NAD+ & sirtuin signalling
One of 6 mechanistic pathways to ⏳ Longevity & healthspan · 13 options
NAD+ falls by roughly half between young adulthood and old age. It is the obligate cofactor for the sirtuins that regulate DNA repair, mitochondrial biogenesis and inflammation. The precursors reliably raise the pool — the honest gap is what that buys you clinically.
NAD+ itself isn't routinely measurable, so this is indirect. Worth knowing: heavy precursor dosing consumes methyl groups, so watch homocysteine if you are running NMN or NR at scale.
hs-CRP (High-Sensitivity C-Reactive Protein)HbA1c (Hemoglobin A1c)HomocysteineComprehensive Metabolic Panel (CMP)⏳ Longevity Baseline covers these in one panel →
What engages this pathway
Ordered by how directly each one acts on the mechanism above — never by how much trial evidence exists. Each links to its full breakdown with dosing, half-life and vendor.
💉 Nad+
Direct IV NAD+. Whether intact NAD+ crosses the cell membrane is genuinely contested — much of it is likely degraded to precursors first, which would make the expensive infusion an inefficient way to deliver NR.
💉 NR
The best-characterised precursor with the most human pharmacokinetic work. Raises NAD+ dependably. Clinical endpoints have been consistently underwhelming, which is worth sitting with rather than skipping past.
💉 5-Amino-1MQ
NNMT inhibition preserves the existing nicotinamide pool rather than adding precursor — a different and arguably smarter lever on the same system.
🧬 NMN
Oral NMN. Raises the NAD+ pool in human trials; whether a raised pool translates into anything you can feel remains the open question for the whole category.
🧬 NR (Nicotinamide Riboside)
NiaCel — the NR material with the most human pharmacokinetic data behind it. The pool rises reliably; the clinical endpoints have been modest.
🧬 ResveraCel
NR plus resveratrol plus TMG — precursor, proposed sirtuin activator and methyl donor. The TMG is there because heavy NAD+ precursor dosing consumes methyl groups, which is a real and often-ignored issue.
🧬 Niacinamide
The cheapest NAD+ precursor. It also inhibits sirtuins at high concentration, which is an awkward and under-discussed contradiction in the longevity case for it.
🧬 Resveratrol
The original proposed sirtuin activator. The direct SIRT1 activation finding was challenged as a fluorescent-assay artifact, and human trials have largely disappointed. Honest position: the story was better than the data.
🧬 Pterostilbene
Methylated resveratrol with far better bioavailability and a longer half-life. Inherits the mechanism and the uncertainty.
🧬 Tocotrienols
Beyond antioxidant activity, delta-tocotrienol has senolytic-adjacent effects in preclinical work and human cholesterol data.
🧬 Cycloastragenol
The astragalus-derived telomerase activator behind TA-65. It does activate telomerase in cell culture — the open question is whether lengthening telomeres in a somatic cell is desirable, since it is also what a cancer cell needs to become immortal. Genuinely double-edged, and rarely presented that way.
🧬 Gynostemma
Jiaogulan contains gypenosides structurally similar to ginseng's, and it activates AMPK in cell work. Traditional use in Chinese longevity villages is the origin of the interest.
🧬 Moringa
Dense polyphenol and micronutrient profile with isothiocyanates related to sulforaphane's. Nutritionally impressive; the longevity claim is extrapolated from its constituents.
The other 5 routes to longevity & healthspan
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Frequently asked questions
NAD+ falls by roughly half between young adulthood and old age. It is the obligate cofactor for the sirtuins that regulate DNA repair, mitochondrial biogenesis and inflammation. The precursors reliably raise the pool — the honest gap is what that buys you clinically.
13 options are mapped to this pathway in the Vault, including Nad+, NR, 5-Amino-1MQ, NMN. They are grouped by the mechanism they act through rather than ranked by how much trial evidence exists — 4 carry clinical validation and 7 are mechanistic predictions.
NAD+ itself isn't routinely measurable, so this is indirect. Worth knowing: heavy precursor dosing consumes methyl groups, so watch homocysteine if you are running NMN or NR at scale. The markers worth checking are hs-CRP (High-Sensitivity C-Reactive Protein), HbA1c (Hemoglobin A1c), Homocysteine, Comprehensive Metabolic Panel (CMP).
Unproven is not the same as ineffective. Of the 13 options on this pathway, 4 have clinical validation and 7 are graded theoretical — meaning the mechanism is sound but the specific human trial has not been run, which is true of a great deal of what works in this space. Nothing on this page is ordered by evidence tier, because sorting by trial count would bury the compounds you came looking for.