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 [Verdin](http://science.sciencemag.org/content/350/6265/1208.long). Proteins on this pathway have targeted assays available via the [CPTAC Assay Portal](https://assays.cancer.gov/available_assays?wp_id=WP3630). f2f Identifier of Olaparib (known approved PARP inhibitor) a72 c17 classic metabolic pathway PW:0000002 Pathway Ontology 16628003 PubMed Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage. Cell Cycle 2006 Kolthur-Seetharam U Dantzer F McBurney MW de Murcia G Sassone-Corsi P Sirtuin mediated pathway PW:0002584 Pathway Ontology ataxia telangiectasia DOID:12704 Disease 26785480 PubMed NAD⁺ in aging, metabolism, and neurodegeneration. Science 2015 Verdin E xeroderma pigmentosum DOID:0050427 Disease 19470756 PubMed SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1. Mol Cell Biol 2009 Rajamohan SB Pillai VB Gupta M Sundaresan NR Birukov KG Samant S Hottiger MO Gupta MP aging pathway PW:0000651 Pathway Ontology Cockayne syndrome DOID:2962 Disease