The role of NAD+ (nicotinamide adenine dinucleotide) in the anti-aging field has been recognized by more and more scientists, and a consensus is gradually forming around supplementing NAD+ with age. However, there has been controversy over the way to supplement NAD+: one group from MIT argues that supplementing with NR (nicotinamide riboside) is superior to NMN, claiming that NMN must first be converted into NR to enter cells; the other group holds a different view. This debate has lasted for years. Recently, a study from the University of Washington confirmed that NMN can enter cells directly!
Previous studies by scientists have shown that administering NMN to aged mice increases their NAD+ levels, which benefits systemic metabolism—it not only extends the mice’s lifespan but also improves motor coordination, enhances eye function, increases bone density, improves insulin sensitivity, strengthens liver and kidney function, boosts physical endurance, increases muscle strength, and enhances the function of stem cells and mitochondria.
Oral NMN can be absorbed in a short time and increase NAD+ concentration in the blood, with the following absorption process:
- A. Absorbed intact through the digestive system;
- B. Enters the bloodstream within 2–3 minutes;
- C. Increases NMN content in tissues within 15 minutes;
- D. Rapidly raises NAD+ levels in organs such as the blood and liver.
Figure Note: Changes in relevant indicators over time (min). Data source: Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metabolism, v.24, no.6, Dec 13, 2016, p.795(12)
However, many scientists have long argued that NMN needs to be dephosphorylated to form NR, which is then transported into cells via ENTs (nucleoside transporters) and subsequently rephosphorylated back to NMN. On January 7, researchers from the University of Washington School of Medicine published a study in Nature Metabolism (a sub-journal of Nature), in which they identified the transporter protein for NMN—proving that NMN can enter cells directly.
How Does NMN Enter Cells?
In their study published in Nature Metabolism, researchers from the University of Washington School of Medicine stated that a transporter protein called Slc12a8 (solute carrier family 12 member 8) plays a key role in the cellular energy supply chain, as it can directly deliver the "fuel" needed for cellular metabolism into cells.
Diagram Note: NAD+ precursor NMN enters cells via the transporter Slc12a8. (Key components: Mitochondria; PARPs/CD38/Sirtuins; NAD+; NAM; NMNAT1/2/3; NAMPT; NMN; NRK1/2; NR; Intracellular/Extracellular; Slc12a8; ENT; CD73; Food or microbiome)
After conducting multiple experiments on cells and mice, the researchers finally uncovered the delivery mechanism of NMN: the Slc12a8 protein, with the help of sodium ions, directly transports NMN into cells, where it quickly acts to produce NAD+. When NAD+ levels decline, cells further enhance the expression of the Slc12a8 gene to increase their ability to transport NMN.
Slc12a8 is a transporter for NMN, and it also belongs to the family of transporters for amino acids and polyamines. It has many surprising properties: the co-transport of NMN requires sodium ions (not chloride ions), and it exhibits high selectivity for NMN—even excluding nicotinic acid mononucleotide (NaMN), which differs from NMN by only one atom.
This discovery of the NMN transporter opens up a new avenue for understanding NMN delivery mechanisms. It is important to note that the identification of the NMN transporter does not diminish the importance of NMN uptake via dephosphorylation; instead, it provides a new mechanism, demonstrating diverse ways in which NAD+ precursors are absorbed and distributed.
Transporter Expression Increases with Age
Interestingly, the expression of Slc12a8 in the intestines of aged mice increases—at a time when NAD+ levels decline. This suggests that the upregulation of Slc12a8 during aging is a compensatory mechanism. It also explains why oral NMN takes effect more quickly in the elderly.
Both NMN and NR are present in food, but their content is less than 1mg/kg. However, the human body requires hundreds of milligrams of NMN to synthesize NAD+, so the amount of NMN from food is far lower than the body’s needs. The authors speculate that Slc12a8 in intestinal endothelial cells is responsible for absorbing NMN from natural foods (such as fruits, vegetables, and milk) or NAD+ breakdown products, supplementing the body’s required NMN.
Perhaps in the near future, we will truly be able to break the limit of human lifespan—after all, limits are meant to be broken, aren’t they?
Note: 2018 Anti-Aging Research Highlights (Summary of the latest progress in anti-aging research in 2018) – Related content omitted as it is not core to the study.
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[7] Hafner, C. D. et al. J. Med. Chem. 58, 3548–3571 (2015).
[8] Gerdts, J., Brace, E. J., Sasaki, Y., DiAntonio, A. & Milbrandt, J. Science 348, 453–457 (2015).
[9] Katsyuba, E. et al. Nature 563, 354–359 (2018).
[10] Trammell, S. A. et al. Nat. Commun. 7, 12948 (2016).
[11] Ratajczak, J. et al. Nat. Commun. 7, 13103 (2016).
[12] Daigle, N. D. et al. J. Cell. Physiol. 220, 680–689 (2009).
[13] Gomes, A. P. et al. Cell 155, 1624–1638 (2013).
[14] Trammell, S. A., Yu, L., Redpath, P., Migaud, M. E. & Brenner, C. J. Nutr. 146, 957–963 (2016).
[15] Liu, L. et al. Cell Metab. 27, 1067–1080.e5 (2018)