs that control DNA repair, gene expression, inflammation, circadian rhythm.
After that, circulating levels of NAD+ are down to about 50% of their level in young adulthood by the time most people reach their forties. Reasons for this decline include continual net utilization by CD38, an enzyme whose expression increases rapidly with age and inflammation; diminished activity of catabolic NAD + biosynthesis pathways; and heightened demand on PARP enzymes activated in response to damage-inducing DNA. So the result is a cell that by definition becomes worse at generating usable energy and also less able to make good on repairs due to that damage.
Where does Stem Cell Therapy play a role
Stem Cell MSCs do not produce NAD+ for other cells. The link between stem cell therapy and NAD+ metabolism is a more nuanced and perhaps fascinating one: mitochondrial activity & intercellular signalling.
One of the universal hallmarks of cellular ageing and declining stem cell function is mitochondrial dysfunction. Mitochondrial dysfunction, as evidenced by reduced ATP production and increased reactive oxygen species levels is associated with dysfunctional resident stem cell populations. Nicholass: NAD+ depletes mitochondrial respiration.
Paracrine mechanisms underlie how MSC therapy deals with this environment. Endothelial cells are exposed to secretome of adipose stem cell-derived exosomes, which leads to functional mitochondria and microRNAs that target genes involved in metabolism pathway expression and signalling molecules can upregulate NAD + biosynthesis. A number of preclinical studies have shown that MSC-derived exosomes an enhance mitochondrial membrane potential and ATP production in aged or stressed recipient cells, effects mediated at least partly via NAD+ dependent pathways.
Figure 1. Integrating NAD+ Biology with Stem Cell Therapy for Cellular Energy and Regenerative Signaling
The Sirtuin Connection
One, and perhaps the most clinically relevant connection between NAD+ biology and MSC activity lies in sirtuins — a family of NAD+-dependent deacetylases that regulate longevity pathways. SIRT1, SIRT3 and SIRT6 have been involved in the regulation of inflammation, mitochondrial biogenesis, DNA repair or stem cell self-renewal. Their activity is completely dependent on sufficient availability of NAD+.
MSC secretome upregulates SIRT1 and SIRT3 expression in nearby cells when MSCs are administered into a senescent or inflamed tissue environment, but this effect is attenuated when the availability of NAD+ precursors is limited by experimental means. This indicates an interplay: MSC signalling induces sirtuin pathways dependant on levels of NAD+ for their action, while sufficient amounts of this cofactor maintain the host scenario in which signals from MSC can act more effectively.
Using NAD+ Supplementation as a Clinical Adjunct
This mechanistic connection has resulted in a number of regenerative medicine programmes—particularly those with clinical centres focused on longevity—that combine MSC therapy and supplementation with NAD+ precursors, most commonly nicotinamide riboside (NR) or its direct metabolite nicotinamide mononucleotide (NMN). The underlying reason is simple: if MSC-mediated regenerative signalling partly relies on recipient cell NAD+ availability, optimising that supply prior to or in conjunction with the application of such cells may maximise therapeutic benefits.
Clinical data supporting this particular combination is so far based on small observational studies and case series. Since then, what is out there – whilst hopeful – simply does not yet provide an adequate foundation for formal guidelines. Yet the combination is biologically coherent as many supplement-therapy pairings are not — which is why it has attracted research attention and not just marketing hype.
A Grounded Perspective
NAD+ is not a youth serum. We know that MSC therapy is not the cellular reset button. However, the overlap between these two strategies — one focuses on providing the energy substrate that cells require to carry out maintenance and repair processes; while the other provides an appropriate signalling environment for guiding those repairs — is arguably among the most rigorous scientific frontiers in longevity medicine.
For patients thinking about this combo in the context of a regimented, doctor-guided programme, the most relevant questions to pose at a clinician should not appeal so much as science-fiction but rather details: which NAD+ precursor (e.g. written with niagen), what dose/unit-of-measure and when relative to MSC infustion reflexively measuring against which markers. The biology is promising. A proper implementation of it into patient care – carefully guided by discipline – is what distinguishes serious programmes from the rest.
References
Cantó, C., Menzies, K.J., & Auwerx, J. (2015). NAD+ metabolism and the control of energy homeostasis: A balancing act between mitochondria and the nucleus. Cell Metabolism, 22(1), 31–53.
Gomes, A.P., Price, N.L., Ling, A.J.Y., et al. (2013). Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155(7), 1624–1638.
Igarashi, M., Miura, M., Williams, E., et al. (2019). NAD+ supplementation rejuvenates aged gut adult stem cells. Aging Cell, 18(3), e12935.
Pittenger, M.F., Discher, D.E., Péault, B.M., Phinney, D.G., Hare, J.M., & Caplan, A.I. (2019). Mesenchymal stem cell perspective: Cell biology to clinical progress. NPJ Regenerative Medicine, 4(1), 22.
Yoshino, J., Baur, J.A., & Imai, S.I. (2018). NAD+ intermediates: The biology and therapeutic potential of NMN and NR. Cell Metabolism, 27(3), 513–528.