BLOG
January 7, 2019

NMN enters cells via a specific NMN transporter
One of the properties that makes NMN such a highly promising molecule is its potential speed of absorption into the body. Seneque Chief Scientist Dr. Alessia Grozio was part of a team that in 2019 published groundbreaking research which highlighted a key driver of NMN’s efficiency – a transporter that carries NMN directly into cells [1] within ten minutes of ingestion.

Until then, research had shown that increasing NAD+ levels through treatment with metabolic precursors extends lifespan in yeast and, in aged mice, improves motor coordination, eye function, bone density, insulin sensitivity, liver and kidney function, physical endurance, muscle strength, and the function of stem cells and mitochondria [2] [3].

But the question of how mammals absorb and manufacture NAD+ had not been fully resolved.
Dr. Grozio and the team showed that the Slc12a8 gene encodes a protein that is a specific NMN transporter in mammals.

This protein uses a sodium ion to transport NMN (but not nicotinamide riboside (NR) [4]) across cell membranes and facilitates direct uptake of NMN into the gut and other organs. There, it is immediately used for NAD+ biosynthesis and significantly increases NAD+ concentration in cells over the course of 60 minutes following ingestion [5].

Previously, NMN was known to enter cells by the removal of a phosphate group which turned it into NR. In this form, it was carried through the cell membrane by equilibrative nucleotide transporters and, once inside the cell, re-phosphorylated back into NMN [6].

To test the existence of a specific NMN transporter, the scientists inhibited cellular pathways that NR uses to enter liver cells. They observed that NMN levels increased with NMN administration, despite the inhibition of NR uptake, confirming the presence of a specific NMN transporter facilitating NMN movement into cells. Conversely, rapid cellular uptake of NMN to cells was lost when the scientists decreased levels of Slc12a8 [7].

Slc12a8 is highly expressed in the small intestine of mice (related transporters exist in other organisms – including humans – so it is possible for us to have these NMN transporters in the gut). Its expression increases in the intestines of old mice as NAD+ levels decline, which suggests that this may be a function designed to compensate for the degradation and decline of NAD+ that accompanies the aging process [8].

The identification and characterization of the Slc12a8 NMN transporter significantly enhanced our understanding of how mammals absorb and manufacture NAD+. It has opened the door to ever-more effective methods of NMN administration, which we are exploring at Seneque with Dr Grozio and other NAD+ experts through our clinical research pipeline.

You can access a free version of the full article Slc12a8 is a nicotinamide mononucleotide transporter here:

References
[1] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[2] Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D'Amico D, Ropelle ER, Lutolf MP, Aebersold R, Schoonjans K, Menzies KJ, Auwerx J. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016 Jun 17;352(6292):1436-43. https://doi.org/10.1126/science.aaf2693
[3] Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016 Dec 13;24(6):795-806. https://doi.org/10.1016/j.cmet.2016.09.013
[4] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[5] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[6] Ratajczak J, Joffraud M, Trammell SA, Ras R, Canela N, Boutant M, Kulkarni SS, Rodrigues M, Redpath P, Migaud ME, Auwerx J, Yanes O, Brenner C, Cantó C. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun. 2016 Oct 11;7:13103. https://doi.org/10.1038/ncomms13103
[7] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[8] Schultz MB, Sinclair DA. Why NAD(+) Declines during Aging: It's Destroyed. Cell Metab. 2016 Jun 14;23(6):965-966. https://doi.org/10.1016/j.cmet.2016.05.022


News
January 7, 2019

NMN enters cells via a specific NMN transporter
One of the properties that makes NMN such a highly promising molecule is its potential speed of absorption into the body. Seneque Chief Scientist Dr. Alessia Grozio was part of a team that in 2019 published groundbreaking research which highlighted a key driver of NMN’s efficiency – a transporter that carries NMN directly into cells [1] within ten minutes of ingestion.

Until then, research had shown that increasing NAD+ levels through treatment with metabolic precursors extends lifespan in yeast and, in aged mice, improves motor coordination, eye function, bone density, insulin sensitivity, liver and kidney function, physical endurance, muscle strength, and the function of stem cells and mitochondria [2] [3].

But the question of how mammals absorb and manufacture NAD+ had not been fully resolved.
Dr. Grozio and the team showed that the Slc12a8 gene encodes a protein that is a specific NMN transporter in mammals.

This protein uses a sodium ion to transport NMN (but not nicotinamide riboside (NR) [4]) across cell membranes and facilitates direct uptake of NMN into the gut and other organs. There, it is immediately used for NAD+ biosynthesis and significantly increases NAD+ concentration in cells over the course of 60 minutes following ingestion [5].

Previously, NMN was known to enter cells by the removal of a phosphate group which turned it into NR. In this form, it was carried through the cell membrane by equilibrative nucleotide transporters and, once inside the cell, re-phosphorylated back into NMN [6].

To test the existence of a specific NMN transporter, the scientists inhibited cellular pathways that NR uses to enter liver cells. They observed that NMN levels increased with NMN administration, despite the inhibition of NR uptake, confirming the presence of a specific NMN transporter facilitating NMN movement into cells. Conversely, rapid cellular uptake of NMN to cells was lost when the scientists decreased levels of Slc12a8 [7].

Slc12a8 is highly expressed in the small intestine of mice (related transporters exist in other organisms – including humans – so it is possible for us to have these NMN transporters in the gut). Its expression increases in the intestines of old mice as NAD+ levels decline, which suggests that this may be a function designed to compensate for the degradation and decline of NAD+ that accompanies the aging process [8].

The identification and characterization of the Slc12a8 NMN transporter significantly enhanced our understanding of how mammals absorb and manufacture NAD+. It has opened the door to ever-more effective methods of NMN administration, which we are exploring at Seneque with Dr Grozio and other NAD+ experts through our clinical research pipeline.

You can access a free version of the full article Slc12a8 is a nicotinamide mononucleotide transporter here:

References
[1] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[2] Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D'Amico D, Ropelle ER, Lutolf MP, Aebersold R, Schoonjans K, Menzies KJ, Auwerx J. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016 Jun 17;352(6292):1436-43. https://doi.org/10.1126/science.aaf2693
[3] Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016 Dec 13;24(6):795-806. https://doi.org/10.1016/j.cmet.2016.09.013
[4] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[5] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[6] Ratajczak J, Joffraud M, Trammell SA, Ras R, Canela N, Boutant M, Kulkarni SS, Rodrigues M, Redpath P, Migaud ME, Auwerx J, Yanes O, Brenner C, Cantó C. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun. 2016 Oct 11;7:13103. https://doi.org/10.1038/ncomms13103
[7] Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME, Imai SI. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019 Jan;1(1):47-57. https://doi.org/10.1038/s42255-018-0009-4
[8] Schultz MB, Sinclair DA. Why NAD(+) Declines during Aging: It's Destroyed. Cell Metab. 2016 Jun 14;23(6):965-966. https://doi.org/10.1016/j.cmet.2016.05.022