NAD metabolism, sirtuins and aging (Homo sapiens)

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31, 2Possible therapeutic interventionIncreased inflammationHigh-fat dietCockayne syndromeDecreased insulin secretionInflammationDNA DamageAgingNAMPTP7C3TFAMNADNFKB1Nicotinamide ribosideHIF1AFOXO1ResveratrolPARP1SIRT1ROS1FOXO3PGC-1aTORC2PPARGPancreasXeroderma pigmentosumAtaxia telangiectasiaPARP inhibitorsSIRT3BrainSkeletal muscleLiverDecreased cognitive functionDecreased mitochondrial functionDecreased insulin sensitivity DepletionDeacetylation


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

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  1. Verdin E; ''NAD⁺ in aging, metabolism, and neurodegeneration.''; Science, 2015 PubMed Europe PMC Scholia
  2. 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 Scholia
  3. 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 Scholia


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106745view13:22, 17 September 2019MaintBotHMDB identifier normalization
106655view21:16, 12 September 2019KhanspersModified description
105656view05:15, 10 August 2019KhanspersModified description
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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
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External references


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NameTypeDatabase referenceComment
FOXO1GeneProductENSG00000150907 (Ensembl)
FOXO3GeneProductENSG00000118689 (Ensembl)
HIF1AGeneProductENSG00000100644 (Ensembl)
NADMetaboliteHMDB00902 (HMDB)
NAMPTGeneProductENSG00000105835 (Ensembl)
NFKB1GeneProductENSG00000109320 (Ensembl)
Nicotinamide ribosideMetaboliteHMDB00855 (HMDB)
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

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