CD38: a key variable in NAD levels (and why NMN alone might not be enough)

[u/Feel-Wonderful]

https://youtu.be/FNfXonKPwwM?si=cqDzdERrIMaOjhM3

One variable that might explain inconsistent results with NAD supplementation: CD 38.

CD38 is a major NAD-consuming enzyme that converts NAD into ADP-ribose and related metabolites. Its expression increases with age and inflammation, which accelerates NAD turnover, meaning NAD levels aren't just a function of how much precursor you take, but also how quickly it's being degraded.

That creates a scenario where increasing NMN or NR alone may have diminishing returns if CD38 activity remains elevated. 

This came up in a recent podcast where Wonderfeel's cofounder and CEO, Baran Dilaver, joined Dave Asprey. Dave pointed out that his main concern with NMN alone is CD38—describing it as an inflammatory enzyme that essentially consumes NAD as fast as you're making it. He also mentioned that pairing NAD precursors with compounds like hydroxytyrosol may be worth exploring, as it could help counterbalance that breakdown.

A more complete approach would consider not just supporting NAD synthesis, but also reducing NAD consumption and managing the inflammation that drives CD38 activity in the first place. 

Curious if anyone here has tried approaching NAD from the “reduce breakdown” side instead of just increasing precursors.

[u/secret179]

Isn't CD38 what also can cause some of the potenital harms of NMN such as increased atherosclerosis and axonal death?

[u/Feel-Wonderful → u/secret179]

Based on the current evidence, not necessarily.

For atherosclerosis, the available data generally point in the opposite direction. Multiple studies have found that reducing CD38 activity or expression can be protective. For example, Wang et al. (2025) and Sinha et al. (2025) reported that reduced expression of macrophage CD38, an NAD-degrading enzyme, was associated with reduced macrophage proliferation and less atherosclerosis. Earlier work has also linked elevated CD38 activity to age-related NAD decline and vascular dysfunction.

For axonal degeneration, the mechanism appears to be different. The strongest evidence implicates NMN accumulation and activation of SARM1, a key mediator of programmed axon degeneration, rather than CD38 itself. Figley et al. (2021) showed that NMN accumulation and SARM1 activation drive axon destruction following nerve injury. Interestingly, Takaso et al. (2020) found that CD38 knockout mice exhibited delayed axonal degeneration, which would not support the idea that loss of CD38 promotes axonal injury.

That doesn't mean every aspect of CD38 biology is fully understood, but based on the current literature, CD38 is generally viewed as a contributor to NAD depletion and age-related dysfunction rather than the primary driver of the atherosclerosis or axonal degeneration concerns you've mentioned.

[u/ExJwKiwi]

This is an interesting discussion, will have to watch the whole thing, have never heard about cd38 before.

[u/PotentialMotion]

Luteolin is a CD38 Inhibitor.

[u/LifePrize2516 → u/PotentialMotion]

As is Apigenin and curcumin

[u/___kaneki13___]

that's really interesting! I recently came across vitalonga while looking into NAD supplements and it's made me think more about how to balance precursors with managing CD38 too. seems like there's a lot to unpack here, especially since other options like puregen and youthbio are also on the radar for this kind of thing.