NAD+ boosting increases atherosclerotic plaques and inflammation in Apoe knockout mice

Wang YJ, Gaul DS, Gorica E, Pahla J, Wang Z, Mohammed SA · Atherosclerosis

Set out to show that nicotinamide riboside protects arteries and found the opposite at the top dose. The 2.4 g/kg arm had larger plaque lesions in the aortic sinus and higher plasma TNF-alpha, IL-6 and LDL cholesterol. Liver and plasma NAD+ did not rise, while the terminal metabolite 4PY did, which is the finding that makes the result mechanistic rather than anomalous: in liver, SIRT1 and lipoprotein receptors fell and CD38 rose, and in macrophages treated with oxidised LDL, high nicotinamide riboside raised CD38 and CD86. The authors read this as NAD+ metabolism being diverted from the sirtuins towards CD38 and PARP1, and advise caution with NAD+ boosters in people with atherosclerosis.

Population

Male apolipoprotein E knockout mice, 8 weeks old, on a 1.25 percent high-cholesterol diet for 12 weeks, plus cultured mouse macrophages

Intervention

Nicotinamide riboside in the diet at 0, 1.2 or 2.4 g/kg of feed

Comparator

The unsupplemented high-cholesterol arm

Limitations

A genetically atherosclerosis-prone mouse on a high-cholesterol diet, males only, and the dietary doses are high. It reports plaque area and biomarkers, not events. Whether the same diversion happens at supplement doses in people is untested, and the paper's own framing is a caution rather than a finding about human risk.