Sirtuin activation, PARP-mediated DNA repair, and NRF2 antioxidant signaling share more biology than their names suggest — NAD+ fuels the first two, and glutathione status underwrites the third. Here are TNiC's highest-conviction picks for each, and the mechanistic reason each one made the list.
What this is
TNiC's highest-conviction compound picks across three overlapping pathways — sirtuin activation, PARP/DNA-repair support, and NRF2 antioxidant signaling.
Why it matters
The same NAD+ pool fuels both sirtuins and PARP, and NRF2 activation both switches on antioxidant genes and reduces the DNA damage those repair pathways face — picks here reflect that shared biology instead of treating each pathway in isolation.
What to do next
Open a pick to read its full compound module, then check the Systems Map for how these pathways interact with the rest of the hallmarks.
Sirtuins are NAD+-dependent deacetylases that regulate DNA repair, mitophagy, and inflammatory gene expression — the closest known molecular mimic of caloric restriction. Two different strategies show up here: supplying more NAD+ substrate, or activating SIRT1 directly.
NAD+ is the obligate substrate every one of the seven sirtuins runs on — restoring NAD+ supply is a more complete lever than activating SIRT1 alone, and NMN has the deepest human RCT base of any NAD+ precursor on this list.
The original SIRT1 allosteric activator — increases SIRT1 affinity for acetylated substrates 8–13×, deacetylating PGC-1α and FOXO3a to mimic caloric restriction. Bioavailability is the real limiting factor (~1% for standard powder).
Mechanistically identical to resveratrol at the SIRT1 level, but two methoxy groups instead of two hydroxyl groups mean far less intestinal glucuronidation — 4–5× higher plasma concentration per equivalent dose, plus added PPARα activation resveratrol lacks.
PARP1/2 repair DNA strand breaks and consume NAD+ to do it — the same NAD+ pool sirtuins draw from, which is exactly why chronically low NAD+ leaves both systems under-resourced at once. The second lever here is upstream: reducing the oxidative DNA damage that PARP has to repair in the first place.
Directly supplies the NAD+ that PARP1/2 consume during strand-break repair — the same restored pool that fuels sirtuins. This is substrate supply for the repair machinery itself, not an upstream antioxidant effect.
A different lever on the same hallmark: sulforaphane's KEAP1-NRF2 activation upregulates NQO1 and phase-II detox enzymes that shield DNA from oxidative adducts before they happen — lowering the repair burden PARP faces, rather than fueling the repair reaction directly.
NRF2 is the master transcription factor for the cell's antioxidant and detoxification response — normally held inactive by KEAP1 until a trigger causes its release. Once free, NRF2 switches on 200+ cytoprotective genes at once, which is why a single well-chosen activator outperforms most single-antioxidant strategies.
The most direct KEAP1-NRF2 activator on the list — covalently modifies KEAP1 cysteine residues, releasing NRF2 to the nucleus and switching on NQO1, GST, GCLC/GCLM, and HO-1. The clearest human RCT evidence of any NRF2 intervention here.
Restores the glutathione pool that directly protects the KEAP1-NRF2 switch itself from irreversible oxidation — supporting the sensor, not just the downstream genes it controls.
Feeds the same glutathione cycle from a different entry point — R-ALA regenerates GSH via its dihydrolipoic acid reduction, reinforcing the redox environment NRF2 signaling depends on.
Editorial synthesis from peer-reviewed literature already cited on each compound's evidence page — not a new evidence claim. See evidence tier grading for study-level detail.