NAD metabolism, sirtuins and aging (WP3630)

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. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP3630 CPTAC Assay Portal]
last edited

Authors

Khanspers, Susan, AlexanderPico, Jmelius, Mkutmon, MaintBot, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: Sirtuin mediated pathway aging pathway classic metabolic pathway

Participants

Label Type Compact Identifier
PARP1 GeneProduct ensembl:ENSG00000143799
TFAM GeneProduct ensembl:ENSG00000108064
NFKB1 GeneProduct ensembl:ENSG00000109320
Nicotinamide riboside Metabolite hmdb:HMDB0000855
NAMPT GeneProduct ensembl:ENSG00000105835
P7C3 GeneProduct None
NAD Metabolite hmdb:HMDB0000902
Resveratrol Metabolite cas:501-36-0
FOXO1 GeneProduct ensembl:ENSG00000150907
HIF1A GeneProduct ensembl:ENSG00000100644
SIRT1 GeneProduct ensembl:ENSG00000096717
ROS1 GeneProduct ensembl:ENSG00000047936
FOXO3 GeneProduct ensembl:ENSG00000118689
TFAM GeneProduct ensembl:ENSG00000108064
TORC2 GeneProduct ensembl:ENSG00000108064
PPARG GeneProduct ensembl:ENSG00000132170
PARP inhibitors Metabolite chebi:83766
SIRT3 GeneProduct ensembl:ENSG00000142082

References

  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 Apr;5(8):873–7. PubMed Europe PMC Scholia
  2. Rajamohan SB, Pillai VB, Gupta M, Sundaresan NR, Birukov KG, Samant S, et al. SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1. Mol Cell Biol. 2009 Aug;29(15):4116–29. PubMed Europe PMC Scholia
  3. Verdin E. NAD⁺ in aging, metabolism, and neurodegeneration. Science. 2015 Dec 4;350(6265):1208–13. PubMed Europe PMC Scholia