NAD metabolism, sirtuins and aging (Homo sapiens)

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31, 2Decreased insulin secretionPossible therapeutic interventionHigh-fat dietIncreased inflammationCockayne syndromeInflammationDNA DamageAgingNADP7C3FOXO1Nicotinamide ribosidePARP1HIF1ANAMPTTFAMResveratrolNFKB1SIRT1ROS1FOXO3PGC-1aTORC2PPARGPancreasXeroderma pigmentosumAtaxia telangiectasiaPARP inhibitorsSIRT3BrainSkeletal muscleLiverDecreased cognitive functionDecreased mitochondrial functionDecreased insulin sensitivity DepletionDeacetylation


Description

A model for DNA damage, inflammation, NAD+, and aging. 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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Ontology Terms

 

Bibliography

  1. Kolthur-Seetharam U, Dantzer F, McBurney MW, de Murcia G, Sassone-Corsi P; ''Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage.''; Cell Cycle, 2006 PubMed Europe PMC
  2. Rajamohan SB, Pillai VB, Gupta M, Sundaresan NR, Birukov KG, Samant S, Hottiger MO, Gupta MP; ''SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1.''; Mol Cell Biol, 2009 PubMed Europe PMC
  3. Verdin E; ''NAD⁺ in aging, metabolism, and neurodegeneration.''; Science, 2015 PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
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

External references

DataNodes

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NameTypeDatabase referenceComment
FOXO1GeneProductENSG00000150907 (Ensembl)
FOXO3GeneProductENSG00000118689 (Ensembl)
HIF1AGeneProductENSG00000100644 (Ensembl)
NADMetaboliteHMDB00902 (HMDB)
NAMPTGeneProductENSG00000105835 (Ensembl)
NFKB1GeneProductENSG00000109320 (Ensembl)
Nicotinamide ribosideMetaboliteHMDB00855 (HMDB)
P7C3GeneProduct
PARP inhibitorsMetaboliteCHEBI:83766 (ChEBI) Identifier of Olaparib (known approved PARP inhibitor)
PARP1GeneProductENSG00000143799 (Ensembl)
PGC-1aGeneProductENSG00000108064 (Ensembl)
PPARGGeneProductENSG00000132170 (Ensembl)
ROS1GeneProductENSG00000047936 (Ensembl)
ResveratrolMetabolite501-36-0 (CAS)
SIRT1GeneProductENSG00000096717 (Ensembl)
SIRT3GeneProductENSG00000142082 (Ensembl)
TFAMGeneProductENSG00000108064 (Ensembl)
TORC2GeneProductENSG00000108064 (Ensembl)

Annotated Interactions

No annotated interactions

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