NAD metabolism, sirtuins and aging (Homo sapiens)

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Two key events, the activation of PARP by DNA damage and the decreased NAMPT expression associated with inflammation, lead to decreased SIRT1 and SIRT3 activity in the nucleus and mitochondria, respectively. Decreased SIRT1 activity is associated with further PARP activation and increased DNA damage. Decreased SIRT1 also leads to NF-kB activation and decreased FOXO3a activity, two factors that lead to increased inflammation. These contribute to the establishment of two parallel feed-forward self reinforcing loops that further accelerate the aging process. This process is initiated earlier and faster in patients with DNA damage repair defects (such as CS, XPA, and AT). Mitochondrial function is diminished as a result of decreased SIRT3 activity, leading to mitochondrial protein hyperacetylation, whereas decreased SIRT1 is associated with decreased TFAM (necessary for mitochondrial DNA replication and transcription) and decreased PGC-1a (necessary for mitochondrial biogenesis). Possible therapeutic interventions to restore NAD+ levels are illustrated for each of the key enzymes (red arrows). Based on fig 4 from http://science.sciencemag.org/content/350/6265/1208.long.
Two key events, the activation of PARP by DNA damage and the decreased NAMPT expression associated with inflammation, lead to decreased SIRT1 and SIRT3 activity in the nucleus and mitochondria, respectively. Decreased SIRT1 activity is associated with further PARP activation and increased DNA damage. Decreased SIRT1 also leads to NF-kB activation and decreased FOXO3a activity, two factors that lead to increased inflammation. These contribute to the establishment of two parallel feed-forward self reinforcing loops that further accelerate the aging process. This process is initiated earlier and faster in patients with DNA damage repair defects (such as CS, XPA, and AT). Mitochondrial function is diminished as a result of decreased SIRT3 activity, leading to mitochondrial protein hyperacetylation, whereas decreased SIRT1 is associated with decreased TFAM (necessary for mitochondrial DNA replication and transcription) and decreased PGC-1a (necessary for mitochondrial biogenesis). Possible therapeutic interventions to restore NAD+ levels are illustrated for each of the key enzymes (red arrows). Based on fig 4 from http://science.sciencemag.org/content/350/6265/1208.long.
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This pathway is part the [https://assays.cancer.gov/available_assays?wp_id=WP3630 CPTAC Assay Portal].</Comment>
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Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP3630 CPTAC Assay Portal]</Comment>
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   <BiopaxRef>f2f</BiopaxRef>
   <Graphics BoardWidth="1037.9999999999998" BoardHeight="642.0"/>
   <Graphics BoardWidth="1037.9999999999998" BoardHeight="642.0"/>

Revision as of 21:16, 12 September 2019

Error rendering pathway page

This revision of the pathway probably contains invalid GPML code. If this happens to the most recent revision, try reverting the pathway using the pathway history displayed below or contact the site administrators (see WikiPathways:About) to resolve this problem.

Pathway history

View all...
CompareRevisionActionTimeUserComment
106745view13:22, 17 September 2019MaintBotHMDB identifier normalization
106655view21:16, 12 September 2019KhanspersModified description
105656view05:15, 10 August 2019KhanspersModified description
94184view13:55, 25 August 2017Mkutmonadded missing metabolite identifier
92696view19:24, 28 June 2017Mkutmonremoved undefined xref
88178view16:25, 29 July 2016JmeliusOntology Term : 'classic metabolic pathway' added !
85545view23:30, 27 May 2016AlexanderPicoUpdated layout and groupings
85544view23:17, 27 May 2016AlexanderPicoQuick edit to datanode annotation or property
85530view18:53, 26 May 2016Khanspersfixed unconnected interactions
85439view20:40, 15 May 2016SusanQuick edit to datanode annotation or property
85406view05:09, 13 May 2016Khanspersinteractions
85394view05:35, 12 May 2016Khansperslayout
85393view05:32, 12 May 2016Khanspersadded literature references
85392view18:32, 11 May 2016Khanspersupdate to interactions
85236view23:18, 3 May 2016Khanspersadded identifier to reservatrol
85235view23:10, 3 May 2016KhanspersModified description
85234view23:07, 3 May 2016Khanspersoverhaul
85231view04:59, 3 May 2016KhanspersModified description
85230view04:57, 3 May 2016KhanspersModified description
85227view20:08, 2 May 2016Khanspersrearrange
84991view20:35, 4 April 2016KhanspersPeriodical save, work in progress
84988view20:25, 4 April 2016KhanspersNew pathway

Error details

exception 'Exception' with message 'Unable to convert to /var/www/wikipathways/images/8/8e/WP3630_prev.svg:
<BR>Status:1
<BR>Message:Exception in thread "main" java.lang.NullPointerException
	at org.pathvisio.core.Engine.getPathwayImporters(Unknown Source)
	at org.pathvisio.core.Engine.importPathway(Unknown Source)
	at org.pathvisio.core.util.Converter.main(Unknown Source)

<BR>Command:java -Xmx1024M -jar /var/www/wikipathways/wpi/bin/pathvisio_core.jar "/var/www/wikipathways" "/var/www/wikipathways/images/8/8e/WP3630_prev.svg" 2>&1<BR>' in /var/www/wikipathways/wpi/extensions/Pathways/Pathway.php:1255
Stack trace:
#0 /var/www/wikipathways/wpi/extensions/Pathways/Pathway.php(1227): Pathway::convertWithPathVisio(false, '/var/www/wikipa...')
#1 /var/www/wikipathways/wpi/extensions/Pathways/Pathway.php(1137): Pathway->saveConvertedByPathVisioCache('svg')
#2 /var/www/wikipathways/wpi/extensions/Pathways/PathwayPage.php(21): Pathway->updateCache('svg')
#3 [internal function]: renderPathwayPage(Object(Parser), '<?xml version="...', Object(StripState))
#4 /var/www/wikipathways/includes/Hooks.php(125): call_user_func_array('renderPathwayPa...', Array)
#5 /var/www/wikipathways/includes/parser/Parser.php(318): wfRunHooks('ParserBeforeStr...', Array)
#6 /var/www/wikipathways/includes/OutputPage.php(405): Parser->parse('<?xml version="...', Object(Title), Object(ParserOptions), true, true, 106655)
#7 /var/www/wikipathways/includes/OutputPage.php(391): OutputPage->addWikiTextTitle('<?xml version="...', Object(Title), true, true)
#8 /var/www/wikipathways/includes/OutputPage.php(500): OutputPage->addWikiTextTitleTidy('<?xml version="...', Object(Title), true)
#9 /var/www/wikipathways/includes/DifferenceEngine.php(313): OutputPage->addWikiTextTidy('<?xml version="...')
#10 /var/www/wikipathways/includes/DifferenceEngine.php(271): DifferenceEngine->renderNewRevision()
#11 /var/www/wikipathways/includes/Article.php(729): DifferenceEngine->showDiffPage(false)
#12 /var/www/wikipathways/includes/Wiki.php(437): Article->view()
#13 /var/www/wikipathways/includes/Wiki.php(59): MediaWiki->performAction(Object(OutputPage), Object(Article), Object(Title), Object(User), Object(WebRequest))
#14 /var/www/wikipathways/index.php(93): MediaWiki->initialize(Object(Title), Object(Article), Object(OutputPage), Object(User), Object(WebRequest))
#15 {main}
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