NAD+ precursors (NR, NMN) and CD38 inhibition
NR and NMN feed the NAD+ salvage pathway to offset the age-related NAD+ decline driven partly by CD38.
Summary
Debbie explains that NAD+ powers mitochondrial energy production and DNA repair, and that levels fall with age partly because inflammation and senescence raise CD38, which consumes NAD+. She covers human trials of NMN and NR (including NR as one of four 'combined metabolic activators' in a phase II Alzheimer's trial) and says results show some benefits but 'aren't spectacular.' She pairs an NAD+ booster with flavonoid CD38 inhibitors (apigenin, quercetin, luteolin), while flagging a mouse study where high-dose NR increased atherosclerosis and open questions about how much is too much.
Takes powdered NMN, sometimes switching to NR. "Personally, I find that it gives me a little more energy throughout the day."From Boosting NAD+ Function While Inhibiting CD38
The evidence
-
Human trial
In a placebo-controlled human study of 80 participants, oral NMN (300, 600 or 900 mg) raised blood NAD, improved six-minute walk results (best at 600 and 900 mg) and lowered biological age; insulin resistance did not change.
Read the study Discussed in NMN: A Review of Current Research (draft) -
Human trial
A randomized, placebo-controlled phase II trial in 69 Alzheimer's patients using a combination that included 1 g nicotinamide riboside (plus L-serine, NAC and L-carnitine) improved ADAS-Cog scores by day 84.
-
Human trial
Debbie summarizes that multiple clinical trials of NR or NMN show some benefits for heart health or specific biomarkers, but the results aren't spectacular.
Discussed in Boosting NAD+ Function While Inhibiting CD38 -
Human trial
In older men (average age 81), NMN at 250 mg/day did not improve grip strength or walking speed compared with placebo.
Read the study Discussed in NMN: A Review of Current Research (draft) -
Animal
In atherosclerosis-prone mice on a high-cholesterol diet, high-dose NR increased atherosclerotic plaque lesions, the niacin metabolite 4PY and inflammatory markers; low and medium doses did not promote atherosclerosis.
-
Animal
A small-molecule CD38 inhibitor called 78c increased lifespan in mice by about 10%.
Doses used in studies
Amounts reported in the research, not dosing recommendations.
| Dose | Context |
|---|---|
| NMN 300, 600 or 900 mg/day | Placebo-controlled study of 80 participants (walk test, biological age) |
| NMN 300, 600 or 1,200 mg/day | Clinical trial in runners; aerobic capacity rose in the 600 and 1,200 mg groups |
| NMN 250 mg in the afternoon | Older adults; improved sit-to-stand time and reduced afternoon drowsiness |
| NMN 500 mg/day | Overweight middle-aged adults for one month; slight drops in weight, blood pressure, cholesterol |
| NR 1 g/day for 10 weeks | Pilot study in people with mild cognitive impairment |
| NR 1 g once daily for 28 days, then twice daily for two months | Combined metabolic activator phase II Alzheimer's trial (with L-serine, NAC, L-carnitine) |
Cautions
- She cites clinical studies showing NMN is likely safe short term at doses up to 1,250 mg, but questions long-term safety because of possible increased cancer growth; anyone with cancer should talk to their oncologist first.
- A Cleveland Clinic study linked higher levels of excess-niacin metabolites (2PY, 4PY) to major cardiovascular events, especially in people with certain genetic variants; she wonders whether NR/NMN raise these metabolites.
- High-dose NR increased atherosclerosis in mice; she says she still doesn't know how much NR, NMN or niacin is too much, and mouse doses can't be extrapolated to humans.
- CD38 has important jobs (activating T cells, brain calcium signaling), so the aim is to prevent its excess rise, not to inhibit it completely; talk with your doctor.