They remove acetyl groups from lysine residues on proteins, altering how those proteins interact with other molecules.

Why do they need NAD+?

It is chemically unnecessary for the reaction. Requiring it couples the enzyme's activity to the cell's metabolic state — a sensing mechanism.

Is NAD+ recycled in the reaction?

No. It is consumed as a co-substrate, which is why sirtuin activity draws down the pool.

NAD+

Enzymes That Consume a Cofactor Rather Than Recycling It

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-233 cited sources

Sirtuins are deacetylases that remove acetyl groups from proteins, and they require NAD+ as a co-substrate rather than a recycled cofactor. Because the reaction consumes NAD+, sirtuin activity is coupled to how much of it the cell has.

Key facts

Function: Protein deacetylation
Requires: NAD+ as a co-substrate
NAD+ is: Consumed, not recycled
Distinguishes them from: Other deacetylase families
Mechanism review: Sauve 2012 (PMID 23102634)
SIRT1 and inflammation: Yang 2022 (PMID 35359990)

What deacetylation does

Acetyl groups attached to lysine residues neutralise the positive charge those residues carry, which changes how a protein interacts with other molecules. On histones this alters how tightly DNA is packaged and therefore what can be transcribed. Adding and removing acetyl groups is a general regulatory switch, not a specialised one.

Why sirtuins are unusual among deacetylases

Most deacetylases simply hydrolyse the acetyl group off, requiring no cofactor. Sirtuins do not. They require NAD+ and consume it in the reaction, which is chemically unnecessary for removing an acetyl group. Sauve reviewed the mechanism in Current Opinion in Chemical Biology in 2012.

Research material referenced

NAD+ 500mg — third-party HPLC tested

View — £49.99

What that requirement achieves

It couples the enzyme to metabolic state. An enzyme requiring nothing works whenever its substrate is present. An enzyme requiring NAD+ works only when NAD+ is available, so its activity reports on the cell's metabolic condition. The cofactor requirement is a sensing mechanism rather than a chemical necessity.

Why this is the source of the ageing interest

If NAD+ declines with age and sirtuin activity depends on NAD+, then sirtuin activity would decline too. That is the chain of reasoning connecting this enzyme family to the ageing literature. Each link is plausible and the chain is longer than it is usually presented as being.

Where sirtuins act

Different family members occupy different compartments and act on different substrates — nuclear, mitochondrial and cytosolic. Yang and colleagues reviewed SIRT1 specifically and its roles in inflammation in Frontiers in Immunology in 2022. Treating the family as one enzyme obscures that they do different jobs in different places.

What is not claimed

That supplying NAD+ or its precursors increases sirtuin activity or produces any effect in any person. This describes enzyme biochemistry. Material supplied here is for laboratory research only, and this category's regulatory article sets out why ageing language is the specific hazard.

Extended research context

The NAD+ deep dive

Deep dive: the compound in this catalogue that is not a peptide

NAD+ contains no amino acids and no peptide bonds. It is a dinucleotide - a nicotinamide nucleotide and an adenine nucleotide joined through a pyrophosphate bridge - which is the structural grammar of ATP and of RNA, not of a protein. It sits in a peptide catalogue because it reaches the same buyers, not because it belongs there. Saying so matters practically rather than pedantically: essentially all of the general handling guidance on this site is written for peptides and is the wrong guidance here. There is no sequence to verify, so purity by amino acid analysis is meaningless. There are no deletion sequences, because there is no stepwise coupling to produce them. Net peptide content, the figure that decides how much material a lyophilised peptide vial actually contains, has no analogue at all. Even the instruction that does carry over - dry, cold, dark - protects different chemistry, guarding glycosidic and pyrophosphate bonds rather than peptide bonds and methionine residues.

Deep dive: why the finished molecule is the least deliverable of the three

NAD+ carries two negatively charged phosphates and weighs 663.4 Da, and neither property is compatible with crossing a lipid bilayer. Extracellular NAD+ is also actively consumed: CD38 is an ectoenzyme with its active site facing outward, and Covarrubias and colleagues reported in Nature Metabolism in 2020 that senescent cells drive tissue NAD+ decline specifically by raising CD38 activity. Put those together and administered NAD+ is a molecule that cannot get in and is being degraded while it waits. Whatever follows most plausibly runs through its breakdown to smaller nicotinamide-containing species, which cells then take up and rebuild NAD+ from internally - which is to say, through exactly the precursors people otherwise take directly. This is why every substantial randomised trial in the field used nicotinamide riboside at 255.25 Da or nicotinamide mononucleotide at 334.22 Da rather than the coenzyme itself. The naming inverts the pharmacology: the finished molecule sounds like the most direct option and is the least.

Deep dive: good early evidence, and the gap that keeps getting closed rhetorically

The randomised human literature here is better than for most of this catalogue. NADPARK was a randomised phase I trial of nicotinamide riboside in Parkinson disease in Cell Metabolism. Orr and colleagues ran a randomised placebo-controlled study in older adults in GeroScience. Yoshino and colleagues published NMN and muscle insulin sensitivity in Science. These are real trials in real journals. What they measured, largely, is whether the intervention does what it is supposed to biologically - and raising a biomarker is not the same as changing an outcome. The step that gets taken rhetorically is from a decline that is real, through a mechanism that is identified, to a benefit that has not been demonstrated. Each link looks small; the chain is not. Nothing in this field approaches the scale of what settled the incretin questions, where TRIUMPH alone enrolled more than 5,800 participants with hard clinical endpoints.

Research applications

▸Cellular NAD+ metabolism and salvage pathway research
▸Sirtuin, PARP and CD38 enzyme activity studies
▸Redox biochemistry and NAD+/NADH ratio measurement
▸Cellular senescence and ageing biology research
▸Mitochondrial function and metabolic assay work
▸Comparative precursor uptake and conversion studies

Handling checklist

✓Verify against CID 5892, 663.4 Da, C21H27N7O14P2 - not by sequence
✓Do not apply peptide purity or net peptide content logic - neither exists here
✓Store lyophilised, cold, dry and protected from light
✓Prepare solutions fresh; nucleotide bonds hydrolyse readily in water
✓Be aware NAD+ and NADH are separately quantifiable oxidation states
✓Identity is confirmed by mass and chromatography against a reference standard

Common research-handling mistakes

Learnt from thousands of researcher orders across our UK labs.

✗ Applying peptide handling and purity guidance to NAD+

Fix: It is a dinucleotide with no peptide bonds. Sequence verification, protease concerns, disulfide chemistry and net peptide content are all inapplicable.

✗ Assuming administered NAD+ enters cells intact

Fix: Two negative phosphate charges and 663 Da prevent membrane crossing, and CD38 degrades it extracellularly. Effects most plausibly run through breakdown products.

✗ Reading precursor trial results as evidence for NAD+ itself

Fix: Every substantial randomised trial used NR or NMN. NAD+ has essentially no comparable human literature.

✗ Treating a biomarker increase as a demonstrated benefit

Fix: Raising NAD+-related markers is reasonably supported. Durable clinical outcome data does not exist.

✗ Taking a precursor's food supplement status as evidence of efficacy

Fix: Supplement frameworks assess safety for consumption, not efficacy, and permit no therapeutic claims.

Continue researching

Peer-reviewed guides, comparators and matched reference materials.

Frequently asked questions

What do sirtuins do?: They remove acetyl groups from lysine residues on proteins, altering how those proteins interact with other molecules.
Why do they need NAD+?: It is chemically unnecessary for the reaction. Requiring it couples the enzyme's activity to the cell's metabolic state — a sensing mechanism.
Is NAD+ recycled in the reaction?: No. It is consumed as a co-substrate, which is why sirtuin activity draws down the pool.

Primary sources & clinical trials

Peer-reviewed research and registered trials from PubMed, ClinicalTrials.gov, PubChem, FDA and NIH. All links open in a new tab and point to the primary source, so every claim can be verified at origin.

Written and reviewed by

Jack Muncaster · Founder, UK Peptides

Jack founded UK Peptides in Manchester after repeatedly receiving research compounds with missing or recycled paperwork. He is responsible for supplier selection, batch release decisions and the content published in this research library. Every article here is sourced to primary literature and every product page to a signed third-party certificate.

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