Difference between revisions of "Sirtuins"

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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.
 
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.
  
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SIRT6 also plays a role in maintaining genome stability thereby suppressing gene activity, along with SIRT1 and SIRT7.<ref name=":02">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>
 +
 +
SIRT6 plays a role in cellular aging, or senescence, through regulating genes involved in cellular aging.<ref name=":02" />
 
===SIRT7===
 
===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>
 
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>
 +
 +
SIRT7 plays a role in maintaining genome stability by suppressing gene activity, along with SIRt1 and SIRT6.<ref name=":04">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>
  
 
==Research==
 
==Research==
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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.
 
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.
 +
 +
The use of nicotinamide adenine dinucleotide (NAD+)-boosting molecules, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), also constitute a way to improve sirtuin function. Since the actions of sirtuins depend on availability of NAD+ and since NAD+ levels decrease with age, some have started taking NMN and NR to boost sirtuin function by increasing NAD+ levels.
 
 
−
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.
+
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. Some of these functional foods include green vegetables, soy foods such as tofu, green tea, olive oil, and turmeric.
  
 
==Further reading==
 
==Further reading==

Latest revision as of 21:27, 5 June 2020

Sirtuins
Nicotinamide mononucleotide
Background
AliasesSIRT
ClassProtein
FunctionsDNA repair, genome stability, cellular senescence

Sirtuins are 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

Sirtuin Activity Function in aging
SIRT1 ADP-ribosyl-transferase

Deacetylase

Lifespan extension

DNA repair Cell cycle arrest Cellular senescence Cell cycle regulation Mitochondrial function Oxidative 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

[1]


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.[2] 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.[3] SIRT1 levels also decrease with age in liver cells, mostly due to lower NAD+ availability.[4] 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.[5] The mice without SIRT1 are sterile, smaller than normal, and develop slower compared to normal mice.[6]

Located in the nucleus of cells and outside the nucleus, the cytoplasm, SIRT1 suppresses gene activity with stabilizing the organization of DNA, the chromatin structure. SIRT1 also functions to promote DNA repair at damaged regions of DNA.[1]

SIRT2

SIRT2 levels may be a marker of obesity. In obese individuals, the levels of the protein drops in fat tissue.[7] In mice undergoing calorie restriction, SIRT2 levels increase in white fat tissue and kidneys.[8]

SIRT2 can also serve as a marker of cellular aging, also termed "cellular senescence." It was shown levels of SIRT2 increased in senescent cells. This effect was attributed to the occurrence of aging, senescence, rather than constituting a cause of aging[9]

SIRT3

Evidence suggests that SIRT3 plays a role in human longevity.[10] A particular gene marker in the SIRT3 gene, a polymorphism, is found more often in people who live longer.[11] Mice lacking SIRT3 have decreased oxygen consumption and increased markers of cellular stress, reactive oxygen species.[12]

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.[13] Three weeks after birth, these mice exhibit premature aging and degeneration, which results in death around the fourth week of life.[14] Mice without SIRT6 are also smaller than ‘normal’ individuals.

SIRT6 also plays a role in maintaining genome stability thereby suppressing gene activity, along with SIRT1 and SIRT7.[15]

SIRT6 plays a role in cellular aging, or senescence, through regulating genes involved in cellular aging.[15]

SIRT7

Mice lacking SIRT7 age prematurely and have heart complications, lethal heart hypertrophy.[16]

SIRT7 plays a role in maintaining genome stability by suppressing gene activity, along with SIRt1 and SIRT6.[17]

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)</ref>.

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.[18] 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.[19] Increasing SIRT1 and SIRT6 gene expression through over-expression suppresses cellular senescence.[20] 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.[21] 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.[22] 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 [23].

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.[24] The first study of the longevity enhancing effects of SIR2 occurred approximately 20 years ago in yeast.[25] 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%. [26] 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. [27] 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.[28]

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.[29] Sirtuin-activating compounds derived from plants include flavones, stilbenes, chalcones, and anthocyanidins can directly activate SIRT1.[30] Other agents reported to have anti-aging effects through modulating the SIRT1 cellular pathway include resveratrol,[31] cilostazol,[32] paeonol,[33] statins,[34] hydrogen sulfide,[35] and persimmon.[36] Polyphenols, including curcumin, can also modulate sirtuins.[37] 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.[38] Natural anti-aging compounds also include quercetin, butein, fisetin, kaempferol, catechins, and proanthocyanidins.[39] Some traditional Chinese medicines have natural compounds with potent SIRT1-activating effects.[40] Activating sirtuins through the regulation of NAD+ levels offers an alternative method of stimulating sirtuin function.

The use of nicotinamide adenine dinucleotide (NAD+)-boosting molecules, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), also constitute a way to improve sirtuin function. Since the actions of sirtuins depend on availability of NAD+ and since NAD+ levels decrease with age, some have started taking NMN and NR to boost sirtuin function by increasing NAD+ levels.

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. Some of these functional foods include green vegetables, soy foods such as tofu, green tea, olive oil, and turmeric.

Further reading

  1. ↑ 1.0 1.1 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Anwar T, Khosla S, Ramakrishna G. Increased expression of SIRT2 is a novel marker of cellular senescence and is dependent on wild type p53 status. Cell Cycle. 2016;15(14):1883–1897.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 15.0 15.1 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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.
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