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.
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
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
Nicotinamide riboside (NR)
Score 88 · Human NAD+ restoration
Nicotinamide mononucleotide (NMN)
Score 84 · Human NAD+ restoration
Trans-resveratrol
Score 62 · Human pathway signal
Metformin
Score 57 · Human pathway signal
Quercetin / isoquercetin
Score 39 · Preclinical direct
Curcumin
Score 30 · Preclinical indirect
Translation resolution
Human target engagement
Human pharmacology with direct or selective target evidence.
1 mapped candidate
Human pathway signal
Human biological signal consistent with the pathway, without clean selective target proof.
3 mapped candidates
Human NAD+ restoration
Human evidence for increasing NAD+ substrate availability; family-wide rather than isoform-selective.
2 mapped candidates
Preclinical direct
Direct enzyme/allosteric activation established in biochemical, cell, or animal systems.
6 mapped candidates
Preclinical indirect
Expression or upstream/downstream signaling evidence without clean direct activation.
2 mapped candidates
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+.
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.
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
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
NAD+ precursor
Best-supported broad sirtuin substrate support; intriguing direct SIRT5 signal.
7/7
coverage
strongest mode
3
primary reads
NAD+ precursor
Strong NAD+ restoration lever; family-wide support rather than a direct selective activator.
7/7
coverage
strongest mode
4
primary reads
Polyphenol / STAC candidate
Real sirtuin biology, but much messier than “direct SIRT1 activator” marketing implies.
2/7
coverage
strongest mode
4
primary reads
Magnolia lignan
Most compelling natural SIRT3-directed candidate, still preclinical for target engagement.
1/7
coverage
strongest mode
2
primary reads
Flavonoid SIRT6 modulator
Structurally validated SIRT6 allosteric modulation, with isoquercetin showing greater site selectivity in vitro.
2/7
coverage
strongest mode
2
primary reads
Anthocyanidin
A fascinating SIRT6 lead, not a clinically validated SIRT6 intervention.
1/7
coverage
strongest mode
1
primary reads
Polyphenol signaling modulator
Potential SIRT1/SIRT3 expression-signaling modulator; not a clean direct activator.
2/7
coverage
strongest mode
1
primary reads
AMPK / metabolic signaling
Indirect SIRT1-axis candidate, primarily through upstream metabolic signaling.
1/7
coverage
strongest mode
1
primary reads
Stilbene
More bioavailable than resveratrol, but weaker direct evidence for reliable human SIRT1 activation.
1/7
coverage
strongest mode
1
primary reads
Cross-isoform resolution
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.
| Candidate | Stage | SIRT1 | SIRT2 | SIRT3 | SIRT4 | SIRT5 | SIRT6 | SIRT7 |
|---|---|---|---|---|---|---|---|---|
Nicotinamide riboside (NR) consumer | HN | N | N | NE | N | DN | N | N |
Nicotinamide mononucleotide (NMN) consumer | HN | N | N | N | N | N | N | N |
Trans-resveratrol consumer | HP | D | D | — | — | — | — | — |
Honokiol consumer | PD | — | — | D | — | — | — | — |
Cyanidin / anthocyanidins consumer | PD | — | — | — | — | — | D | — |
Curcumin consumer | PI | E | — | E | — | — | — | — |
Berberine consumer | PI | E | — | — | — | — | — | — |
Pterostilbene consumer | HP | ? | — | — | — | — | — | — |
Metformin rx | HP | E | — | — | — | — | — | — |
Quercetin / isoquercetin 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 | — | — |
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
Restore the substrate
NR/NMN → NAD+ availability across the family.
Demand isoform evidence
Direct binding/activity beats pathway storytelling.
Demand human engagement
Blood/tissue target data beat cell-culture potency.
Separate mechanism from outcome
Activating a sirtuin is not proof of slower human aging.
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.