NAD+ Boosters May Worsen Heart Disease Despite Anti-Aging Claims
High-dose nicotinamide riboside increased atherosclerotic plaques and inflammation in mice, challenging NAD+ supplement safety.
Summary
Researchers tested whether NAD+ boosting supplements protect against heart disease in atherosclerosis-prone mice. Contrary to expectations, high-dose nicotinamide riboside (NR) actually increased arterial plaques and systemic inflammation rather than providing protection. The study found that NR shifted cellular metabolism away from beneficial sirtuin pathways toward inflammatory CD38 pathways, raising important safety questions about popular NAD+ supplements for cardiovascular health.
Detailed Summary
This study challenges the widespread belief that NAD+ boosting supplements provide cardiovascular protection. Researchers investigated whether nicotinamide riboside (NR), a popular NAD+ precursor supplement, could prevent atherosclerosis in apolipoprotein E knockout mice—a standard model for studying heart disease.
The team fed 8-week-old male mice a high-cholesterol diet for 12 weeks with three different NR doses: none (NR−), 1.2 g/kg diet (NR+), and 2.4 g/kg diet (NR++). They measured arterial plaque formation, inflammation markers, and metabolic pathways. Surprisingly, the highest NR dose increased plaque lesions in aortic root sections and elevated plasma levels of inflammatory cytokines TNFα and IL-6. LDL cholesterol and triglycerides also increased with high-dose NR.
Crucially, liver and plasma NAD+ levels remained unchanged despite supplementation, but the downstream metabolite 4PY increased—a compound recently linked to cardiovascular risk in humans. The study revealed that NR supplementation decreased beneficial SIRT1 and lipoprotein receptors while increasing CD38, an enzyme that competes with sirtuins for NAD+. In cultured macrophages, high NR levels increased inflammatory markers CD38 and CD86.
These findings suggest that high-dose NAD+ precursors may paradoxically harm cardiovascular health by shifting metabolism away from protective sirtuin pathways toward inflammatory CD38 pathways. The results align with clinical trial data showing that NAD+ precursor niacin failed to reduce cardiovascular events in the AIM-HIGH trial, despite improving cholesterol profiles. The authors recommend caution with NAD+ boosters in patients with atherosclerosis.
Key Findings
- High-dose NR (2.4 g/kg diet) increased atherosclerotic plaque lesions in aortic root sections compared to controls
- Plasma TNFα and IL-6 inflammatory cytokines were elevated in the highest NR dose group
- LDL cholesterol levels were highest in the NR++ group, with triglycerides also significantly increased vs NR+ group
- Liver and plasma NAD+ concentrations remained unchanged despite NR supplementation across all doses
- The NAD+ metabolite 4PY increased with NR supplementation, a compound linked to cardiovascular risk
- SIRT1 and lipoprotein receptors (LDLR, LRP1) decreased while CD38 increased in liver tissue with high-dose NR
- In macrophages treated with oxidized LDL, high NR levels increased inflammatory markers CD38 and CD86
Methodology
Controlled study using 8-week-old male apolipoprotein E knockout mice fed high-cholesterol diet for 12 weeks with three NR doses (0, 1.2, 2.4 g/kg diet). Researchers measured atherosclerotic plaques via Oil Red O staining, plasma cytokines via ELISA, and protein expression via Western blot. Additional in vitro studies used RAW264.7 macrophages and bone marrow cells treated with oxidized LDL and NR. Statistical analysis used Kruskal-Wallis tests and one-way ANOVA with Tukey post hoc comparisons.
Study Limitations
Study conducted only in male mice, limiting generalizability to females and humans. The atherosclerosis model (Apoe knockout mice) may not fully represent human disease progression. Researchers noted that NAD+ levels didn't increase despite supplementation, suggesting potential issues with bioavailability or metabolism that may differ in humans. Long-term effects beyond 12 weeks were not assessed.
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