19. Yuan H, Su L, Chen WY (2013) The emerging and diverse roles of sirtuins in cancer: a clinical
perspective. Onco Targets Ther 6:1399–1416. https://doi.org/10.2147/OTT.S37750
20. Anderson KA, Madsen AS, Olsen CA et al (2017) Metabolic control by sirtuins and other
enzymes that sense NAD+, NADH, or their ratio. Biochim Biophys Acta Bioenerg 1858
(12):991–998. https://doi.org/10.1016/j.bbabio.2017.09.005
21. Mendes KL, Lelis DF, Santos SHS (2017) Nuclear sirtuins and inflammatory signaling
pathways. Cytokine Growth Factor Rev 38:98–105. https://doi.org/10.1016/j.cytogfr.2017.
11.001
22. Luo XY, Qu SL, Tang ZH et al (2014) SIRT1 in cardiovascular aging. Clin Chim Acta
437:106–114. https://doi.org/10.1016/j.cca.2014.07.019
23. Jęśko H, Wencel P, Strosznajder RP et al (2017) Sirtuins and their roles in brain aging and
neurodegenerative disorders. Neurochem Res 42(3):876–890. https://doi.org/10.1007/s11064016-2110-y
24. Tang BL (2017) Sirtuins as modifiers of Parkinson’s disease pathology. J Neurosci Res
95(4):930–942. https://doi.org/10.1002/jnr.23806
25. Wong SY, Tang BL (2016) SIRT1 as a therapeutic target for Alzheimer’s disease. Rev
Neurosci 27(8):813–825. https://doi.org/10.1515/revneuro-2016-0023
26. Rizzi L, Roriz-Cruz M (2018) Sirtuin 1 and Alzheimer’s disease: an up-to-date review.
Neuropeptides 71:54–60. https://doi.org/10.1016/j.npep.2018.07.001
27. Donmez G, Outeiro TF (2013) SIRT1 and SIRT2: emerging targets in neurodegeneration.
EMBO Mol Med 5(3):344–352. https://doi.org/10.1002/emmm.201302451
28. Naia L, Rego AC (2015) Sirtuins: double players in Huntington’s disease. Biochim Biophys
Acta 1852(10 Pt A):2183–2194. https://doi.org/10.1016/j.bbadis.2015.07.003
29. Pan M, Yuan H, Brent M et al (2012) SIRT1 contains N- and C-terminal regions that potentiate
deacetylase activity. J Biol Chem 287(4):2468–2476. https://doi.org/10.1074/jbc.M111.
285031
30. Sanders BD, Jackson B, Marmorstein R (2010) Structural basis for sirtuin function: what we
know and what we don’t. Biochim Biophys Acta 1804(8):1604–1616. https://doi.org/10.1016/
j.bbapap.2009.09.009
31. You W, Rotili D, Li TM et al (2017) Structural basis of Sirtuin 6 activation by synthetic
small molecules. Angew Chem Int Ed Engl 56(4):1007–1011. https://doi.org/10.1002/anie.
201610082
32. Avalos JL, Bever KM, Wolberger C (2005) Mechanism of sirtuin inhibition by nicotinamide:
altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Mol Cell 17(6):855–868. https://
doi.org/10.1016/j.molcel.2005.02.022
33. Imai S, Guarente L (2016) It takes two to tango: NAD+ and sirtuins in aging/longevity control.
NPJ Aging Mech Dis 2:16017. https://doi.org/10.1038/npjamd.2016.17
34. Madsen AS, Andersen C, Daoud M et al (2016) Investigating the sensitivity of NAD+dependent sirtuin deacylation activities to NADH. J Biol Chem 291(13):7128–7141. https://
doi.org/10.1074/jbc.M115.668699
35. Nguyen GT, Schaefer S, Gertz M et al (2013) Structures of human sirtuin 3 complexes
with ADP-ribose and with carba-NAD+ and SRT1720: binding details and inhibition mechanism. Acta Crystallogr D Biol Crystallogr 69(Pt 8):1423–1432. https://doi.org/10.1107/
S0907444913015448
36. Szczepankiewicz BG, Dai H, Koppetsch KJ et al (2012) Synthesis of carba-NAD and the
structures of its ternary complexes with SIRT3 and SIRT5. J Org Chem 77(17):7319–7329.
https://doi.org/10.1021/jo301067e
37. Pesnot T, Kempter J, Schemies J et al (2011) Two-step synthesis of novel, bioactive derivatives of the ubiquitous cofactor nicotinamide adenine dinucleotide (NAD). J Med Chem 54
(10):3492–3499. https://doi.org/10.1021/jm1013852
38. Trapp J, Jochum A, Meier R et al (2006) Adenosine mimetics as inhibitors of NAD+dependent histone deacetylases, from kinase to sirtuin inhibition. J Med Chem 49
(25):7307–7316. https://doi.org/10.1021/jm060118b
Sirtuin Inhibitors and Activators
83
perspective. Onco Targets Ther 6:1399–1416. https://doi.org/10.2147/OTT.S37750
20. Anderson KA, Madsen AS, Olsen CA et al (2017) Metabolic control by sirtuins and other
enzymes that sense NAD+, NADH, or their ratio. Biochim Biophys Acta Bioenerg 1858
(12):991–998. https://doi.org/10.1016/j.bbabio.2017.09.005
21. Mendes KL, Lelis DF, Santos SHS (2017) Nuclear sirtuins and inflammatory signaling
pathways. Cytokine Growth Factor Rev 38:98–105. https://doi.org/10.1016/j.cytogfr.2017.
11.001
22. Luo XY, Qu SL, Tang ZH et al (2014) SIRT1 in cardiovascular aging. Clin Chim Acta
437:106–114. https://doi.org/10.1016/j.cca.2014.07.019
23. Jęśko H, Wencel P, Strosznajder RP et al (2017) Sirtuins and their roles in brain aging and
neurodegenerative disorders. Neurochem Res 42(3):876–890. https://doi.org/10.1007/s11064016-2110-y
24. Tang BL (2017) Sirtuins as modifiers of Parkinson’s disease pathology. J Neurosci Res
95(4):930–942. https://doi.org/10.1002/jnr.23806
25. Wong SY, Tang BL (2016) SIRT1 as a therapeutic target for Alzheimer’s disease. Rev
Neurosci 27(8):813–825. https://doi.org/10.1515/revneuro-2016-0023
26. Rizzi L, Roriz-Cruz M (2018) Sirtuin 1 and Alzheimer’s disease: an up-to-date review.
Neuropeptides 71:54–60. https://doi.org/10.1016/j.npep.2018.07.001
27. Donmez G, Outeiro TF (2013) SIRT1 and SIRT2: emerging targets in neurodegeneration.
EMBO Mol Med 5(3):344–352. https://doi.org/10.1002/emmm.201302451
28. Naia L, Rego AC (2015) Sirtuins: double players in Huntington’s disease. Biochim Biophys
Acta 1852(10 Pt A):2183–2194. https://doi.org/10.1016/j.bbadis.2015.07.003
29. Pan M, Yuan H, Brent M et al (2012) SIRT1 contains N- and C-terminal regions that potentiate
deacetylase activity. J Biol Chem 287(4):2468–2476. https://doi.org/10.1074/jbc.M111.
285031
30. Sanders BD, Jackson B, Marmorstein R (2010) Structural basis for sirtuin function: what we
know and what we don’t. Biochim Biophys Acta 1804(8):1604–1616. https://doi.org/10.1016/
j.bbapap.2009.09.009
31. You W, Rotili D, Li TM et al (2017) Structural basis of Sirtuin 6 activation by synthetic
small molecules. Angew Chem Int Ed Engl 56(4):1007–1011. https://doi.org/10.1002/anie.
201610082
32. Avalos JL, Bever KM, Wolberger C (2005) Mechanism of sirtuin inhibition by nicotinamide:
altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Mol Cell 17(6):855–868. https://
doi.org/10.1016/j.molcel.2005.02.022
33. Imai S, Guarente L (2016) It takes two to tango: NAD+ and sirtuins in aging/longevity control.
NPJ Aging Mech Dis 2:16017. https://doi.org/10.1038/npjamd.2016.17
34. Madsen AS, Andersen C, Daoud M et al (2016) Investigating the sensitivity of NAD+dependent sirtuin deacylation activities to NADH. J Biol Chem 291(13):7128–7141. https://
doi.org/10.1074/jbc.M115.668699
35. Nguyen GT, Schaefer S, Gertz M et al (2013) Structures of human sirtuin 3 complexes
with ADP-ribose and with carba-NAD+ and SRT1720: binding details and inhibition mechanism. Acta Crystallogr D Biol Crystallogr 69(Pt 8):1423–1432. https://doi.org/10.1107/
S0907444913015448
36. Szczepankiewicz BG, Dai H, Koppetsch KJ et al (2012) Synthesis of carba-NAD and the
structures of its ternary complexes with SIRT3 and SIRT5. J Org Chem 77(17):7319–7329.
https://doi.org/10.1021/jo301067e
37. Pesnot T, Kempter J, Schemies J et al (2011) Two-step synthesis of novel, bioactive derivatives of the ubiquitous cofactor nicotinamide adenine dinucleotide (NAD). J Med Chem 54
(10):3492–3499. https://doi.org/10.1021/jm1013852
38. Trapp J, Jochum A, Meier R et al (2006) Adenosine mimetics as inhibitors of NAD+dependent histone deacetylases, from kinase to sirtuin inhibition. J Med Chem 49
(25):7307–7316. https://doi.org/10.1021/jm060118b
Sirtuin Inhibitors and Activators
83