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Pillar 2: Sirtuins & Gene Regulation | Longevity Protocol
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The Longevity Protocol · Pillar Two
Pillar Two of Five

Sirtuins &Gene Regulation

The seven NAD+-dependent enzymes most studied in longevity biology. What SIRT1–SIRT7 do, how they depend on NAD+ to function, and why resveratrol and pterostilbene are studied in this context.

10 min read 8 studies cited Not health claims
The Fundamentals

What are sirtuins?

Sirtuins are a family of seven NAD+-dependent deacetylase enzymes — they remove acetyl groups from target proteins in a chemical reaction that consumes NAD+. Seven sirtuins have been identified in humans, named SIRT1 through SIRT7, each with distinct cellular locations and biological functions.

The connection between sirtuins and longevity biology was established in landmark research published in 2000, which linked sirtuin activity to lifespan extension in model organisms. This triggered a wave of research that has made sirtuins one of the most studied enzyme families in ageing biology over the past two decades.

Sirtuins regulate an extraordinarily wide range of cellular processes — gene expression, DNA repair, metabolic regulation, mitochondrial function and stress responses. They are sometimes described as "longevity genes" — though this is a simplification of a complex biology. What is accurate is that sirtuin activity is directly tied to NAD+ availability, and NAD+ declines with age, creating a direct mechanistic link between NAD+ metabolism and sirtuin function.

Sirtuins require NAD+ to function. As NAD+ declines with age, sirtuin activity is directly constrained.
7
Sirtuin enzymesidentified in humans
2000
Landmark researchlinking sirtuins to longevity
NAD+
Required substratefor all sirtuin activity
SIRT1
Most studiedprimary resveratrol target
The Critical Connection

Sirtuins and NAD+

The relationship between sirtuins and NAD+ is not incidental — it is mechanistic. Sirtuins are NAD+-dependent deacetylase enzymes. The chemical reaction they catalyse — removing acetyl groups from target proteins — consumes NAD+ as a co-substrate. Without NAD+, the reaction cannot proceed. This means sirtuin activity is directly coupled to cellular NAD+ levels.

This mechanistic link is why the documented decline of NAD+ with age has such significant implications for sirtuin biology. As NAD+ falls — driven by PARP activation, CD38 expression and reduced biosynthesis (covered in Pillar 1) — the availability of the substrate sirtuins need to function is progressively reduced.

This is also the research rationale for the combination of NAD+ precursors and sirtuin-pathway polyphenols like resveratrol. The logic: if sirtuins require NAD+ to function, and resveratrol activates sirtuins, then having adequate NAD+ available is prerequisite to sirtuin activation. Supplementing an NAD+ precursor alongside a sirtuin activator addresses both sides of this equation.

The NAD+ — Sirtuin Activation Pathway
NMN
→
NAD+ ↑
→
Sirtuin substrate available
Resveratrol / Pterostilbene
→
SIRT1 activation signal
NAD+ (substrate)
+
SIRT1 activation
→
Sirtuin deacetylase activity
This describes the research rationale — not a health claim for any food supplement product.
The research rationale: resveratrol activates sirtuins, but sirtuins need NAD+ to function. Supporting both simultaneously is the basis of the NMN + resveratrol combination in published research.
The Seven Sirtuins

SIRT1 through SIRT7

Each of the seven sirtuins has a distinct cellular location and distinct biological functions. The following summarises what published research has documented about each — not health claims, but accurate descriptions of their known biology.

S1
SIRT1
Nuclear · Most studied
The most extensively studied sirtuin in longevity biology. Regulates gene expression through histone deacetylation, metabolic pathways, DNA repair coordination and stress responses. The primary target of resveratrol research. SIRT1 activity has been most directly linked to longevity-related biology in published research.
Primary resveratrol target
S2
SIRT2
Cytoplasmic
Located primarily in the cytoplasm. Involved in cell cycle regulation, cytoskeletal organisation and metabolic regulation. Translocates to the nucleus during specific cellular events. Published research has explored its role in neurological contexts.
S3
SIRT3
Mitochondrial
Located in the mitochondria — the cell's energy-producing organelles. Involved in mitochondrial metabolism, energy production regulation and oxidative stress management. Closely connected to the mitochondrial health pillar. One of the most studied mitochondrial sirtuins.
Covered in Pillar 3
S4
SIRT4
Mitochondrial
Located in the mitochondria. Involved in fatty acid oxidation regulation and amino acid metabolism. Has ADP-ribosyltransferase activity in addition to deacetylase activity. Published research has explored its role in metabolic regulation and cellular stress responses.
S5
SIRT5
Mitochondrial
Located in the mitochondria. Has desuccinylase and demalonylase activity in addition to deacetylase function. Involved in metabolic regulation and detoxification processes. Published research has explored its role in cellular metabolism under stress conditions.
S6
SIRT6
Nuclear · DNA Repair
Located in the nucleus. Involved in DNA repair, telomere maintenance and metabolic regulation. Published research has explored SIRT6's role in genomic stability and its connection to ageing biology — SIRT6-deficient mice show accelerated ageing phenotypes in published studies.
Genomic stability
S7
SIRT7
Nucleolar
Located in the nucleolus. Involved in ribosomal RNA transcription regulation and DNA damage response. The least studied of the seven sirtuins. Published research has begun to document its role in cellular stress responses and metabolic regulation. Active area of ongoing research.
The Sirtuin Polyphenols

Resveratrol & Pterostilbene

Two stilbenoid polyphenols have been most extensively studied in the sirtuin research context: resveratrol and pterostilbene. Both are found in plants — resveratrol in red grapes and Japanese knotweed, pterostilbene in blueberries and grapes. Both have been studied in relation to SIRT1 activation. They are distinct compounds with different structures, different bioavailability profiles and different research histories.

Trans-Resveratrol
Stilbenoid Polyphenol · 2 hydroxyl groups
Extensively studied
Primary research focus
SIRT1 activation — published research from 2003 onwards
Natural sources
Red grape skin, Japanese knotweed (Polygonum cuspidatum), peanuts
Active isomer
Trans-resveratrol — the biologically relevant form used in research
Oral bioavailability
Lower than pterostilbene — rapidly metabolised
Research base
Extensive — one of the most studied polyphenols in science
Vitality purity
98% trans-isomer · 600mg per serving · verified every batch
Pterostilbene
Stilbenoid Polyphenol · 2 methoxy groups
~4x bioavailability
Primary research focus
SIRT1 pathway · metabolic regulation · antioxidant activity
Natural sources
Blueberries, grapes, Indian kino tree (Pterocarpus marsupium)
Structural difference
Two methoxy groups instead of hydroxyl groups — enhances lipophilicity
Oral bioavailability
~4x higher than resveratrol — documented in published pharmacokinetic studies
Research base
Growing — smaller than resveratrol but active research
Vitality
50mg per serving in NMN Complete 1350mg

Which is better? Resveratrol and pterostilbene are not directly comparable — they are distinct compounds. Resveratrol has a far larger published research base. Pterostilbene has documented higher oral bioavailability. Some researchers prefer pterostilbene for this reason. Vitality Supplements provides both: resveratrol in NMN + Trans-Resveratrol 1100mg, and pterostilbene in NMN Complete 1350mg.

As food supplement ingredients, neither has an authorised health claim under UK regulations.

Published Research

Key sirtuin research

The following summarises landmark published research in sirtuin biology. These are descriptions of what research has documented — not health claims for any food supplement product.

Landmark 2000
Sirtuins and lifespan extension in model organisms
Landmark research published in 2000 documented that sirtuin activation extended lifespan in model organisms. This finding triggered the modern era of sirtuin longevity research and established the link between sirtuin activity and ageing biology that has driven research for over two decades.
Landmark 2003
Resveratrol activates SIRT1
Published research documented that resveratrol activates SIRT1 — the NAD+-dependent sirtuin most associated with longevity biology. This finding connected plant polyphenol research with sirtuin biology and triggered extensive subsequent research into resveratrol as a potential longevity compound.
Human Research
SIRT1 and metabolic regulation in humans
Multiple peer-reviewed human studies have explored SIRT1 activity and its relationship to metabolic regulation, insulin sensitivity and inflammatory markers. The research base for SIRT1 in human biology is substantial — it is one of the most studied enzymes in human longevity research contexts.
Pharmacokinetic Research
Pterostilbene bioavailability — ~4x higher than resveratrol
Published pharmacokinetic research documented that pterostilbene has approximately 4x higher oral bioavailability than resveratrol in comparative studies. The structural difference — two methoxy groups vs two hydroxyl groups — results in greater lipophilicity and reduced first-pass metabolism for pterostilbene.
FAQ

Common questions

Sirtuins are seven NAD+-dependent deacetylase enzymes (SIRT1–SIRT7) present in all human cells. They regulate gene expression, DNA repair, metabolic function and stress responses. They require NAD+ to function — meaning sirtuin activity is directly coupled to NAD+ availability. As NAD+ declines with age, sirtuin activity is progressively constrained. This mechanistic link is why sirtuin research is central to longevity biology.
Sirtuins catalyse a chemical reaction — deacetylation of target proteins — that uses NAD+ as a co-substrate. The NAD+ molecule is consumed in the reaction. Without adequate NAD+, the deacetylase reaction cannot proceed. This makes sirtuin activity directly dependent on cellular NAD+ levels, creating the mechanistic link between NAD+ metabolism and sirtuin function.
Resveratrol has been studied as an activator of SIRT1 — an NAD+-dependent enzyme. Since SIRT1 requires NAD+ to function, the research rationale for combining resveratrol with an NAD+ precursor like NMN is that sirtuin activation requires adequate NAD+ as substrate. This describes the published research rationale — not a health claim for any food supplement product. Read our full NMN and Resveratrol guide →
They are distinct compounds — not directly comparable. Resveratrol has a far larger published research base, including the landmark 2003 SIRT1 research. Pterostilbene has documented ~4x higher oral bioavailability. Some researchers prefer pterostilbene for the bioavailability advantage. Vitality Supplements provides resveratrol in NMN + Trans-Resveratrol 1100mg and pterostilbene in NMN Complete 1350mg . As food supplements, neither has an authorised health claim under UK regulations.
SIRT1 is a nuclear deacetylase enzyme that removes acetyl groups from target proteins, altering their function. Published research has documented SIRT1's involvement in regulating gene expression via histone deacetylation, metabolic regulation, DNA repair coordination and stress response pathways. It is the most extensively studied sirtuin and the primary research focus of resveratrol and related polyphenol studies in longevity biology.

Shop sirtuin-pathway supplement formulas

NMN + Trans-Resveratrol 1100mg · NMN Complete with Pterostilbene. UK manufactured. Every batch independently tested.

Shop NMN + Resveratrol → NMN Complete with Pterostilbene
Pillar 1: NAD+ & Cellular Energy Pillar 3: Mitochondrial Health
Related Guides

This page is part of The Vitality Longevity Protocol — an educational resource covering published peer-reviewed research. Not medical advice. All Vitality Supplements products are food supplements regulated under UK food supplement legislation — not medicines. Not intended to diagnose, treat, cure or prevent any disease. Consult a qualified healthcare professional before starting any supplement. Contact: info@vitality-supplements.co.uk