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Resveratrol Increases Intracellular NAD+ Levels Through Up regulation of The NAD+ Synthetic Enzyme Nicotinamide Mononucleotide Adenylyltransferase

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Resveratrol Increases Intracellular NAD+ Levels Through Up regulation of The NAD+ Synthetic Enzyme Nicotinamide Mononucleotide Adenylyltransferase

Abstract

Resveratrol is a polyphenol with major health benefits that is thought to operate through direct activation of the 'anti-aging' enzyme SIRT1. However recent reports have challenged this 'direct-activation' hypothesis, suggesting the mechanism by which resveratrol increases SIRT1 function is still unknown. We report for the first time that resveratrol induces a dose dependent increase in activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenylyl transferase (NMNAT1). Activation of NMNAT1 by resveratrol in cultured primary human astrocytes and neurons increased NAD+ levels by up to 5 fold. As SIRT1 requires NAD+ as a substrate to perform its gene silencing function, higher NAD+ levels will enhance SIRT1 activity. This finding suggests that resveratrol may promote SIRT1 function by enhancing NAD+ synthesis in whole cell systems without requiring direct activation.
Letter to the Editor
Resveratrol Increases Intracellular NAD+ Levels Through Up regulation of
The NAD+Synthetic Enzyme Nicotinamide Mononucleotide
Adenylyltransferase
Nady Braidy 1; Gilles J. Guillemin 1,2; Ross Grant *1
1University of New South Wales, Faculty of Medicine, Sydney, Australia
2St Vincent’s Centre for Applied Medical Research, Sydney, Australia
*CorrespondingAuthor.DepartmentofPharmacology,FacultyofMedicine,Universityof
NSW,Sydney,Australia2052.r.grant@unsw.edu.au
Resveratrol is a polyphenol with major health benefits1 that is thought to operate
through direct activation of the ‘anti-aging’ enzyme SIRT12. However recent reports
have challenged this ‘direct-activation’ hypothesis3-4, suggesting the mechanism by
which resveratrol increases SIRT1 function is still unknown. We report for the first
time that resveratrol induces a dose dependent increase in activity of the NAD+
synthetic enzyme nicotinamide mononucleotide adenylyl transferase (NMNAT1).
Activation of NMNAT1 by resveratrol in cultured primary human astrocytes and
neurons increased NAD+ levels by up to 5 fold. As SIRT1 requires NAD+ as a substrate
to perform its gene silencing function5, higher NAD+ levels will enhance SIRT1 activity6.
This finding suggests that resveratrol may promote SIRT1 function by enhancing NAD+
synthesis in whole cell systems without requiring direct activation.
Resveratrol is a non-vitamin antioxidant common in the diet and particularly abundant in
teas, juices, and red wines that is thought to harbour major health benefits1. Experiments in
single and multicellular organisms and human tissue cultures suggest that resveratrol can
extend the lifespan in diverse organisms by activating the NAD+ dependent, enzyme, SIRT17.
The neuroprotective ability of SIRT1 induced by resveratrol has been demonstrated in vitro6.
While resveratrol has been claimed to be a direct SIRT1 activator using the Fluor de Lys-
SIRT1 peptide substrate, recent reports indicate that this finding may represent an
experimental artefact3-4. Our study indicates resveratrol directly activates the enzyme
NMNAT1 which likely influences downstream SIRT1 activity.
We demonstrate for the first time that resveratrol significantly increases intracellular
NAD+ levels in primary human astrocytes and neurons (Fig 1). We have shown that
resveratrol can induce a dose dependent increase in NAD+ of 3-5 fold in human astrocytes
(Fig 1A) and neurons (Fig 1B) after 24-hour treatment. It has been known for some time that
resveratrol can influence NAD+ responsive enzymes, such as the energy-sensing AMP-
activated kinase (AMPK)8 and SIRT22 and its mammalian homologue, SIRT12, 9. However to
date no study has reported a link between resveratrol and changes in NAD+ concentration.
Elevated cellular levels of NAD+, the required substrate for SIRT1, will increase its activity.
Nicotinamide mononucleotide adenylyltransferase (NMNAT) is an NAD+ synthetic
enzyme which catalyses the conversion of nicotinamide mononucleotide (NMN) to NAD+.
NMNAT1 is the predominant human isoform of NMNAT and is located in the nucleus6.
Increased NMNAT1 expression has been reported to protect against axonal degradation via
increased NAD+ production in mouse neurons6. In the same study, neurons treated with
resveratrol prior to axotomy showed a decrease in axonal degeneration that was comparable
to that obtained with NAD+ 6. It has also been previously demonstrated that increased SIRT1
deacetylase activity can protect against axonal degradation in models of AD, although the
exact mechanism is still unknown10. As NAD+ is an essential substrate for SIRT1, the effect
of resveratrol on SIRT1 proteins may be due, at least in part, to an NMNAT mediated
increase in NAD+.
We tested the effect of resveratrol on NMNAT activity in cell homogenates of human foetal
astrocytes and human recombinant-NMNAT1. We found that resveratrol (200 µM) increased
NMNAT1 activity in crude astrocytic homogenates by 70% within 24 hours (Fig 1C). Using
human recombinant NMNAT1, we observed that resveratrol lowered the Km for the substrate
NMN by up to 3-fold, and increased Vmax for the recombinant NMNAT1 by up to 5 fold in a
dose dependent manner (Table 1). Our results are consistent with resveratrol acting as a
heterotropic allosteric modulator of NMNAT1 at an as yet unidentified site. Further work is
required to characterise this novel resveratrol-NMNAT1 interaction.
Our observation that resveratrol increases NAD+ levels in primary human brain cells by
acting on NMNAT supports the view that this polyphenol has considerable therapeutic
potential; particularly for the treatment of neurodegenerative diseases. As NMNAT can
accelerate NAD+ synthesis from all three substrates, quinolinic acid, nicotinic acid and
nicotinamide11, NMNAT activation by resveratrol represents an ideal natural therapeutic to
replenish NAD+ levels. Maintenance of higher cellular NAD+ will enhance SIRT1 activity,
and other NAD+ dependent pathways impacting positively on cell viability and longevity.
This work has therefore formed the basis of relevant patent applications.
REFERENCES
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519.
2. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE,
Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003). Nature. 425, 191-
196.
3. Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M (2009).. Chem Biol
Drug Des. 74(6):619-24.
4. Pacholec M, Bleasdale JE,Chrunyk B, Cunningham D, Flynn D, Garofalo RS,
Griffith D, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V,
Varghese A, Ward J, Withka J, Ahn K. (2010) J. Biol Chem. 285, 8340–8351.
5. Min J, Landry J, Sternglanz R, Xu RM. (2001) Cell. 105(2):269-79.
6. Araki T, Sasaki Y, Milbrandt J (2004). Science. 305, 1010-1013.
7. Sauve AA, Wolberger C, Schramm VL, Boeke JD (2006). Annu. Rev. Biochem. 75,
435-465.
8. Rafaeloff-Phail R, Ding L, Conner L, Yeh WK, McClure D, Guo H, Emerson K,
Brooks H. (2004). J. Biol. Chem. 279, 52934-52939.
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3169-3179.
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Exper. Urif. 27, 357-364.
FIGURE LEGENDS
Figure 1. Resveratrol increases intracellular NAD+ levels in (a) human foetal astrocytes
and (b) human foetal neurons, after 24-hour treatment. (c) Effect of resveratrol (200
µM) on NMNAT-1 activity in astrocytic nuclear homogenates. P<0.05 compared to
control, (n=4 at each drug concentration)
Table 1. Resveratrol increases human recombinant NMNAT1 activity
(A separate kinetic experiment was carried out for each substrate and resveratrol
concentration)
Figure 1 (Grant)
(a)
(b)
(c)
Log10DrugConcentration(PM)
1101001000
[NAD+]
(ng/mg
protein)
118.4IC50
1.705
Hillslope
2.073LOGIC50
Resveratrol
30000
20000
10000

0
Lo
g
10Dru
g
Concentration(
P
M)
1101001000
[NAD+]
(ng/mg
protein)
100.7IC50
1.321
Hillslope
2.073LOGIC50
Resveratrol
2000
1500
1000
500
0
0
20
40
60
80
100
120
140
160
180
200
1234
NMNAT
activity
(%NADH
produced/
minrelative
tocontrol)
Time(hrs)
*
*
*
Control 24 48 72
Table 1 (Grant)
506
Resveratrol (200
P
M)
43062
Resveratrol (100
P
M)
13083
Resveratrol (50
P
M)
83115No Resveratrol
Vmax (nM/min) KmTreatment
43
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Over the past 10 years more than 10,000 papers and in vitro investigations have been published that identify or analyse various critical pathways and biological processes through which the phytoalexin resveratrol has been shown to attenuate the metabolic dysfunctions, acute symptomatology and the consequential downstream pathologies related to type 2 diabetes. More recently, several clinical trials have confirmed resveratrol's potential to substantially enhance the therapeutic effects of the pharmaceutical metformin hydrochloride, particularly related to glucose management, insulin sensitivity and cardioprotection. Metformin is the most commonly prescribed type 2 diabetes treatment worldwide; consequently, any compound with the ability to safely and effectively augment its therapeutic effects warrants intensive investigation. This paper elucidates the principal modes of action that underly resveratrol's promising potential as an effective adjunct treatment for patients currently being administered metformin.
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  • D Beher
  • J Wu
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  • Sc Lu
  • L Atangan
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Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M (2009).. Chem Biol Drug Des. 74(6):619-24.
  • M Pacholec
  • Je Bleasdale
  • B Chrunyk
  • D Cunningham
  • D Flynn
  • Rs Garofalo
  • D Griffith
  • M Griffor
  • P Loulakis
  • B Pabst
  • X Qiu
  • B Stockman
  • V Thanabal
  • A Varghese
  • J Ward
  • J Withka
  • K Ahn
Pacholec M, Bleasdale JE,Chrunyk B, Cunningham D, Flynn D, Garofalo RS, Griffith D, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V, Varghese A, Ward J, Withka J, Ahn K. (2010) J. Biol Chem. 285, 8340–8351.
  • J Min
  • J Landry
  • R Sternglanz
  • Rm Xu
Min J, Landry J, Sternglanz R, Xu RM. (2001) Cell. 105(2):269-79.
  • T Araki
  • Y Sasaki
  • J Milbrandt
Araki T, Sasaki Y, Milbrandt J (2004). Science. 305, 1010-1013.
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  • C Wolberger
  • Vl Schramm
  • Jd Boeke
Sauve AA, Wolberger C, Schramm VL, Boeke JD (2006). Annu. Rev. Biochem. 75, 435-465.
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  • L Conner
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Rafaeloff-Phail R, Ding L, Conner L, Yeh WK, McClure D, Guo H, Emerson K, Brooks H. (2004). J. Biol. Chem. 279, 52934-52939.
  • T Yang
  • Aa Sauve
Yang T, Sauve AA (2005). AAPS J. 8, E632-E643.
  • D Kim
  • Md Nguyen
  • Mm Dobbin
  • A Fischer
  • F Sananbenesi
  • Jt Rodgers
  • I Dealle
  • Ja Baur
  • Suig
  • Sm Armour
  • P Puigserver
  • Da Sinclair
  • Lh Tsai
Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Dealle I, Baur JA, SuiG, Armour SM, Puigserver P, Sinclair DA, Tsai LH (2007). EMBO J. 26, 3169-3179.