NAD methylation leak
Nicotinamide methyltransferase (NNMT)↓
Also searched as Nicotinamide methyltransferase (NNMT).
Every other node here either makes NAD+ or eats it. This one does neither, and that is exactly why it is easy to miss. It takes nicotinamide — the substrate the salvage pathway depends on — and methylates it out of circulation. The practical consequence is uncomfortable for the whole supply-side approach: raising the recycling enzyme cannot help if the material it recycles has already been tagged for disposal, and adding more precursor may simply feed the leak. It is preclinical, with no human intervention, but it is the reason a supply-only strategy can look sound on paper and disappoint in a body.
In depth
An enzyme that methylates nicotinamide and sends it toward excretion. It does not consume NAD+ — it removes the raw material before NAD+ can be made from it. Expression rises in fat and liver with age.
What drives it
Supports weight management increases it.
NNMT expression is upregulated in adipose and liver tissue with adiposity: in high-fat-diet mice NNMT rises in both tissues, and greater obesity propensity correlates with higher adipose NNMT expression and activity. Human relevance is measured, not inferred: in people with type 2 diabetes, insulin sensitivity is inversely correlated with adipose-tissue NNMT expression and with circulating 1-methylnicotinamide. association in humans, causation in mice. PMC11622326 ; Chini 2024 Aging Cell. doi 10.1111/acel.13920 · PMC11622326
What it drives
It reduces Cellular fuel.
The leak, and it is not a consumer at all. NNMT methylates nicotinamide, diverting the salvage pathway’s own substrate toward excretion instead of recycling. Raising NAMPT cannot help if the nicotinamide it needs has already been methylated away. Expression rises in adipose tissue and liver with age. preclinical; no human NNMT intervention exists. Chini 2024, Aging Cell, doi 10.1111/acel.13920 / PMC10776128 — NAD metabolism: role in senescence regulation and aging. doi 10.1111/acel.13920 · PMC10776128
It reduces Universal methyl donor.
NNMT consumes S-adenosylmethionine as the methyl donor for every nicotinamide it methylates. doi 10.1002/advs.202502727
It increases Homocysteine.
SAM consumption yields S-adenosylhomocysteine, which is hydrolyzed to homocysteine. doi 10.3389/fphar.2024.1410479
It reduces DNA methylation.
Lowering the SAM to SAH ratio reduces methyltransferase activity on DNA and histones. PMID 23455543
It increases Fat-cell formation↓.
NNMT knockdown in adipose tissue protects against fat accretion, indicating a permissive role in adipogenesis. doi 10.1038/s41598-023-34916-z
Blends that modulate it
Each blend page names this pathway and carries the study behind its claim.
See it on the map
Open the causal map to follow this pathway upstream and downstream, arrow by arrow, each with its study.