Sirtuins

2020-06-04T20:37:48Z

TheNMNguy:

{{Infobox
| title = Sirtuins
| image = [[File:Sirtuin-2.jpg|350px|Sirtuin 2|alt=Nicotinamide mononucleotide]]
| caption1 = {{{caption|}}}

| data1 = {{Infobox | subbox = yes
| headerstyle = background:#ddd;
| header1 = Background
| label2 = Aliases | data2 = SIRT
| label3 = Class | data3 = Protein
| label4 = Functions | data4 = DNA repair, genome stability, cellular senescence
}}
}}
'''Sirtuins''' are [[NAD+|NAD+-]] dependent proteins which remove molecular tags from other proteins involved in DNA expression.

==Functions of sirtuins in mammals==
The functions of sirtuins play key roles in metabolism, inflammation, DNA repair, insulin secretion, and aging. In general, through removing these molecular tags, sirtuins suppress DNA expression, promote chromosome stability and regulate cellular health.

==Types of sirtuins in mammals==
Mammals have seven different sirtuins. Of these, five sirtuins play a critical function in aging: SIRT1, SIRT2, SIRT3, SIRT6, SIRT7

{| class="wikitable"
|-
!Sirtuin!!Activity!!Function in aging
|-
|SIRT1||ADP-ribosyl-transferase
Deacetylase
||Lifespan extension
DNA repair
Cell cycle arrest
Cellular senescence
Cell cycle regulation
Mitochondrial function
Ocidative stress
Centenarian-linked SNP
|-
|SIRT2||Deacetylase||Cell cycle regulation
|-
|SIRT3||Deacetylase||Mitochondrial function
Oxidative stress
Centenarian-linked SNP
|-
|SIRT4||ADP-ribosyl-transferase
Deacetylase
||Fatty acid oxidation
Apoptosis
|-
|SIRT5||Demalonylase
Desuccinylase
Deacetylase
||Fatty acid oxidation
Oxidative stress
|-
|SIRT6||ADP-ribosyl-transferase
Deacetylase
||Lifespan extension
DNA repair
Genome stability
Telomere maintenance
|-
|SIRT7||Deacetylase||Epigenetic regulation
Stress resistance
Apoptosis
|} <ref>Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.</ref>

===SIRT1===

:''Main article: [[SIRT1]]''

SIRT1, the most studied of the sirtuins family, could play an important role in aging. Mice with an extra copy of the SIRT1 gene produces higher levels of SIRT1 proteins in cells, resulting in lower levels of DNA damage. These mice also have lower levels of "p16," a protein that serves as a marker of aging.<ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9. Daniel Herranz, Marta Canamero, Francisca Mulero, Barbara Martinez-Pastor, Oscar Fernandez-Capetillo, Manuel Serrano. '''Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer syndrome'''. ''Nat Commun'', 2010; DOI: 10.1038/ncomms1001.</ref> SIRT1 suppresses the activity of genes associated with aging. However, the levels of the protein drops in cells as organisms age, reactivating the aging-related genes.<ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9. Jaw-woong Hwang, Hongwei Yao, Samuel Caito, Isaac K. Sundar, Irfan Rahman. '''Redox regulation of SIRT1 in inflammation and cellular senescence'''. ''Free Radic Biol Med'', 2013; DOI: 10.1016/j.freerradbiomed.2013.03.015.</ref> SIRT1 levels also decrease with age in liver cells, mostly due to lower NAD+ availability.<ref>Nady Braidy, Gilles J. Guillemin, Hussein Mansour, Tailoi Chan-Ling, Anne Poljak, Ross Grant. '''Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats'''. ''PLoS One'', 2011; DOI: 10.1371/journal.pone.0019194.</ref> DNA damage occurs with falling SIRT1 levels.

SIRT1 plays a pivotal role in early development as well. In mice without SIRT1, only 20% reach maturity.<ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.</ref> The mice without SIRT1 are sterile, smaller than normal, and develop slower compared to normal mice.<ref>Hwei-Ling Cheng, Raul Mostoslavsky, Shin’ichi Saito, John P. Manis, Yansong Gu, Parin Patel, Roderick Bronson, Ettore Appella, Frederick W. Alt, Katrin F. Chua. '''Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice'''. ''Proc Natl Acad Sci U S A'', 2003; DOI: 10.1073/pna.1934713100. Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9. Michael W. McBurney, Xiaofeng Yang, Karen Jardine, Mary Hixon, Kim Boekelheide, John R. Webb, Peter M. Lansdorp, Madeleine Lemieux. '''The mammalian SIR2α protein has a role in embryogenesis and gametogenesis'''. ''Mol Cell Biol'', 2003; DOI: 10.1128/MCB.23.1.38-54.2003.</ref>
===SIRT2===
SIRT2 levels may be a marker of obesity. In obese individuals, the levels of the protein drops in fat tissue.<ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9. Jaya Krishnan, Carsten Danzer, Tatiana Simka, Josef Ukropec, Katharina Manuela Walter, Susann Kumpf, Peter Mirtschink, Barbara Ukropcova, Daniela Gasperikova, Thierry Pedrazzini, Wilhelm Krek. '''Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system'''. ''Genes Dev'', 2012; DOI: 10.1101/gad.180406.111.</ref> In mice undergoing calorie restriction, SIRT2 levels increase in white fat tissue and kidneys.<ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9. Fei Wang, Margaret Nguyen, F. Xiao-Feng Qin, Qiang Tong. '''SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction'''. ''Aging Cell'', 2007; 6: 505-514.</ref>

===SIRT3===
Evidence suggests that SIRT3 plays a role in human longevity.<ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.</ref> A particular gene marker in the SIRT3 gene, a polymorphism, is found more often in people who live longer.<ref>D. Bellizzi, S. Dato, P. Cavalcante, G. Covello, F. Di Cianni, G. Passarino, G. Rose, G. De Benedictis. '''Characterization of a bidirectional promoter shared between two human genes related to aging: SIRT3 and PSMD13'''. ''Genomics'', 2007; 89(1): 143-150. Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.</ref> Mice lacking SIRT3 have decreased oxygen consumption and increased markers of cellular stress, reactive oxygen species.<ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9. Enxuan Jing, Brice Emanuelli, Matthew D. Hirschey, Jeremie Boucher, Kevin Y. Lee, David Lombard, Eric M. Verdin, C. Ronald Kahn. '''Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production'''. ''Proc Natl Acad Sci U S A'', 2011; DOI: 10.1073/pnas.1111308108.</ref>

===SIRT6===
Research using mice lacking SIRT6 provide the first evidence that sirtuins are involved in regulating mammalian aging. With reduced levels of SIRT6, mice fail to reach a normal lifespan.<ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.</ref> Three weeks after birth, these mice exhibit premature aging and degeneration, which results in death around the fourth week of life.<ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.</ref> Mice without SIRT6 are also smaller than ‘normal’ individuals.

===SIRT7===
Mice lacking SIRT7 age prematurely and have heart complications, lethal heart hypertrophy.<ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9. Olesya Vakhrusheva, Christian Smolka, Praveen Gajawada, Sawa Kostin, Thomas Boettger, Thomas Kubin, Thomas Braun, Eva Bober. '''Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice'''. ''Circ Res'', 2008; 102(6): 703-710.</ref>

==Research==
===Aging===
Research on aging indicates sirtuins are essential factors for delaying cell cellular senescence, deterioration with age. Scientists consider cellular senescence as a beneficial process to inhibit the accumulation of abnormal cells in young organisms caused by stress. Such accumulation of abnormal cells is detrimental to older organisms and thought to induce age-related diseases. Additionally, senescent cells increase with aging <refr>(Krtolica and Campisi, 2002; Lee et al., 2019)<nowiki></ref></nowiki>.

Two sirtuins have been investigated in mammals with protective effects from senescence, SIRT1 and SIRT6. Levels of these two irtuins are reported to decrease in senescent cell lines of mice.<ref>Tarique Anwar, Sanjeev Khosla, Gayatri Ramakrishna. '''Increased expression of SIRT2 is a novel marker of cellular senescence and is dependent on wild type p53 status'''. ''Cell Cycle'', 2016; DOI: 10.1080/15384101.2016.1189041.

Jian Chen, Jun-Jun Xie, Meng-Yun Jin, Yun-Tao Gu, Cong-Cong Wu, Wei-Jun Guo, Ying-Zhao Yan, Zeng-Jie Zhang, Jian-Le Wang, Xiao-Lei Zhang, Yan Lin, Jia-Li Sun, Guang-Hui Zhu, Xiang-Yang Wang, Yao-Sen Wu. '''Sirt6 overexpression suppresses senescence and apoptosis of nucleus pulposus cells by inducing autophagy in a model of intervertebral disc degeneration'''. ''Cell Death Dis'', 2018; DOI: 10.1038/s41419-017-0085-5.

Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.

Tsutomu Sasaki, Bernhard Maier, Andzej Bartke, Heidi Scrable. '''Progressive loss of SIRT1 with cell cycle withdrawal'''. ''Aging Cell'', 2006; DOI: 10.1111/j.1474-9726.2006.00235.x.

Myung Jin Son, Youjeong Kwon, Tawkwon Son, Yee Sook Cho. '''Restoration of mitochondrial NAD+ levels delays stem cell senescence and facilitates reprogramming of aged somatic cells'''. ''Stem Cells'', 2016; DOI: 10.1002/stem.2460.</ref> Reducing SIRT1 and SIRT6's function using molecular inhibitors, siRNA or miRNA, promotes early senescence characteristics in endothelial cells located at the interior of blood vessels.<ref>Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.

Rossella Menghini, Viviana Casagrande, Marina Cardellini, Eugenio Martelli, Alessandro Terrinoni, Francesca Amati, Mariuca Vasa-Nicotera, Arnaldo Ippoliti, Giuseppe Novelli, Gerry Melino, Renato Lauro, Massimo Federici. '''MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1'''. ''Circulation'', 2009; DOI: 10.1161/CIRCULATIONAHA.109.864629.

Raul Mostoslavsky, Katrin F. Chua, David B. Lombard, Wendy W. Pang, Miriam R. Fischer, Lionel Gellon, Pingfang Liu, Gustavo Mostoslavsky, Sonia Franco, Michael W. Murphy, Kevin D. Mills, Parin Patel, Joyce T. Hsu, Andrew L. Hong, Ethan Ford, Hwei-Ling Cheng, Caitlin Kennedy, Nomeli Nunez, Roderick Bronson, David Fredewey, Wojtek Auerbach, David Valenzuela, Margaret Karow, Michael O. Hottiger, Stephen Hursting, J. Carl Barrett, Leonard Guarente, Richard Mulligan, Bruce Demple, George D. Yancopoulos, Frederick W. Alt. '''Genomic instability and aging-like phenotype in the absence of mammalian SIRT6'''. ''Cell'', 2006; DOI: 10.1016/j.cell.2005.11.044.

Hidetaka Ota, Masahiro Akishita, Masato Eto, Katsuya Iijima, Masao Kaneki, Yasuyoshi Ouchi. '''Sirt1 modulates premature senescence-like phenotype in human endothelial cells'''. ''J Mol Cell Cardiol'', 2007; DOI: 101016/j.yjmcc.2007.08.008.</ref> Increasing SIRT1 and SIRT6 gene expression through over-expression suppresses cellular senescence.<ref>Jian Chen, Jun-Jun Xie, Meng-Yun Jin, Yun-Tao Gu, Cong-Cong Wu, Wei-Jun Guo, Ying-Zhao Yan, Zeng-Jie Zhang, Jian-Le Wang, Xiao-Lei Zhang, Yan Lin, Jia-Li Sun, Guang-Hui Zhu, Xiang-Yang Wang, Yao-Sen Wu. '''Sirt6 overexpression suppresses senescence and apoptosis of nucleus pulposus cells by inducing autophagy in a model of intervertebral disc degeneration'''. ''Cell Death Dis'', 2018; DOI: 10.1038/s41419-017-0085-5.

Min Young Kim, Eun Sil Kang, Sun Ah Ham, Jung Seok Hwang, Ttae Sik Yoo, Hanna Lee, Kyun Shin Paek, Chankyu Park, Hoon Taek Lee, Jin-Hoi Kim, Chang Woo Han, Han Geuk Seo. '''The PPARδ-mediated inhibition of angiotensin II-induced premature senescence in human endothelial cells is SIRT1-dependent'''. ''Biochem Pharmacol'', 2012; DOI: 10.1016/j.bcp.2012.09.008.

Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.

Hongwei Yao, Sangwoon Chung, Jae-woong Hwang, Saravanan Rajendrasozhan, Isaac K. Sundar, David A. Dean, Michael W. McBurney, Leonard Guarente, Wei Gu, Mikko ROnty, Vuokko L. Kinnula, Irfan Rahman. '''SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice'''. ''J Clin Invest'', 2012; DOI: 20.1172/JCI60132.

Yi Zu, Ling Liu, Mary Y.K. Lee, Cheng Xu, Yan Liang, Ricky Y. Man, Paul M. Vanhoutte, Yu Wang. '''SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells'''. ''Circ Res'', 2010; DOI: 10.1161/CIRCRESAHA.109.215483.</ref> Altogether, research indicates sirtuins play significant roles in cellular aging.

Suppression of age-caused cellular deterioration with sirtuins stems from two key processes in maintaining DNA integrity -- preventing telomere degradation and promoting DNA damage repair. Telomeres are protective caps that sit on the end of the DNA strands but these caps shorten and fray as cellular senescence occur as one age. Telomere elongation is necessary to avoid premature cellular senescence. SIRT1 and SIRT6 have known roles in regulating telomere reverse transcriptase expression, an enzyme necessary for telomere elongation.<ref>Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.

Shuntaro Yamashita, Kaori Ogawa, Takahiro Ikei, Miyako Udono, Tsukasa Fujiki, Yoshinori Katakura. '''SIRT1 prevents replicative senescence of normal human umbilical cord fibroblast through potentiating the transcription of human telomerase reverse transcriptase gene'''. ''Biochem Biophys Res Commun'', 2012; DOI: 10.1016/j.bbrc.2011.12.021.</ref> SIRT1 and SIRT6 also remove acetyl groups from proteins called histones, the mechanism is also known as deacetylation. DNA wraps around histones for DNA stability. Through deacetylating histones at histone 3 lysine 9 and histone 3 lysine 56, the integrity of telomeres increases along with general DNA integrity.<ref>Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.

Mateusz Watroba, Ilona Dudek, Marta Skoda, Aleksandra Stangret, Przemyslaw Rzodkiewicz, Dariusz Szukiewicz. '''Sirtuins, epigenetics and longevity'''. ''Ageing Res Rev'', 2017; DdOI: 10.1016/j.arr.2017.08.001.</ref> Additionally, research indicates SIRT1 and SIRT6 are recruited to damaged DNA sites. The proteins then promote DNA repair through deacetylating repair proteins such as poly (ADP-ribose) polymerase (PARP)-1, Ku70, NBS, and Werner (WRN) helicase <ref>Jaemin Jeong, Kyungmi Juhn, Hansoo Lee, Sang-Hoon Kim, Bon-Hong Min, Kyung-Mi Lee, Myung-Haeng Cho, Gil-Hong Park, Kee-Ho Lee. '''SIRT1 promotes DNA repair activity and deacetylation of Ku70'''. ''Exp Mol Med'', 2007; DOI: 10.1038/emm.2007.2.

Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.

Eriko Michishita, Ronald A. McCord, Elisabeth Berber, Mitomu Kioi, Hesed Padilla-Nash, Mara Damian, Peggie Cheung, Rika Kusumoto, Tiara L.A. Kawahara, J. Carl Barrett, Howard Y. Chang, Vilhelm A. Bohr, Thomas Ried, Or Gozani, Katrin F. Chua. '''SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin'''. ''Nature'', 2008; DOI: 10.1038/nature06736.

Philipp Oberdoerffer, Shaday Michan, Michael McVay, Raul Mostoslavsky, James Vann, Sang-Kyu Park, Anrea Hartlerode, Judith Stegmuller, Angela Hafner, Patrick Lerch, Sarah M. Wright, Kevin D. Mills, Azad Bonni, Bruce A. Yankner, Ralph Scully, Tomas A. Prolla, Frederick W. Alt, David A. Sinclair. '''SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging'''. ''Cell'', 2008; DOI: 10.1016/j.cell.2008.10.025.

Zhigang Yuan, Edward Seto. '''A functional link between SIRT1 deacetylase and NBS1 in DNA damage response'''. ''Cell Cycle'', 2007; DOI: 10.4161/cc.6.23.5026.</ref>.

In addition to roles in maintaining DNA integrity and repairing damaged sites of DNA to preventing cellular senescence, sirtuins regulate lifespan in several animals. Increased levels of the sirtuin gene, SIR2, in yeast extends its lifespan. The equivalent gene in found in other animals such as roundworms, fruit flies, and mice, also extends their lifespan.<ref>Matt Kaeberlein, Mitch McVey, Leonard Guarente. '''The ''SIR2/3/4'' complex and ''SIR2'' alone promote longevity in ''Saccharomyces cerevisiae'' by two different mechanisms'''. ''Genes Dev'', 1999; DOI: 10.1101/gad.13.19.2570.

Yariv Kanfi, Shoshana Naiman, Gail Amir, Victoria Peshti, Guy Zinman, Liat Nahum, Ziv Bar-Joseph, Haim Y. Cohen. '''The sirtuin SIRT6 regulates lifespan in male mice'''. ''Nature'', 2012; DOI: 10.1038/nature10815.

Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.

Blanka Rogina, Stephen L. Helfand. '''Sir2 mediates longevity in the fly through a pathway related to calorie restriction'''. ''Proc Natl Acad Sci U S A'', 2004; DOI: 10.1073/pnas.0404184101.

Heidi A. Tissenbaum, Leonard Guarente. '''Increased dosage of a ''sir-2'' gene extends lifespan in ''Caenorhabditis elegans'''''. ''Nature'', 2001; DOI: 10.1038/35065638.</ref> The first study of the longevity enhancing effects of SIR2 occurred approximately 20 years ago in yeast.<ref>Matt Kaeberlein, Mitch McVey, Leonard Guarente. '''The ''SIR2/3/4'' complex and ''SIR2'' alone promote longevity in ''Saccharomyces cerevisiae'' by two different mechanisms'''. ''Genes Dev'', 1999; DOI: 10.1101/gad.13.19.2570.

Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.</ref> Follow-up investigations examined effects of Sir2 enhancement in other organisms. Increasing sir2.1expression levels by 7-fold in roundworms extended the lifespan of the worms by 14.8-50.5%. <ref>Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.

Heidi A. Tissenbaum, Leonard Guarente. '''Increased dosage of a ''sir-2'' gene extends lifespan in ''Caenorhabditis elegans'''''. ''Nature'', 2001; DOI: 10.1038/35065638.</ref> Furthermore, a mutation resulting in reduced expression of the sir2.1 gene resulted in decreased lifespan of roundworms. In fruit flies, inducing over expressing the dSir2 gene in neuronal cells or fat cells extended lifespan approximately by 52% and 32.2%, respectively. <ref>Kushal Kr. Banerjee, Champakali Ayyub, Syed Zeeshan Ali, Vinesh Mandot, Nagaraj G. Prasad, Ullas Kolthur-Seetharam. '''dSir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner'''. ''Cell Rep'', 2012; DOI: 10.1016/j.celrep.2012.11.013.

Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.

Blanka Rogina, Stephen L. Helfand. '''Sir2 mediates longevity in the fly through a pathway related to calorie restriction'''. ''Proc Natl Acad Sci U S A'', 2004; DOI: 10.1073/pnas.0404184101.</ref> Mice over-expressing SIRT1 in the brain, more specifically in the hypothalamus, had an increased median lifespan of 16% in females and 9% in males.<ref>Shin-Hae Lee, Ji-Hyeon Lee, Hye-Yeon Lee, Kyung-Jin Min. '''Sirtuin signaling in cellular senescence and aging'''. ''BMB Rep'', 2019; DOI: 10.5483/BMBRep.2019.52.1.290.

Akiko Satoh, Cynthia S. Brace, Nick Rensing, Paul Clifton, David F. Wozniak, Erik D. Herzog, Kelvin A. Yamada, Shin-ichiro Imai. '''Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH'''. ''Cell Metab'', 2013; DOI: 10.1016/j.cmet.2013.07.013.</ref>

==Dietary activators of sirtuins==
Dietary ingredients, functional foods, and nutraceuticals provide great hope for promoting health span and longevity, along with preventing age-related diseases <ref>CKB Ferrari. '''Functional foods, herbs an nutraceuticals: towards biochemical mechanisms of healthy aging'''. ''Biogerontology'', 2004; 5: 275-289.

Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.</ref>. Sirtuin-activating compounds derived from plants include flavones, stilbenes, chalcones, and anthocyanidins, which can directly activate SIRT1 <ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.</ref>. Other agents reported to have anti-aging effects through modulating the SIRT1 cellular pathway include resveratrol <ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.

Chung-Lan Kao, Liang-Kung Chen, Yuh-Lih Chang, Ming-Chih Yung, Chuan-Chih Hsu, Yu-Chih Chen, Wen-Liang Lo, Shih-Jen Chen, Hung-Hai Ku, Shin-Jang Hwang. '''Resveratrol protects human endothelium from H2O2-induced oxidative stress and senescence via SirT1 activation'''. ''J Atheroscler Thromb'', 2010; 17: 970-979.</ref>, cilostazol <ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.

Hidetaka Ota, Masato Eto, Mitsunobu R. Kano, Sumito Ogawa, Katsuya Iijima, Masahiro Akishita, Yasuyoshi Ouchi. '''Cilostazol inhibits oxidative stress-induced premature senescence via upregulation of Sirt1 in human endothelial cells'''. ''Arterioscler Thromb Vasc Biol'', 2008; 28: 1634-1639.</ref>, paeonol <ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.

Juliana Jamal, Mohd Rais Mustafa, Pooi-Fong Wong. '''Paeonol protects against premature senescence in endothelial cells by modulating Sirtuin 1 pathway'''. ''J Ethnopharmacol'', 2014; 154: 428-436.</ref>, statins <ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.

Hidetaka Ota, Masato Eto, Mitsunobu R. Kano, Tomoaki Kahyo, Mitsutoshi Setou, Sumito Ogawa, Katsuya Iijima, Masahiro Akishita, Yasuyoshi Ouchi. '''Induction of endothelial nitric oxide synthase, SIRT1, and catalase by statins inhibits endothelial senescence through the Akt pathway'''. ''Arterioscler Thromb Vasc Biol'', 2010; 30: 2205-2211.</ref>, hydrogen sulfide <ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.

Rong Suo, Zhan-Zhi Zhao, Zhi-Han Tang, Zhong Ren, Xing Liu, Lu-Shan Liu, Zuo Wang, Chao-Ke Tang, Dang-Heng Wei, Zhi-Sheng Jiang. '''Hydrogen sulfide prevents H2O2-induced senescence in human umbilical vein endothelial cells through SIRT1 activation'''. ''Mol Med Rep'', 2013; 7: 1865-1870.

Meihua Zheng, Weili Qiao, Jie Cui, Lei Liu, Hong Liu, Zhirong Wang, Changdong Yan. '''Hydrogen sulfide delays nicotinamide-induced premature senescence via upregulation of SIRT1 in human umbilical vein endothelial cells'''. ''Mol Cell Biochem'', 2014; DOI: 10.1007/s11010-014-2046-y.</ref> and persimmon <ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.

Young A. Lee, Eun Ju Cho, Takako Yokozawa. '''Protective effect of persimmon (''Diospyros kaki'') peel proanthocyanidin against oxidative damage under H2O2-induced cellular senescence'''. ''Biol Pharm Bull'', 2008; 31: 1265-1269.</ref>. Polyphenols, including curcumin, can also modulate sirtuins <ref>Sangwoon Chung, Hongwei Yao, Samuel Caito, Jae-woong Hwang, Gnanapragasam Arunachalam, Irfan Rahman. '''Regulation of SIRT1 in cellular functions: role of polyphenols'''. ''Arch Biochem Biophys'', 2010; DOI: 10.1016/j.abb.2010.05.003.

Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.

T. Jayasena, A. Poljak, G. Smythe, N. Braidy, G. Munch, P. Sachdev. '''The role of polyphenols in the modulation of sirtuins and other pathways involved in Alzheimer’s disease'''. ''Ageing Res Rev'', 2013; DOI: 10.1016/j.arr.2013.06.003.</ref>. The most well-described and recognized natural compound stimulating SIRT1 is resveratrol. Activating SIRT1 with resveratrol supplementation increases lifespan and improves healthspan of several species <ref>Joseph A. Baur, Kevin J. Pearson, Nathan L. Price, Hamish A. Jamieson, Carles Lerin, Avash Kalra, Vinayakumar V. Prabhu, Joanne S. Allard, Buillermo Lepez-Lluch, Kaitlyn Lewis, Paul J. Pistell, Suresh Poosala, Kevin G. Becker, Olivier Boss, Dana Gwinn, Mingyi Wang, Sharan Ramaswamy, Kenneth W. Fishbein, Richard G. Spencer, Edward G. Lakatta, David Le Couteur, Reuben J. Shaw, Placido Navas, Pere Puigserver, Donald K. Ingram, Rafael de Cabo, David A. Sinclair. '''Resveratrol improves health and survival of mice on a high-calorie diet'''. ''Nature'', 2006; DOI: 10.1038/nature05354.

Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.

Laurent Mouchiroud, Laurent Molin, Nicolas Dalliere, Florence Solari. '''Life span extension by resveratrol, rapamycin, and metformin: The promise of dietary restriction mimetics for an healthy aging'''. ''BioFactors'', 2010; DOI: 10.1002/biof.127.</ref>. Natural anti-aging compounds also include quercetin, butein, fisetin, kaempferol, catechins, and proanthocyanidins <ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.

T. Jayasena, A. Poljak, G. Smythe, N. Braidy, G. Munch, P. Sachdev. '''The role of polyphenols in the modulation of sirtuins and other pathways involved in Alzheimer’s disease'''. ''Ageing Res Rev'', 2013; DOI: 10.1016/j.arr.2013.06.003.</ref>. Some Traditional Chinese Medicines have natural compounds with potent SIRT1-activating effects <ref>Wioleta Grabowska, Ewa Sikora, Anna Bielak-Zmijewska. '''Sirtuins, a promising target in slowing down the ageing process'''. ''Biogerontology'', 2017; DOI: 10.1007/s10522-017-9685-9.

Yi Wang, Xxinying Liang, Yaqi Chen, Xiaoping Zhao. '''Screening SIRT1 activators from medicinal plants as bioactive compounds against oxidative damage in mitochondrial function'''. ''Oxid Med Cell Longev'', 2016; DOI: 10.1155/2016/4206392.</ref>. Activating sirtuins through the regulation of NAD+ levels offers an alternative method of stimulating sirtuin function.

Functional food is a promising method for anti-aging interventions. Modulating SIRT1 function through consumption of these foods and dietary ingredients could represent a new way of counteracting the effects of aging.

==Further reading==

[[Category:Health]]
<references />
[[Category:Full index]]

2020-06-01T23:09:47Z

TheNMNguy:

'''Sirtuin 1''' ('''SIRT1''') is the most extensively studied type of sirtuin. Scientists heavily implicate this protein in health span and lifespan extension. SIRT1, a member of the silent mating type information regulation 2 protein (sirtuin) family, has a shared gene in other species, including yeast. The shared gene in other animal species allows scientists to study modulating levels of SIRT1 on lifespan. A study of yeast some 20 years ago reveals genetically increasing SIRT1 levels increases lifespan 30% in this species.
This protein depends on nicotinamide adenine dinucleotide (NAD+) to function. With sufficient NAD+, SIRT1 removes molecular markers from other proteins, including the proteins DNA wraps around (histones). As such, scientists classify it as a class III histone deacetylase.

==SIRT1 function==
Research has not yet fully elucidated the function of sirtuins in humans.<ref>https://www.ncbi.nlm.nih.gov/gene/23411</ref>

Sirt1 has been heavily implicated in control of metabolism and health of the cell’s powerhouse, mitochondria. SIRT1 also plays an important role in the reduction of defective mitochondria. This reduction in defective mitochondria occurs through a process termed mitophagy. Mitophagy entails the cell’s disposal of defective mitochondria

==Research on SIRT1 in aging==
Studies indicate high expression of SIRT1 in the brain, heart, kidney, liver, pancreas, skeletal muscle, spleen, and fat tissue (white adipose tissue).<ref>Wenyan Cao, Ying Dou, Aiping Li. Resveratrol boosts cognitive function by targeting SIRT1. Neurochem Res, 2018; DOI: 10.1007/s11064-018-2586-8.</ref><ref>GS Kelly. A review of the sirtuin system, its clinical implications, and the potential role of dietary activators like resveratrol: part 2. Altern Med Rev, 2010; 15(4): 313-328.</ref><ref>S Voelter-Mahlknecht, U Mahknecht. Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylase gene sirtuin 1. Int J Mol Med, 2006; 17(1):59-67.</ref> An initial study of Sir2 in yeast life span extension demonstrates integrating a second copy of the gene into normal, wild type, yeast increases lifespan 30%.2 In contrast, mice with mutant Sir2 genes have a reduced lifespan of 50%.<ref>Wenyan Cao, Ying Dou, Aiping Li. Resveratrol boosts cognitive function by targeting SIRT1. Neurochem Res, 2018; DOI: 10.1007/s11064-018-2586-8.</ref><ref>M Kaeberlein, M McVey, L Guarente. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev, 1999; 13(19): 2570-2580.</ref>

==SIRT1 and exercise==
Regular exercise promotes health. Research suggests a significant role of SIRT1 in these effects from exercise.<ref>Z Radak, E Koltai, AW Taylor M Higuchi, S Kumagai, H Ohno, S Goto, I Boldogh. Redox regulating sirtuins in aging, carloric restriction, and exercise. Free Radic Biol Med, 2013; 58: 87-97.</ref><ref>Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.</ref>It also suggests SIRT1-related adaptations from exercise occur in the liver, kidney, brain, heart, and skeletal muscle.<ref>Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.</ref>

A major effect of exercise entails protecting brain function. Improvements in brain function from exercise result in increased resistance to cellular stress,<ref>Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.</ref><ref>Z Radak, AW Taylor, H Ohno, S Goto. Adaptation to exercise-induced oxidative stress: from muscle to brain. Exerc Immunol, 2001; 7: 90-107.</ref><ref>S Siamilis, J Jakus, C Nyakas, A Costa, B Mihalik, A Falus, Z Radak. The effect of exercise and oxidant-antioxidant intervention on the levels of neurotrophins and free radicals in spinal cord of rats. Spinal Cord, 2009; 47: 453-457.</ref>increased production of neurons,<Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.<nowiki></ref></nowiki><ref>I Sarga, N Hart, IG Koch, SI Britton, G Hajas, I Boldogh, X Ba, Z Radak. Aerobic endurance capacity affects spatial memory and SIRT1 is a potent modulator of 8-oxoguanine repair. Neuroscience, 2013; 252: 326-336.</ref> and increased production of the cell’s powerhouse in neurons (mitochondria).<ref>K Marosi, K Felszeghy, RD Mehra, Z Radak, C Nyakas. Are the neuroprotective effects of estradiol and physical exercise comparable during ageing in female rats? Biogerontology, 2012; 13: 413-427.</ref><ref>Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.</ref>

Stimulation of SIRT1 function through exercise can result in these effects on protecting brain function.<ref>H Jeong, DE Cohen, I. Cui, A Supinski, JN Savas, JR Mazzulli, JR Yates, L Bordone, L Guarente, D Kraine. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med, 2012; 18: 159-165.</ref><ref>L Liu, Q Zhang, Y Cai, D Sun, X He, L Wang, D Yu, X Li, X Xiong, H Xu, Q Yang, X Fan. Resveratrol counteracts lipopolysaccharide-induced depressivelike behaviors via enhanced hippocampal neurogenesis. Oncotarget, 2016; 7: 56045-56059.</ref><ref>CY Ma, MJ Yao, QW Zhai, JW Jiao, XB Yuan, MM Poo. SIRT1 suppresses self-renewal of adult hippocampal neural stem cells. Development, 2014; 141: 1697-4709.</ref><ref>Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.</ref><ref>SA Shah, M Khan, MH Jo, MG Jo, FU Amin, MO Kim. Melatonin stimulates the SIRT1/nrf2 signaling pathway counteracting lipopolysaccharide (LPS)-induced oxidative stress to rescue postnatal rat brain. CNS Neurosci Ther, 2017; 23: 33-44.</ref><ref>SJ Wang, XH Zhao, W Chen, N Bo, XJ Wang, ZF Chi, W Wu. Sirtuin 1 activation enhances the PGC-1a/mitochondrial antioxidant system pathway in status epilepticus. Mol Med Rep, 2015; 11: 521-526.</ref> Exercise does increase SIRT1 content in the brain. The molecular mechanism mediating exercise’s effects in protecting brain function may very well stem from it increasing SIRT1 levels.<ref>F Gomez-Pinilla, Z Ying. Differential effects of exercise and dietary docosahexaenoic acid on molecular systems associated with control of allostasis in the hypothalamus and hippocampus. Neuroscience, 2010; 168: 130-137.</ref><ref>Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.</ref>

SIRT1 depends on sufficient levels of NAD+, which decline as people age. Exercise makes NAD+ molecules more readily available for SIRT1. NAD+ exists in higher concentrations in its non-reduced form, as opposed to having electrons as NADH. This helps SIRT1 function. Regular exercise rejuvenates aged skeletal muscle, also. This happens partly due to stimulating SIRT1 function. Research has uncovered much related to SIRT1 cellular function. Researchers still have much to learn on this topic.<ref>Zsolt Radak, Katsuhiko Suzuki, Aniko Posa, Zita Petrovszky, Erika Koltai, Istvan Boldogh. The systemic role of SIRT1 in exercise mediated adaptation. Redox Biol, 2020; DOI: 10.1016/j.redox.2020:101467.</ref>

==Resveratrol stimulates SIRT1==
SIRT1 has gained interest due to its role in improving brain functions. [[Resveratrol]], a plant compound found in grapes, berries, and peanuts, improves brain function through stimulating SIRT1.<ref>Wenyan Cao, Ying Dou, Aiping Li. Resveratrol boosts cognitive function by targeting SIRT1. Neurochem Res, 2018; DOI: 10.1007/s11064-018-2586-8.</ref>

Resveratrol stimulates SIRT1 activity up to eight-fold.<ref>MT Borra, BC Smith, JM Denu. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem, 2005; 280: 17187-17195.</ref><ref>Wenyan Cao, Ying Dou, Aiping Li. Resveratrol boosts cognitive function by targeting SIRT1. Neurochem Res, 2018; DOI: 10.1007/s11064-018-2586-8.</ref><ref>BP Hubbard, DA Sinclair. Small molecule SIRT1 acitvators for the treatment of aging and age-related diseases. Trends Pharmacol, 2014; 35: 146-154.</ref>The effectiveness of resveratrol activating SIRT1 remains debatable. Research on various animals, though, demonstrates resveratrol stimulates SIRT1 function to protect against declining brain function.<ref>Wenyan Cao, Ying Dou, Aiping Li. Resveratrol boosts cognitive function by targeting SIRT1. Neurochem Res, 2018; DOI: 10.1007/s11064-018-2586-8.</ref><ref>LL Du, JZ Xie, XS Cheng, XH Li, FL Kong, X Jiang, ZW Ma, JZ Wang, C Chen, XW Zhou. Activation of sirtuin 1 attenuates cerebral ventricular streptozotocin-induced tau hyperphosphorylation and cognitive injuries in rat hippocampi. Age (Dordr), 2014; 36: 613-623.</ref>

==References==
<references />
[[Category:Full index]]

NAD+

2020-05-30T00:28:53Z

TheNMNguy: Created page with "{{Infobox | title = Nicotinamide adenine dinucleotide | image = alt=Nicotinamide adenine dinucleotide | caption1 = {{{caption|}}} <!-- Pharmacokin..."

{{Infobox
| title = Nicotinamide adenine dinucleotide
| image = [[File:Nad.png|200px|alt=Nicotinamide adenine dinucleotide]]
| caption1 = {{{caption|}}}

| data1 = {{Infobox | subbox = yes
| headerstyle = background:#ddd;
| header1 = Pharmacokinetic data
| label2 = Formula | data2 = C21H27N7O14P2
| label3 = Molar mass | data3 = 663.43 g/mol
| label5 = Melting Point | data5 = 160 °C (320 °F; 433 K)
}}

| data2 = {{Infobox | subbox = yes
| headerstyle = background:#ddd;
| header1 = Identifiers
| label2 = CAS Number | data2 = 53-84-9
}}
}}

'''Nicotinamide adenine dinucleotide''' ('''NAD+''') is a co-enzyme, syntesized from [[Vitamin B3|vitamin B3]], found in all living cells . [[nicotinic acid (NA)|Niacin]], [[Nicotinamide|nicotinamide (NAM)]], [[NMN|nicotinamide mononucleotide (NMN)]], and [[NR|nicotinamide riboside (NR)]] all are vitamin precursors of NAD+.<ref name="cell2004">Cell, Vol. 117, 495–502, May 14, 2004, Copyright 2004 by Cell Press Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD in Fungi and Humans</ref>
NAD+ is known as a ‘helper’ molecule which is involved in a choreography of reactions which lead to its binding to proteins and as a result activation of [[Sirtuins|enzymes]] which initiate signaling pathways throughout the body. Evolving evidence highlights boosting levels of NAD+ as playing a pivotal role in reducing the signs of [[Cellular aging|aging]] and age-related disease.<ref> NAD+ in Brain Aging and Neurodegenerative Disorders Lautrup, Sofie et al. Cell Metabolism, Volume 30, Issue 4, 630 – 655 </ref>
NAD+ has been shown to decline with age due to a reduced ability of the cells to recycle or synthesize NAD+. NAD+ regulates protein-protein interactions involved with DNA repair<ref> Massudi, H., Grant, R., Braidy, N., Guest, J., Farnsworth, B., & Guillemin, G. J. (2012). Age-Associated Changes In Oxidative Stress and NAD Metabolism In Human Tissue. PLoS ONE, 7(7). doi:10.1371/journal.pone.0042357 </ref>

==History==
'''1906''' NAD was discovered by British biochemists, [[Arthur Harden]] and [[William John Young]] <ref>https://www.elysiumhealth.com/en-us/science-101/everything-you-need-to-know-about-nicotinamide-adenine-dinucleotide-nad</ref>. Initially Louis Pasteur recognized that yeast cells were responsible for fermentation<ref name="aboutnadcom">https://www.aboutnad.com/announcement/1906-nad-discovered-arthur-harden-william-john-young/</ref> and Arthur Harden was intrigued to learn more about the details of this process. As a result, Harden and Young were able to separate the yeast cells into two fractions, heat stable and heat labile. The heat labile fraction contained proteins required for fermentation whilst the heat stable fraction contained co-factors such as NAD+ that ‘helped’ the proteins perform such functions.

'''1929''' Hans von Euler-Chelpin furthered the work of Harden and Young by extensively separating the components of the heat-stable fraction of yeast cells, which allowed him to obtain a purified form of nucleotide sugar phosphate (NAD) as well as to determine the chemical structure. <ref name="aboutnadcom" /><ref>Arthur Harden and William John Young Published:24 October 1906https://doi.org/10.1098/rspb.1906.0070</ref>

'''1936''' Otto Heinrich Warburg demonstrated NAD’s role in fermentation reactions. He found that the nicotinamide portion of NAD was required for a hydride transfer reaction to occur.<ref name="aboutnadcom" />

'''1938''' [[Conrad Elvehjem|Conrad Elvehjam]] discovered that nicotinic acid extracted from fresh liver was able to cure black tongue (pellagra) in canines.<ref name="aboutnadcom" /><ref>THE ISOLATION AND IDENTIFICATION OF THE ANTI-BLACK TONGUE FACTOR C. A. Elvehjem, Robert J. Madden, F. M. Strong and D. W. Woolley J. Biol. Chem. 1938, 123:137-149.</ref>

'''1940''' Arthur Kornberg studied the synthesis of NAD in the body using advanced purification of proteins and co-enzymes. <ref name="aboutnadcom" />

'''1958''' Jack Priess and Philip Handler uncovered the conversion of nicotinic acid to NAD via a three-step pathway which became known as the Priess-Handler pathway.<ref name="aboutnadcom" />

'''1963''' Mandel and colleagues identified a chemical reaction that broke NAD into two parts, nicotinamide and ADP-ribose.<ref name="aboutnadcom" /><ref>Biochemical and Biophysical Research Communications Volume 11, Issue 1, 2 April 1963, Pages 39-43</ref>

'''2000''' Leonard Guarente and co-workers discovered sirtuin enzymes capable of expanding the lifespan of yeast using NAD to help keep genes in a ‘silent’ or non-functional mode. <ref name="aboutnadcom" /><ref> Imai, S., Armstrong, C., Kaeberlein, M. et al. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000). https://doi.org/10.1038/35001622 </ref>

'''2004''' [[Charles Brenner]] and colleagues uncovered a two-step kinase pathway in which nicotinamide riboside was converted to NAD+.<ref name="cell2004" />

==Structure==
Molecular formula C21H27N7O14P2 <ref> https://pubchem.ncbi.nlm.nih.gov/compound/NAD%2B </ref>
Consists of 2 nucleosides (one joined to an adenine nucleobase and the other to nicotinamide) bridged by a phosphate group. They contain a ribose ring, one with adenine attached to the first carbon atom and one with nicotinamide at the same position. The structure exists as diastereomers meaning the nicotinamide moiety can be attached in two different orientations.

NAD+ is an oxidizing agent and is involved in electron transfer reactions in which it accepts electrons form other molecules to become reduced, hence forming NADH which as a reducing agent is then able to donate electrons. NAD+ (the plus sign represents the formal charge on one of its nitrogen atoms) is known as nicotinamide adenine dinucleotide in the oxidized form, with NADH being the reduced form.

==Biosythesis==

There are 2 ways by which NAD+ is synthesized. It can be produced from amino acids in the de novo pathway or by recycling components such as nicotinamide back to NAD+, in what is called the salvage pathway.

===Quinolinic acid===
Quinolinic acid (QA) is generated from an amino acids such as [[Tryptophan|tryptophans]] in animals or aspartic acid in bacteria or plants. QA is then converted to nicotinic acid mononucleotide (NaMN) via transfer of a phosphoribose group. An adenylate group is then transferred to form NaAD. Finally, the nicotinic acid group undergoes amidation to form nicotinamide (Nam), hence resulting in nicotinamide adenine dinucleotide.<ref> Belenky P, Bogan KL, Brenner C (2007). "NAD+ metabolism in health and disease" (PDF). Trends Biochem. Sci. 32 (1): 12–9. doi:10.1016/j.tibs.2006.11.006. PMID 17161604. Archived from the original(PDF) on 4 July 2009. Retrieved 23 December 2007. </ref>

===Salvage pathway===
Some cells salvage preformed compounds that contain a pyridine base. This requires the three vitamin precursors, nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR). Such precursors termed [[Vitamin B3|vitamin B3]] can be absorbed by the body through the usual dietary intake.

==Functions==
NAD+ is vital for the creation of energy and the regulation of cellular processes within humans, mammals, bacteria and even plants. This critical co-enzyme is involved in an array of metabolic pathways, namely converting nutrients into energy or working as a helper molecule for proteins.

===Cellular Metabolism===
NAD+ is a crucial cofactor which is fundamental to metabolism in humans and many other organisms. NAD+ is a dinucleotide, and its primary mechanism of action in cells is to function as a cofactor in the reactions involved in cellular metabolism. NAD+ primarily acts as an electron accepting molecule, which then allows it to transfer electrons from one compound to another. It plays a central role in cellular reduction-oxidation reactions such as the breakdown of glucose and fatty acids, allowing these substances to be utilized as energy sources<ref> Cantó C, Menzies KJ, Auwerx J. NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metab. 2015;22(1):31-53. </ref>.

===Cell Signaling===
In addition to its central role in metabolism, NAD+ is also involved in a crucial process known as ADP-ribosylation<ref> Ziegler M. New functions of a long-known molecule: Emerging roles of NAD in cellular signaling. Eur J Biochem. 2000;267(6):1550-1564. </ref>. This process involves the addition of one or many ADP-ribose groups to proteins which have already been formed. Protein ribosylation has been demonstrated to play a role in DNA repair processes as well as modification of telomeres – both functions have well-established roles in the progression of cellular aging<ref name="bürkle2005"> Bürkle A. Poly(ADP-ribose): The most elaborate metabolite of NAD+. FEBS J. 2005;272(18):4576-4589. </ref>.

NAD+ has also been identified as an extracellular messenger. Preliminary research has highlighted the potential role of NAD+ in signaling between neurons, blood vessels, and even its potential role as a signaling molecule to allow for communication between nerves and the muscles they innervate<ref> Mutafova-Yambolieva VN, Sung JH, Hao X, et al. β-Nicotinamide adenine dinucleotide is an inhibitory neurotransmitter in visceral smooth muscle. Proc Natl Acad Sci U S A. 2007;104(41):16359-16364. </ref><ref> Smyth LM, Bobalova J, Mendoza MG, Lew C, Mutafova-Yambolieva VN. Release of β-nicotinamide adenine dinucleotide upon stimulation of postganglionic nerve terminals in blood vessels and urinary bladder. J Biol Chem. 2004;279(47):48893-48903. </ref>.

===Sirtuins===
[[File:Sirtuin.jpg|thumb|NAD+ and sirtuins]]
''Main article: [[Sirtuins]]''
In 2000 it became evident that Sirtuins, a class of signaling proteins implicated in influencing cellular processes such as aging, apoptosis and inflammation were involved in transcriptional silencing. They are commonly referred to as “guardians of the genome” due to their role in regulating cellular homeostasis. Sirtuins use NAD+ to remove acetyl groups from proteins, hence they are also termed NAD-dependent deactylases e.g Sir2. Such sirtuin enzymes function by transferring an acetyl group from the substrate protein to ADP-ribose portion of NAD+. <ref> North BJ, Verdin E (2004). "Sirtuins: Sir2-related NAD-dependent protein deacetylases". Genome Biol. 5 (5): 224. doi:10.1186/gb-2004-5-5-224. PMC 416462. PMID 15128440. </ref> Functionally, the sirtuins seem to be mainly involved in regulating transcription by deacetylating histones and consequently altering the structure of the nucleosome.

NAD+ is also utilized in ADP-ribose transfer reactions. Enzymes named ADP-ribosyltransferases add the ADP-ribose moiety to proteins creating a post-translational modification known as ADP-ribosylation. The transfer of ADP-ribose to long branched chain proteins was known as poly(ADP-ribosyl)ation. The poly(ADP-ribose) structure has gained much attention in the regulation of cellular events such as DNA repair and telomere maintenance.

In addition to intracellular functions, NAD+ has become increasingly recognized as an extracellular signaling molecule. NAD+ has been shown to be released from neurons in the blood vessels, bladder and large intestine.<ref> Billington RA, Bruzzone S, De Flora A, Genazzani AA, Koch-Nolte F, Ziegler M, Zocchi E (2006). "Emerging functions of extracellular pyridine nucleotides". Mol. Med. 12 (11–12): 324–7. doi:10.2119/2006-00075.Billington. PMC 1829198. PMID 17380199. </ref>

==NAD+ Precursors==

===Nicotinamide Riboside===

:''Main article: [[NR]]''

Nicotinamide Riboside (NR), often termed the ‘cousin’ of vitamin B3, is a natural substance found in trace amounts in milk, for example. NR is available to all cells and does not cause the flushing effects seen with those administering Niacin. Levels of NR do not decline in effectiveness with age, in fact it becomes more readily available during stress.

Dr Charles Brenner discovered the NR Kinase pathway in which cells use NR to create NAD+.<ref name="aboutnadcom" /> During times of stress the NR Kinase pathway increases its activity and hence cells take up NR to produce NAD+ in order to repair.

===Nicotinamide mononucleotide===

:''Main article: [[NMN]]''

Nicotinamide mononucleotide (NMN) is the immediate precursor to NAD+ in the salvage pathway of NAD+ synthesis. NMN is similar to NR in that NR becomes NMN with the addition of a phosphate group. In the past, scientists believed the addition of this phosphate on NMN makes it more difficult for NMN to enter cells and replenish NAD+ levels; however, a transporter specific for NMN, Slc12a8, has been recently identified in the gut of mice, which allows efficient transport of NMN into cells in this species. If this transporter has the same function in humans, the possibility exists for efficient transport of NMN into cells in humans. Determining how well humans can absorb NMN in comparison to NR requires further research.

===Nicotinic Acid===

:''Main article: [[Niacin]]''

Nicotinic Acid (NA) or niacin is another vitamin B3. This organic compound is an essential nutrient for humans and is commonly used to fortify packaged foods such as cereals and grains. Supplemental niacin is primarily known to be used for treating high cholesterol and pellagra.<ref> Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. 8 October 2018. Retrieved 16 September2019. </ref>

===Nicotinamide===

:''Main article: [[Nicotinamide]]''

Nicotinamide (NAM) is yet another form of vitamin B3. Also known as niacinamide, it is found in yeast, milk, meat and green vegetables. It is also used as a dietary supplement and added to foods for such benefits as treating acne <ref> British National Formulary: BNF 69 (69th ed.). British Medical Association. 2015. p. 822. ISBN 978-0-85711-156-2. </ref> and reducing the risk of skin cancers.<ref> Minocha R, Damian DL, Halliday GM (January 2018). "Melanoma and nonmelanoma skin cancer chemoprevention: A role for nicotinamide?". Photodermatology, Photoimmunology & Photomedicine. 34 (1): 5–12. doi:10.1111/phpp.12328. PMID 28681504. </ref>

===Tryptophan===

:''Main article: [[Tryptophan]]''

Tryptophan (TRP) is an alpha-amino acid which is a vital building block in synthesizing proteins. It is also a precursor to serotonin, melatonin and vitamin B3. Tryptophans are obtained from the diet in the form of cheese, eggs and meats such as turkey.

==Research==
NAD+ and the process concerning its formation and depletion with age is of great importance for the future treatments of many inflammatory conditions as well as in reducing or slowing the process of aging. This fundamental biological process is associated with metabolic disorders, cancers and various neurodegenerative diseases. As research advances it is becoming more apparent that boosting NAD+ levels can be used as a potential therapeutic strategy to slowing the progression of age-related diseases such as Alzheimer’s and Parkinson’s.<ref> Belenky P, Bogan KL, Brenner C (2007). "NAD+ metabolism in health and disease" (PDF). Trends Biochem. Sci. 32 (1): 12–9. doi:10.1016/j.tibs.2006.11.006. PMID 17161604. Archived from the original(PDF) on 4 July 2009. Retrieved 23 December 2007. </ref>

The differences in metabolic pathways of NAD+ biosynthesis between bacteria and humans allows for the exploitation of these differences for the development of possible new antibiotics. An example would be nicotinamidase which converts nicotinamide to nicotinic acid. This enzymes is present in bacteria but not in humans and hence is a target for drug design.<ref> Begley TP, Kinsland C, Mehl RA, Osterman A, Dorrestein P (2001). The biosynthesis of nicotinamide adenine dinucleotides in bacteria. Vitam. Horm. Vitamins & Hormones. 61. pp. 103–19. doi:10.1016/S0083-6729(01)61003-3. ISBN 978-0-12-709861-6. PMID 11153263. </ref>

NAD+ is widely sought after for supplementation, particularly in the intravenous form at various health clinics that offer treatments for those who want to improve overall health, reduce risks of cancers, or even to treat those suffering from alcohol abuse or substance misuse addictions. NAD+ supplements are readily available for purchase, particularly online.

The study of NAD+ is also implicated in the notion of a ‘biological age’ <ref> Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a andomized, double-blind, placebo-controlled study Ryan W. Dellinger, Santiago Roel Santos, Mark Morris, Mal Evans, Dan Alminana, Leonard Guarente and Eric Marcotulli1</ref> as well as a chronological age. The biological age tracks the way in which our cells have changed as we have aged, this can even be specific to each organ.

The phenomenon of a biological age is a measurement based on various biomarkers and the age can change depending upon lifestyle and other health related factors. A cumulative rate of aging is the biological age relative one’s chronological age. Biological age can be a reflection of genetics, lifestyle factors and other variables such as demographics, exercise and diet.

==References==
<references />
[[Category:Compounds]]
[[Category:Full index]]

NMN

2020-05-30T00:27:11Z

TheNMNguy: Created page with "{{Infobox | title = Nicotinamide mononucleotide | image = alt=Nicotinamide mononucleotide | caption1 = {{{caption|}}}  | dat..."

{{Infobox
| title = Nicotinamide mononucleotide
| image = [[File:Nmn.gif|200px|alt=Nicotinamide mononucleotide]]
| caption1 = {{{caption|}}}

| data1 = {{Infobox | subbox = yes
| headerstyle = background:#ddd;
| header1 = Clinical data
| label2 = Routes of administration | data2 = Oral
}}

| data2 = {{Infobox | subbox = yes
| headerstyle = background:#ddd;
| header1 = Legal status
| label2 = Legal status | data2 = US, CA, UK, EU, JP, CN, AU
}}

| data3 = {{Infobox | subbox = yes
| headerstyle = background:#ddd;
| header1 = Pharmacokinetic data
| label2 = Formula | data2 = C11H15N2O8P
| label3 = Molecular weight | data3 = 334.22 g·mol−1
| label6 = Solubility | data6 = 1.8 mg/mL
}}

| data4 = {{Infobox | subbox = yes
| headerstyle = background:#ddd;
| header1 = Identifiers
| label2 = CAS Number | data2 = [https://chem.nlm.nih.gov/chemidplus/rn/1094-61-7 1094-61-7]
}}
}}

<onlyinclude>{{PageTitle|Nicotinamide mononucleotide|link=NMN}} ('''NMN, NAMN, and β-NMN''') is a [[wikipedia:Nucleotide|nucleotide]] derived from ribose and nicotinamide. NMN is a precursor of [http://wik.andretest.site/NAD+ nicotinamide adenine dinucleotide (NAD+)], a form of niacin, also known as [[vitamin B3|vitamin B3]]<ref name="imai2013"> Imai S, Yoshino J. The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing. Diabetes, Obes Metab. 2013;15(S3):26-33.</ref>. Because it is a [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359187/ source of cellular energy] due to its role in the production of NADH/NAD+, NMN is involved in numerous cellular reactions. Inside the mitochondria, NADH is converted to NAD+ in the process of oxidative phosphorylation. NAD plays a critical role in the TCA cycle, by alternately accepting and donating an electron at various steps of the cycle. NAD+ also plays a key role in regulating enzymes called [[sirtuins]] that play an important role in DNA repair. Numerous studies, mostly done in mice and roundworms, have focused on the potential health benefits of NMN. Formally, NMN may also be known as ‘Nicotinamide D-ribonucleotide’ or ‘β-Nicotinamide ribose monophosphate’ and has the chemical formula C11H15N2O8P<ref name="nationalcenterforbiotechnologyinformation"> National Center for Biotechnology Information. [(2S,3S,4R,5R)-5-(3-Carbamoylpyridin-1-ium-1-yl)-3,4-dimethyloxolan-2-yl]methyl hydrogen phosphate | C13H19N2O6P - PubChem. PubChem Database. </ref>. It occurs naturally in small amounts in [[Dietary sources of NMN|dietary sources]] such as cabbage, avocado, and broccoli.
</onlyinclude>

==History==
NMN first gained notoriety in 1963, when Chambon, Weill, and Mandell [https://www.ncbi.nlm.nih.gov/pubmed/14019961/ reported] that the molecule activated a newly-discovered DNA-dependent polyadenylic acid synthesizing nuclear enzyme. This led to a series of discoveries concerning nuclear enzymes called poly-ADP-ribose and poly-ADP-ribose polymerases (PARPs). Further work throughout the 1960s helped scientists to understand the biosynthetic pathway that connected niacin, nicotinamide, and NMN<ref> IKEDA M, TSUJI H, NAKAMURA S, ICHIYAMA A, NISHIZUKA Y, HAYAISHI O. STUDIES ON THE BIOSYNTHESIS OF NICOTINAMIDE ADENINE DINUCLEOTIDE. II. A ROLE OF PICOLINIC CARBOXYLASE IN THE BIOSYNTHESIS OF NICOTINAMIDE ADENINE DINUCLEOTIDE FROM TRYPTOPHAN IN MAMMALS. J Biol Chem. 1965;240:1395-1401.</ref>. Through this initial research, scientists came to understand the vital role that NMN and NAD+ played in cellular metabolism and oxidation-reduction reactions. Following this, renewed interest in NMN and NAD+ came in the 2000s, when researchers discovered that these compounds were linked to sirtuins, a class of enzymes, whose DNA repair activity plays an active role in [[Aging|aging]].

==Structure==
NMN is a nucleotide product of a nucleoside, composed of ribose and nicotinamide, that reacts with a phosphate group. The chemical formula for NMN is C11H15N2O8P, and the nucleotide exists as a combination of two anomers, of which the beta-anomer is the biologically active form<ref name="nationalcenterforbiotechnologyinformation" />.

==Mechanism of action==

:''Main article: [[NAD+]]''

NMN is the immediate precursor to NAD+, a compound with myriad reported biological activities. Previous research has shown that NMN functions primarily as an intermediate, with few direct mechanisms of action<ref name="yoshino2011"> Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528-536.</ref>. Instead, it has been shown that NMN supplementation or administration leads to an increase in the measured levels of NAD+<ref name="yoshino2011" />.

===Mechanism of NAD+===
[[File:NAD biosynthesis.jpg|thumb|NAD+ biosynthesis from NMN]]
''Cellular metabolism''

NAD+ is a crucial cofactor, which is fundamental to metabolism in humans and many other organisms. NAD+ is a dinucleotide, and its primary mechanism of action in cells is to function as a cofactor in reactions involving cellular metabolism. In its primary function as an electron-accepting molecule, NAD+ transfers electrons between other molecules in biochemical reactions. It plays a central role in cellular reduction-oxidation reactions such as the breakdown of glucose and fatty acids, allowing these substances to be utilized as energy sources<ref> Cantó C, Menzies KJ, Auwerx J. NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metab. 2015;22(1):31-53. </ref>.

''Cell signaling''

In addition to its central role in metabolism, NAD+ is also involved in a process known as ADP-ribosylation<ref> Ziegler M. New functions of a long-known molecule: Emerging roles of NAD in cellular signaling. Eur J Biochem. 2000;267(6):1550-1564. </ref>. This process consists of the addition of one or more ADP-ribose groups to mature proteins. Protein ribosylation has been demonstrated to play a role in DNA repair processes as well as the modification of telomeres – both functions have well-established roles in the progression of cellular aging<ref name="bürkle2005"> Bürkle A. Poly(ADP-ribose): The most elaborate metabolite of NAD+. FEBS J. 2005;272(18):4576-4589. </ref>.

NAD+ has also been identified as an extracellular messenger. Preliminary research has highlighted the potential role of NAD+ in signaling between neurons, blood vessels, and even its potential role as a signaling molecule to allow for communication between nerves and the muscles they innervate<ref> Mutafova-Yambolieva VN, Sung JH, Hao X, et al. β-Nicotinamide adenine dinucleotide is an inhibitory neurotransmitter in visceral smooth muscle. Proc Natl Acad Sci U S A. 2007;104(41):16359-16364. </ref><ref> Smyth LM, Bobalova J, Mendoza MG, Lew C, Mutafova-Yambolieva VN. Release of β-nicotinamide adenine dinucleotide upon stimulation of postganglionic nerve terminals in blood vessels and urinary bladder. J Biol Chem. 2004;279(47):48893-48903. </ref>.

''NAD+ and sirtuins''

Another potentially relevant mechanism of action of NAD+ is that of its role as a cofactor for sirtuins. Sirtuins are enzymes that act in mitochondrial function and cellular aging. Because NAD+ is considered the rate-limiting substrate for reactions involving sirtuins, significant attention has been placed on modulating its levels to influence the downstream effects through sirtuin-mediated reactions<ref name="imai2013" /><ref name="csiszar2009">Csiszar A, Labinskyy N, Jimenez R, et al. Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: Role of circulating factors and SIRT1. Mech Ageing Dev. 2009;130(8):518-527. </ref><ref name="csiszar2008">Csiszar A, Labinskyy N, Podlutsky A, et al. Vasoprotective effects of resveratrol and SIRT1: Attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. Am J Physiol - Hear Circ Physiol. 2008;294(6):H2721-35. </ref>.<gallery>
File:Sirtuin.jpg|NAD+ and sirtuins
</gallery>

==Usage==

:''Main article: [[NMN usage]]''

NMN is present in several nutritional sources including avocados, cabbage, broccoli, and tomato. The total concentration from these food sources ranges from 0.25 – 1.5 mg NMN / 100 g food source<ref name="mills2016"> Mills KF, Yoshida S, Stein LR, et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016;24(6):795-806. </ref>. Once ingested, NMN is absorbed into the circulation. Recently, researchers identified a transporter which is crucial for intestinal absorption of NMN in mice, Slc12a8<ref name="mills2016" />. They showed that this transporter is specific for NMN and does not transport NAD+ or other precursors of nicotinic acid. Although this transporter may play a role in the human absorption of NMN as well, the corresponding human studies have not yet been carried out.

===Bioavailability===

Several studies have investigated the bioavailability of NMN in animal models<ref name="yoshino2011" /><ref name="mills2016" /><ref> Grozio A, Mills KF, Yoshino J, et al. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019;1(1):47-57. </ref>. One study of NMN pharmacokinetics in mice found that plasma levels of NMN increased significantly around 2-3 minutes following oral administration. Following this, plasma levels continued to increase through the following 5 - 10 minutes and then returned to baseline by 15 minutes<ref name="mills2016" />. Further investigation into the bioavailability of NMN using radiolabeled NMN showed that after initial absorption, NMN is quickly converted into biologically active NAD+, which then is rapidly transported to end-effect tissue such as muscle. This study revealed that at 10 minutes post administration, the radiolabeled NMN was only present in the liver and not muscle, but that by 30 minutes the concentrations of peripheral NAD+ had increased while the liver concentration had decreased<ref name="mills2016" />.
[[File:Nmn-graphics-charts-figure-6-1024x668.jpg|thumb|NMN administration increases NAD+ in 15 minutes in the liver in mice.]]

Little research has so far been done to examine the bioavailability or pharmacokinetics of NMN in humans. [https://pubmed.ncbi.nlm.nih.gov/31685720/ One recent study] examined the effects of NMN supplementation in 10 healthy adult volunteers. The researchers administered single oral doses of between 100mg to 500mg NMN. The researchers were not able to directly measure NMN levels in the blood (likely due to sample processing error), but they were able to show dose-dependent increases of two key NMN metabolites from administration through 300 minutes post administration.

===Supplementation===

Although NMN is found in small quantities in food sources, there is significant interest in supplementing NMN intake to boost its potential positive effects. Animal models have demonstrated improvements in several outcomes related to increased NMN intake, such as metabolism, insulin sensitivity and suppression of age-related weight gain<ref name="yoshino2011" /><ref name="mills2016" />. Although human supplements currently exist, little research has been done investigating the efficacy of human NMN supplementation.

===Medical uses===

NMN has been used as a so-called ‘nutraceutical’. Nutraceuticals are a class of supplement, which are essentially foods or compounds other than synthetic pharmaceuticals which are used for a supposed medicinal purpose. NMN’s purported role as a nutraceutical is based on significant animal research that demonstrated that supplementation was associated with increased longevity, primarily by fighting the age-related decline of the cell’s energy production and mitochondrial functioning. NMN has also been shown to be useful for reducing insulin resistance (the underlying problem in the most common form of a diabetes) in mice<ref name="mills2016" />.

==Effects==

:''See also: [[Health]]''

NMN has been shown to have a number of downstream effects in several animal-based studies.

:'''Decreased insulin resistance'''

Insulin resistance is a medically important condition, as this is the primary problem in type 2 or adult-onset diabetes, the most common form of diabetes. NMN supplementation has been shown to improve insulin resistance and promote insulin sensitivity via previously described mechanisms involving sirtuins, as well as by increasing the overall rate of NAD+ biosynthesis<ref name="yoshino2011" /><ref> Caton PW, Kieswich J, Yaqoob MM, Holness MJ, Sugden MC. Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function. Diabetologia. 2011;54(12):3083-3092. </ref>.

:'''Improved mitochondrial function'''

The mitochondria are the energy centers of cells and their overall decline with age is thought to be one of the primary mechanisms through which aging exerts its negative effects. Several studies have demonstrated the relationship between NMN supplementation and improved mitochondrial function in several different tissue types including skeletal muscle, the eye, and even blood vessels<ref> Uddin GM, Youngson NA, Sinclair DA, Morris MJ. Head to head comparison of short-term treatment with the NAD+ precursor nicotinamide mononucleotide (NMN) and 6 weeks of exercise in obese female mice. Front Pharmacol. 2016;7(AUG). </ref><ref name="tarantini2019"> Tarantini S, Valcarcel-Ares MN, Toth P, et al. Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol. 2019;24. </ref><ref> Lin JB, Kubota S, Ban N, et al. NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice. Cell Rep. 2016;17(1):69-85. </ref>.

:'''Reduction of age-related DNA damage'''

Aging has been linked with DNA damage as well as premature telomere shortening. Previously studies have established the relationship between the effects of NMM and NAD+ on ADP-ribosylation, as they relate to DNA damage and telomere modification<ref name="bürkle2005" />. A recent study of NMN supplementation in mice found that NMN stabilized telomere length while reducing markers associated with DNA damage and improving markers related to mitochondrial functioning and liver damage<ref> Amano H, Chaudhury A, Rodriguez-Aguayo C, et al. Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease. Cell Metab. 2019;29(6):1274-1290.e9. </ref>.

:'''Rescue of age-related decline in female fertility'''

Additional research has also highlighted the potential effects of NMN supplementation on female oocyte viability and health. A recent animal study, published in the journal Cell Reports, showed that loss of oocyte quality with age was an NAD+ dependent process<ref>Michael Bertoldo AJ, Listijono DR, Jonathan Ho W-H, Sinclair DA, Homer HA, Wu LE. NAD+ Repletion Rescues Female Fertility during Reproductive Aging. Cell Rep. 2020;30.</ref>. The authors found that when they supplemented the animals with NMN, there was an increase in oocyte quality in aged female animals. The results also demonstrated that this improved quality was transferred to the resultant embryos, where NMN supplementation reversed the age-associated adverse effects on embryo viability and development. Based on these results, the authors concluded that NMN supplementation may offer an avenue to reverse age-related declines in female fertility in humans, although further studies are needed.

==Research==

:''See also: [[NMN research]]''

The studies that led to the recognition of NMN and NAD+ as biologically relevant compounds took place in the first half of the twentieth century. This initial research elucidated the role that these compounds played in reduction-oxidation reactions in cells and the importance of this pathway for diseases involving metabolism such as pellagra (a deficiency of nicotinic acid). This first ‘era’ of NMN studies helped researchers to understand the vital role that NMN plays in helping to promote cellular energy production, especially within the mitochondria.

More recently, in the 2000s, renewed interest in NMN began after scientists discovered the role that this compound plays in interacting with sirtuins, which are important for aging and mitochondrial functioning. This revitalization of interest in NMN and NAD+ has resulted in several animal studies which have reported on the potential benefits of NMN supplementation including: improved insulin sensitivity, improved mitochondrial functioning, and even a decrease in neuronal cell death in Alzheimer’s animal models<ref name="mills2016" /><ref name="tarantini2019" /><ref> Wang X, Hu X, Yang Y, Takata T, Sakurai T. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 2016;1643:1-9. </ref>.

Given the significant results that have been observed after NMN supplementation in animals, attention has turned to the potential effects of human supplementation. Recently, a study evaluating human NMN dosing concluded, demonstrating safety of several doses of oral NMN including 100 mg, 250 mg, and 500 mg doses19. After this first pilot study verifying the safety of oral NMN dosing in humans, further research studies attempting to verify beneficial effects in human trials are likely forthcoming.

Some key figures in NMN research today include [[David Sinclair]] and [[Shin-ichiro Imai]].

==Synthesis==
===Biosynthesis===

NMN is an intermediate in the eventual production of NAD+, which is the predominant biologically active compound. NAD+ can be synthesized biologically via three mechanisms. However, NMN is only involved in two of these pathways. The two pathways are 1) the nicotinamide salvage pathway and 2) the nicotinamide riboside (NR) pathway.

====Nicotinamide salvage pathway====

This pathway relies on the biological salvage of the nicotinamide compound. This is the most utilized pathway in mammalian cells and makes use of the byproducts of NAD+ breakdown<ref> Venter G, Oerlemans FTJJ, Willemse M, Wijers M, Fransen JAM, Wieringa B. NAMPT-Mediated Salvage Synthesis of NAD+ Controls Morphofunctional Changes of Macrophages. Dzeja P, ed. PLoS One. 2014;9(5):e97378. </ref>. In this pathway, the enzyme nicotinamide phosphoribosyltransferase catalyzes the transfer of a phosphoribosyl group from phosphoribosylpyrophosphate to nicotinamide to form NMN.

====Nicotinamide riboside pathway====

This pathway is less commonly utilized than the corresponding salvage pathway. Here, NMN is formed via the phosphorylation of NR by nicotinamide riboside kinase<ref> Bieganowski P, Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a preiss-handler independent route to NAD+ in fungi and humans. Cell. 2004;117(4):495-502. </ref>.

===In vitro synthesis===

The literature surrounding industrial synthetic production of NMN is currently sparse. One recent investigation showed a ‘proof of concept’ by utilizing Escherichia coli<ref> Marinescu GC, Popescu RG, Stoian G, Dinischiotu A. β-nicotinamide mononucleotide (NMN) production in Escherichia coli. Sci Rep. 2018;8(1):1-11. </ref>. The group reported that by utilizing plasmids that incorporated nicotinamide phosphoribosyl transferase, nicotinamide, and phosphoribosyl pyrophosphate synthetase, they were able to produce NMN at a yield of about 15 mg per 1 L of bacterial culture.

==Distribution==

:''Main article: [[NMN Products]]''

While the research concerning NMN and its potential benefits is ongoing, several companies have developed commercial products containing NMN.

==Notable users==
Notable users of NMN include:

[[David Sinclair]] is probably the best-known user of NMN. A professor of genetics at Harvard Medical School, Dr. Sinclair [https://fastlifehacks.com/david-sinclair-supplements/ reportedly] takes 1g of NMN daily, among other supplements.

Joe Rogan [https://jrelibrary.com/articles/joe-rogans-supplement-stack/ reportedly] began taking NMN supplements after he interviewed David Sinclair on his podcast in 2019.
==Legality==

:''Main article: [[Legality of NMN]]''

'''United States''' - NMN is legal as a dietary supplement, but without a designation as “Generally Regarded as Safe”.

'''United Kingdom''' - NMN containing products are currently available for sale within the UK.

'''Canada''' - Currently NMN is not available for sale in Canada. No company has been issued a Natural Products Number which would permit the sale of NMN in Canada.

'''Japan''' - NMN containing products are currently available for sale within Japan.

'''China''' - Several NMN containing supplements are currently available for sale in China.

'''Australia ''' - NMN is currently available for sale in Australia.

==References==
<references />