The NMN Transporter Slc12a8: New Areas of Research

Last year's discovery of the "elusive transporter" that efficiently shuttles NMN (nicotinamide mononucleotide) into cells to be converted into NAD (nicotinamide adenine dinucleotide) and used as fuel has opened up new doors - both for anti-aging and health research and quite literally, in the case of NMN entering cells. Additionally, the NMN transporter, Slc12a8, may have a relationship with the pathogenesis of autoimmune-related skin conditions and kidney function. Keep reading to learn more about the elusive transporter and its various roles in the body.

NAD+ and NMN: The Basics

NAD (also known as NAD+ when in its oxidized form) is a coenzyme that all life depends on; it helps us to metabolize food into fuel, repairs damaged DNA, and is a key component in the healthy aging process.

Unfortunately, it's well-known that NAD+ levels decline with age, leading to increased cellular aging. NAD+ is also involved with regulating the family of proteins called sirtuins, which play a central role in longevity and the aging process. Sirtuins, which are dependent on NAD+, can increase cell survival after oxidative damage, which is a key component in many chronic age-related disorders.

Since NAD+ is so important for healthy aging but naturally declines as the years go by, it would be wise to worry about maintaining your NAD+ levels. Two ways to do that are by using the precursors to NAD+, which are NMN and NR (nicotinamide riboside). These molecules are related to niacin (vitamin B3), and they are found in some foods. For example, NMN is found in cucumbers and cabbage. However, the amounts are minuscule compared to what would be needed to boost the decline in NAD+ levels we see in aging or disease.

Supplementing with NMN has been shown to quickly and efficiently boost NAD+ levels in mice, as reported in the journal Cell Metabolism. Not only that, but the mice showed enhanced energy metabolism and insulin sensitivity, reduced age-related weight gain, and even, improved eye function, all of which are important for healthy aging.

Moreover, until last year, it was not known how NMN was able to get into cells so quickly and be converted into NAD+; it was presumed that it had to be converted into NR first, and then NAD+. However, in the same mice studies, NMN traveled from the gut to the bloodstream in under three minutes, indicating that a specific NMN transporter was likely being used as the delivery vehicle.

A Recap: Discovery of the NMN Transporter

In January 2019, a study published in Nature Metabolism proved the theory of an NMN transporter: a protein encoded by the gene Slc12a8. This protein uses a sodium ion to transport NMN across cell membranes to be converted directly into NAD+, rather than using NR as an intermediary first.

The research team, led by Shin-ichiro Imai, MD, Ph.D., discovered that Slc12a8 is a specific transporter for NMN, meaning that NR isn't able to enter cells by that pathway. Our cells attempt to maintain a consistent fuel supply by increasing the amounts of the NMN transporter in times of low NAD+, which would then enable NMN to be quickly converted into NAD+. However, as much as our cells try to combat the decline in NAD+ with this mechanism, there is still a bottleneck of NAD+ production that occurs with increased age.

Providing your cells with NMN as well as enhancing the function of its transporter would be an ideal way to increase cellular energy throughout the lifespan. Hopefully, it's only a matter of time before we have new ways to enhance the functioning of Slc12a8.

The Slc Super-Family of Genes

Now that Slc12a8 has been linked to its involvement in transporting NMN into cells for fuel, researchers are looking into what else the gene and its encoded protein may be associated with. The Slc gene, which stands for ‘solute carriers', is a super-family of over 395 membrane transport proteins, whose roles range from nutrient transport to drug delivery.

While the entire Slc gene family is typically involved with the uptake of small molecules into cells, there are 52 sub-families reported and the specificity of what each protein can transport varies widely, even within sub-families. More and more sub-families and genes are constantly being discovered; the known number of Slc-associated genes increased from 298 to 395 from the years 2004 to 2013, as reported in Molecular Aspects of Medicine.

The nomenclature system begins with the root symbol Slc, followed by a number that indicates the family, then by a letter designating the sub-family (however, only ‘a' is used when the family has not been subdivided), and lastly another number that defines the individual transporter gene. For example, the gene Slc12a8 is in the solute carrier family 12, member 8, with a family that has not been subdivided.

Typically, the Slc12 family is a group of cation-coupled chloride transporters, with important roles in kidney health and transport of diuretic drugs. However, the Slc12a8 gene differs from its relatives in that it uses a sodium ion rather than chloride to transport NMN into cells.

Slc12a8: Promising Areas of Research

Researchers at the American Society of Nephrology's Kidney Week in November 2019 presented results from a study on mice with poor metabolic and kidney health and the relationship to NMN and Slc12a8.

It's known that levels of NAD+ are decreased in aging kidneys, thus their research aimed to look at how the location and expression of Slc12a8 in the kidney plays a role in the pathogenesis of metabolic-related kidney conditions.

In the study, mice with poor metabolic health showed increased renal (kidney) loss of NAD+, as expected. The researchers found that Slc12a8 is expressed in the distal renal tubules in both metabolically healthy and unhealthy mice, but the unhealthy mice showed increased expression, as well as translocation of Slc12a8 to the apical side of the distal tubules of the kidney.

They also found that the metabolically damaged mice had increased resorption of NMN at their tubules and concluded that the translocation of Slc12a8 is an attempt to compensate for the NAD+ loss seen.

Another area of research related to the NMN transporter is with autoimmune-related skin and joint conditions, as Slc12a8 is thought to be a candidate gene in the development of these disorders. 

Research from the journal Genomics looked at the genetics of 195 families with inflammatory skin conditions in Sweden (where rates tend to be higher), which led to an identification of high expression of the gene Slc12a8 in these families. However, the authors caution that the involvement of Slc12a8 in this pathogenesis may not apply to countries worldwide.

Research on the roles of NMN, and especially its newly discovered transporter Slc12a8, is still in its infancy. As more studies get published, we'll have a better idea of the relationship between the two, as well as the relationship between Slc12a8 and the other health conditions it may impact.

References:

Grozio A, Mills KF, Yoshino J, et al. Slc12a8 is a nicotinamide mononucleotide transporter. Nature Metabolism. 2019; 1: 47–57. doi: 10.1038/s42255-018-0009-4

Hediger MA, Clémençon B, Burrier RE, Bruford EA. The ABCs of membrane transporters in health and disease (SLC series): introduction. Molecular Aspect of Medicine. 2013; 34(2-3): 95–107. doi:10.1016/j.mam.2012.12.009

Hewett D, Samuelsson L, Polding J, et al. Identification of a susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map. Genomics. 2002; 79(3): 305–314. doi:10.1006/geno.2002.6720

Increased Expression of NMN Transporter in the Kidneys. American Society of Nephrology website. https://www.asn-online.org/education/kidneyweek/2019/program-abstract.aspx?controlId=3224565

Mills KF, Yoshida S, Stein LR, et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metabolism. 2016; 24(6): 795–806. doi:10.1016/j.cmet.2016.09.013