88
NAD+ precursor
Best-supported broad sirtuin substrate support; intriguing direct SIRT5 signal.
SIRT1 NAD+
S1SIRT2 NAD+
S2SIRT3 NAD+
S3SIRT4 NAD+
S4SIRT5 Direct
S5SIRT6 NAD+
S6SIRT7 NAD+
S77/7
coverage
D
strongest mode
3
primary reads
TNiC Molecular Atlas · SIRT1–SIRT7
The Sirtuin Atlas
A high-resolution map of what actually activates, supports, or merely correlates with the seven human sirtuins — separating human target engagement from animal, cell, and marketing claims.
Evidence reviewed through August 2026 · Vector-native interactive edition · Educational, not medical advice
What this is
Seven NAD+-dependent regulatory enzymes tied to metabolism, stress response, genome maintenance, inflammation, proteostasis, and mitochondrial function.
Why it matters
“Sirtuin activator” is often used too loosely. The useful question is whether a compound directly activates an isoform, raises NAD+, changes expression, or only has a plausible association.
What to do next
Explore the network, inspect translation maturity, then use the evidence explorer and comparison console.
Evidence signal console
7
Human sirtuins
SIRT1 → SIRT7
14
Mapped candidates
Consumer + Rx + research
6
Human-stage candidates
Target, pathway or NAD+ data
5
Consumer direct leads
Direct ≠ proven anti-aging
17
High-confidence mappings
Target-level confidence flags
Direct answer
There is no OTC supplement proven to selectively activate SIRT1–SIRT7 in humans.
The most defensible consumer strategy is NAD+ restoration for family-wide substrate support, then isoform-specific candidates only where the evidence earns it.
Best broad lever
NR / NMN
Human NAD+ restoration. Not selective direct activation.
Best direct natural lead
Honokiol → SIRT3
Compelling direct/preclinical signal; human target engagement still missing.
Live target topology
01 Select isoform
02 Inspect biology
03 Compare target mode
04 Read primary evidence
SIRT1Nucleus ↔ cytosol
Metabolic + stress-response coordinator
9
mapped
2
direct
6
human-stage
Current best lever
SRT2104 has human pharmacology as a research SIRT1 activator. For consumer compounds, NAD+ precursors are the cleanest substrate-support strategy.
Core biological jobs
- PGC-1α / mitochondrial biogenesis
- FOXO stress signaling
- NF-κB inflammatory restraint
- DNA repair and circadian control
Evidence boundary
Resveratrol is not a universally direct SIRT1 switch. Activation is substrate-dependent in biochemical work, while the 2025 RCT meta-analysis found no significant overall increase in human SIRT1 gene, protein, or serum measures.
Mapped candidates
mode · confidenceSRT2104
Score 91 · Human target engagement
D
Nicotinamide riboside (NR) — open the NR (Nicotinamide Riboside) deep-dive
Score 88 · Human NAD+ restoration
N
Nicotinamide mononucleotide (NMN) — open the NMN (Nicotinamide Mononucleotide) deep-dive
Score 84 · Human NAD+ restoration
N
Trans-resveratrol — open the Trans-Resveratrol deep-dive
Score 62 · Human pathway signal
D
Metformin — open the Metformin deep-dive
Score 57 · Human pathway signal
E
Quercetin / isoquercetin — open the Quercetin deep-dive
Score 39 · Preclinical direct
E
Curcumin — open the Curcumin (Curcuminoids) deep-dive
Score 30 · Preclinical indirect
E
Translation resolution
Evidence maturity ladder
01
HTHuman target engagement
Human pharmacology with direct or selective target evidence.
1 mapped candidate
02
HPHuman pathway signal
Human biological signal consistent with the pathway, without clean selective target proof.
3 mapped candidates
03
HNHuman NAD+ restoration
Human evidence for increasing NAD+ substrate availability; family-wide rather than isoform-selective.
2 mapped candidates
04
PDPreclinical direct
Direct enzyme/allosteric activation established in biochemical, cell, or animal systems.
6 mapped candidates
05
PIPreclinical indirect
Expression or upstream/downstream signaling evidence without clean direct activation.
2 mapped candidates
Three claims worth fixing
01
NMN + resveratrol
Complementary ≠ required
NMN raises NAD+, which sirtuins consume. Resveratrol is a separate STAC/signaling candidate. NMN does not “activate resveratrol,” and NMN does not require resveratrol to restore NAD+.
02
Metformin
Indirect, not a SIRT1 agonist
Metformin can influence AMPK–NAD–SIRT1 signaling, but that is fundamentally different from binding SIRT1 and directly increasing catalytic activity.
03
Resveratrol
Substrate-dependent + clinically mixed
The mechanistic story is real but not universal. Human trials do not consistently show increased SIRT1, and direct activation depends on assay/substrate context.
Ranked target-engagement map
Evidence explorer
Search, filter, sort, inspect, and compare. Scores rank confidence in the claimed sirtuin mechanism, not overall longevity benefit, safety, or product quality.
9 results · 0/2 comparison slots
DNE?
84
NAD+ precursor
Strong NAD+ restoration lever; family-wide support rather than a direct selective activator.
SIRT1 NAD+
S1SIRT2 NAD+
S2SIRT3 NAD+
S3SIRT4 NAD+
S4SIRT5 NAD+
S5SIRT6 NAD+
S6SIRT7 NAD+
S77/7
coverage
N
strongest mode
4
primary reads
62
Polyphenol / STAC candidate
Real sirtuin biology, but much messier than “direct SIRT1 activator” marketing implies.
SIRT1 Direct
S1SIRT2 Direct
S2SIRT3 no mapped target
S3SIRT4 no mapped target
S4SIRT5 no mapped target
S5SIRT6 no mapped target
S6SIRT7 no mapped target
S72/7
coverage
D
strongest mode
4
primary reads
48
Honokiol
ConsumerPDMagnolia lignan
Most compelling natural SIRT3-directed candidate, still preclinical for target engagement.
SIRT1 no mapped target
S1SIRT2 no mapped target
S2SIRT3 Direct
S3SIRT4 no mapped target
S4SIRT5 no mapped target
S5SIRT6 no mapped target
S6SIRT7 no mapped target
S71/7
coverage
D
strongest mode
2
primary reads
39
Flavonoid SIRT6 modulator
Structurally validated SIRT6 allosteric modulation, with isoquercetin showing greater site selectivity in vitro.
SIRT1 Expression / signaling
S1SIRT2 no mapped target
S2SIRT3 no mapped target
S3SIRT4 no mapped target
S4SIRT5 no mapped target
S5SIRT6 Direct
S6SIRT7 no mapped target
S72/7
coverage
D
strongest mode
2
primary reads
36
Cyanidin / anthocyanidins
ConsumerPDAnthocyanidin
A fascinating SIRT6 lead, not a clinically validated SIRT6 intervention.
SIRT1 no mapped target
S1SIRT2 no mapped target
S2SIRT3 no mapped target
S3SIRT4 no mapped target
S4SIRT5 no mapped target
S5SIRT6 Direct
S6SIRT7 no mapped target
S71/7
coverage
D
strongest mode
1
primary reads
30
Polyphenol signaling modulator
Potential SIRT1/SIRT3 expression-signaling modulator; not a clean direct activator.
SIRT1 Expression / signaling
S1SIRT2 no mapped target
S2SIRT3 Expression / signaling
S3SIRT4 no mapped target
S4SIRT5 no mapped target
S5SIRT6 no mapped target
S6SIRT7 no mapped target
S72/7
coverage
E
strongest mode
1
primary reads
28
AMPK / metabolic signaling
Indirect SIRT1-axis candidate, primarily through upstream metabolic signaling.
SIRT1 Expression / signaling
S1SIRT2 no mapped target
S2SIRT3 no mapped target
S3SIRT4 no mapped target
S4SIRT5 no mapped target
S5SIRT6 no mapped target
S6SIRT7 no mapped target
S71/7
coverage
E
strongest mode
1
primary reads
24
Stilbene
More bioavailable than resveratrol, but weaker direct evidence for reliable human SIRT1 activation.
SIRT1 Uncertain
S1SIRT2 no mapped target
S2SIRT3 no mapped target
S3SIRT4 no mapped target
S4SIRT5 no mapped target
S5SIRT6 no mapped target
S6SIRT7 no mapped target
S71/7
coverage
?
strongest mode
1
primary reads
Cross-isoform resolution
SIRT1–SIRT7 mechanism matrix
A cell can contain more than one badge because the same candidate may provide NAD+ support while also carrying a separate direct or signaling claim for that isoform.
DDirectEvidence of direct enzyme activation or allosteric stimulation.
NNAD+Raises/provides NAD+, the required sirtuin cosubstrate; not isoform-selective.
EExpression / signalingChanges expression or upstream/downstream pathway signaling rather than clean direct activation.
?UncertainCommonly claimed or mechanistically plausible, but target engagement is not established.
| Candidate | Stage | SIRT1 | SIRT2 | SIRT3 | SIRT4 | SIRT5 | SIRT6 | SIRT7 |
|---|---|---|---|---|---|---|---|---|
consumer | HN | N | N | NE | N | DN | N | N |
consumer | HN | N | N | N | N | N | N | N |
consumer | HP | D | D | — | — | — | — | — |
Honokiol consumer | PD | — | — | D | — | — | — | — |
Cyanidin / anthocyanidins consumer | PD | — | — | — | — | — | D | — |
consumer | PI | E | — | E | — | — | — | — |
consumer | PI | E | — | — | — | — | — | — |
consumer | HP | ? | — | — | — | — | — | — |
rx | HP | E | — | — | — | — | — | — |
consumer | PD | E | — | — | — | — | D | — |
SRT2104 research | HT | D | — | — | — | — | — | — |
MDL-800 research | PD | — | — | — | — | — | D | — |
UBCS039 research | PD | — | — | — | — | — | D | — |
1,4-dihydropyridine SIRT3/5 activators research | PD | — | — | D | — | D | — | — |
Important interpretation rule
Sirtuins are not universally “more is better.” Their effects are tissue-, substrate-, disease-, dose-, and context-dependent. Several family members can be protective in one setting and harmful in another, especially in cancer biology.
The practical hierarchy
- 01
Restore the substrate
NR/NMN → NAD+ availability across the family.
- 02
Demand isoform evidence
Direct binding/activity beats pathway storytelling.
- 03
Demand human engagement
Blood/tissue target data beat cell-culture potency.
- 04
Separate mechanism from outcome
Activating a sirtuin is not proof of slower human aging.
Primary reading set
Core sources used to calibrate the atlas. Candidate cards contain additional study-level citations.
The sirtuin family in health and disease
PMID 36581622 · 2022
Meta-analysis: resveratrol and human SIRT1
PMID 40158656 · 2025
NR activates SIRT5 deacetylation
PMID 37289138 · 2023
Honokiol activates SIRT3
PMID 25871545 · 2015
Natural polyphenols as SIRT6 modulators
PMID 29515203 · 2018
MDL-800 as a selective SIRT6 activator
PMID 30374165 · 2018
Quercetin / isoquercetin SIRT6 structural activation
PMID 31844103 · 2019
Metformin and human SIRT1 activity
PMID 25921843 · 2015
SRT2104 in elderly volunteers
PMID 23284689 · 2013
TNiC evidence rule: “Direct activator,” “NAD+ support,” “expression/signaling,” and “translation stage” are intentionally separate. A compound only moves up the hierarchy when target engagement is demonstrated in increasingly relevant systems.
Mechanism → target → translation → outcome
Where this connects
The sirtuin layer, and what sits either side of it.
Sirtuin activity is one mechanism among several. These are the compounds the atlas scores that have a full evidence module, the pathways this layer belongs to, and the hallmarks of aging those pathways act on.
Scored here, with a deep-dive