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Strategies to restore levels of the enzyme cofactor nicotinamide adenine dinclueotide (NAD) late in life to maintain health by treatment with NAD precursors, such as nicotinamide mononucleotide (NMN), represent an exciting area of research in aging and age-related diseases. A study in Nature Metabolism provides an answer to the hotly debated yet fundamental question: how NMN actually gets into cells.
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PHYSIOLOGY
The elusive NMN transporter is found
Strategies to restore levels of the enzyme cofactor nicotinamide adenine dinclueotide (NAD) late in life to maintain
health by treatment with NAD precursors, such as nicotinamide mononucleotide (NMN), represent an exciting
area of research in aging and age-related diseases. A study in Nature Metabolism provides an answer to the hotly
debated yet fundamental question: how NMN actually gets into cells.
LindsayE.Wu and DavidA.Sinclair
The enzyme cofactor NAD is essential
for life. Originally discovered in 1906
as an accelerator of yeast fermentation,
NAD is once again at the forefront of
biology, thanks largely to research, again in
yeast, that has identified the oxidized form
of NAD (NAD+) as a signalling molecule
that dictates the health and lifespan of
eukaryotes13. In yeast, increasing NAD
levels through treatment with metabolic
precursors extends lifespan, and in aged
mice, this extends lifespan and improves
motor coordination, eye function, bone
density, insulin sensitivity, liver and kidney
function, physical endurance, muscle
strength, and the function of stem cells and
mitochondria2,3.
These findings have raised an important
question: how do cells take up these
precursors to make NAD?4,5 In this issue of
Nature Metabolism, Grozio et al.6 identify
the transporter for NMN, the immediate
precursor to NAD, helping to explain how
mammals absorb and manufacture NAD.
There are three main approaches to
raising NAD+ levels in mammals: inhibiting
NAD destruction by CD38 (ref. 7) or
SARM1 (ref. 8); inhibiting the enzyme
ACMSD, which siphons off NAD precursors
in the de novo NAD synthesis pathway9;
and providing NAD+ precursors such as
nicotinamide riboside (NR)10 and NMN3.
Once taken up by cells via equilibrative
nucleoside transporters, NR is
phosphorylated by nicotinamide riboside
kinase (NMRK1 and NMRK2 (NRK1/2)) to
generate NMN, which is then immediately
converted to NAD+ by nicotinamide
mononucleotide adenylyltransferases
(NMNATs; Fig. 1)11. NR and NMN have
been used in preclinical animal studies5, and
NR raises NAD+ levels in blood lymphocytes
of human subjects10.
A question that has been debated for
years is whether NMN is simply a pro-
drug of NR. For NMN to enter cells, it was
thought to require a dephosphorylation
step on the extracellular surface of cells to
convert it to NR before being taken up by
the equilibrative nucleotide transporters
(ENTs) and then re-phosphorylated by NRK
back into NMN11. This view is consistent
with the metabolism of nucleoside-based
drugs, such as HIV inhibitors, which
are usually first dephosphorylated in the
gut. It remains unclear whether the rapid
kinetics of NMN uptake exhibited by certain
cell types can be explained by a similar
mechanism3.
This new study from Grozio et al.6
identifies a previously characterized amino
acid and polyamine transporter called
Slc12a8 (ref. 12) as an NMN transporter.
Slc12a8 has a number of surprising
attributes. It requires sodium and not
chloride for NMN co-transport and is highly
selective for NMN, excluding even nicotinic
acid mononucleotide (NaMN), which differs
from NMN by only one atom.
It is important to note that the discovery
of an NMN transporter by no means
diminishes the importance of uptake via
dephosphorylation11. It does, however,
enrich our knowledge by providing a new
mechanism through which the absorption
and distribution of NAD precursors might
Sirtuins
PARPs/CD38
NAD+
NAD+
NRK1/2
Mitochondria
Extracellular
Intracellular
Food or microbiome
ENT
NR
NR
?
?
NAM
NAMPT NMN
CD73
Slc12a8
NMN CD73
Pi
NMNAT1/2/3
Fig. 1 | The NAD precursor NMN enters cells through the co-transporter Slc12a8. Pharmacological
treatment with the metabolic precursor NMN can be used to relieve the age-associated decline in NAD.
The transport of NMN into the cell was thought to require a dephosphorylation step to produce NR
before it could be taken up by ENTs. The discovery of an NMN transporter raises new questions about
the uptake, distribution, and utilization of NMN from the diet and in circulation. NAMPT, nicotinamide
phosphoribosyltransferase; NMNAT1/2/3, NMNAT1–NMNAT3; PARPs, poly (ADP-ribose) polymerases;
Pi, inorganic phosphate.
NATURE METABOLISM | VOL 1 | JANUARY 2019 | 8–9 | www.nature.com/natmetab
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be differentially regulated. For example,
the authors find that Slc12a8 is highly
enriched in the small intestine of mice, with
expression that is at least 100-fold higher
in this tissue than in fat or brain tissue.
Interestingly, the expression of Slc12a8
increases in the intestines of old mice as
NAD levels decline4,13, suggesting that
upregulation during aging is a compensatory
mechanism.
The authors speculate that Slc12a8 in the
gut endothelium serves to take up NMN
from naturally occurring dietary sources,
such as fruits, vegetables, and milk, or from
the breakdown of NAD+. But the amount
of NMN needed to raise NAD in a mouse
or human is far beyond what is available
naturally. Both NMN and NR are present
in food3,14 but at concentrations of less than
1 mg per kg of food, whereas hundreds of
milligrams per dose are needed to raise
NAD+ in humans3. And given that cells
make their own NAD from tryptophan, it
is unclear whether dietary uptake of NMN
can meaningfully influence NAD+ levels
or whether Slc12a8 affects NAD synthesis
beyond the liver, where NMN is primarily
metabolised15. One intriguing possibility
is that NMN could be produced by the
microbiome. If so, NMN transport may
prove more important than the low NMN
levels in food imply.
There is no doubt that this new work
will spark a debate about the relative
contributions of NMN transport and
the previously described mechanism11,
which could be addressed by head-to-
head comparisons of NAD precursors
and by following the in vivo metabolism
of isotopically labelled NAD precursors
in knockout animals. Given that NAD
precursors are sold as supplements and are
under development as pharmaceuticals, this
new understanding of NAD physiology is
an important addition to the field, but also
raises new questions about where NAD
precursors are taken up and processed, and
where they naturally come from.
LindsayE.Wu1 and DavidA.Sinclair1,2*
1School of Medical Sciences, UNSW Sydney, Sydney,
New South Wales, Australia. 2Paul F. Glenn Center
for the Biology of Aging, Harvard Medical School,
Boston, MA, USA.
*e-mail: david_sinclair@hms.harvard.edu
Published online: 7 January 2019
https://doi.org/10.1038/s42255-018-0015-6
References
1. Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. &
Sinclair, D. A. Nature 423, 181–185 (2003).
2. Zhang, H. et al. Science 352, 1436–1443 (2016).
3. Mills, K. F. et al. Cell Metab. 24, 795–806 (2016).
4. Massudi, H. et al. PLoS One 7, e42357 (2012).
5. Rajman, L., Chwalek, K. & Sinclair, D. A. C ell Metab. 27,
529–547 (2018).
6. Grozio, A. et al. Nat. Metab. http://doi.org/10.1038/s42255-018-
0009-4 (2018).
7. Haner, C. D. et a l. 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. N utr. 146, 957–963 (2016).
15. Liu, L. et al. Cell Metab. 27, 1067–1080.e5 (2018).
Competing interests
L.W. is a is a founder, equity owner, advisor to, and/or
director of Intravital, EdenRoc Sciences (Metro Biotech/
Bauhaus, Liberty Biosecurity), Jumpstart Fertility, and
Life Biosciences and its daughter companies (Continuum
Biosciences, Jumpstart Fertility, Senolytic Therapeutics,
Animal Biosciences, Selphagy, Spotlight Therapeutics).
D.S. is a founder, equity owner, advisor to, director of,
consultant to, and/or inventor of patents licensed to
Jupiter Orphan Therapeutics, Cohbar, Galilei Biosciences,
EdenRoc Sciences (Arc-Bio, Dovetail Genomics, Claret,
Revere Biosciences, UpRNA, MetroBiotech/Bauhaus,
Liberty Biosecurity), Life Biosciences (Selphagy,
InsideTracker, Senolytic Therapeutics, Spotlight
Therapeutics, Immetas, Animal Biosciences, Iduna,
Continuum Biosciences, and Jumpstart Fertility),
Wellomics, and Vium. MetroBiotech, Liberty Biosecurity,
and Jumpstart are developing NAD boosting molecules/
precursors for the treatment of diseases. D.S. is an inventor
on an invention filed by Mayo Clinic and Harvard Medical
School that has been licensed to Elysium Health. For more
information see https://genetics.med.harvard.edu/sinclair/
people/sinclair-other.php.
NATURE METABOLISM | VOL 1 | JANUARY 2019 | 8–9 | www.nature.com/natmetab
... Thus, NMN must first be dephosphorylated to NR by the enzyme CD73, and then NR enters the cell through nucleoside transporters (ENTs) to equilibrate the pools [3]. However, Grozio et al. recently identified an NMN transporter in the cell membrane called Slc12a8 [44,45]. However, the expression of Slc12a8 is limited to the intestine and others have questioned its ability to transport NMN [46]. ...
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