NAD+ Explained: What It Does, Why Levels Fall, and Why the Flush Happens

NAD+ has the strange distinction of being both the most-hyped compound in longevity and one of the few with an entirely uncontroversial biological role. The hype is about what supplementing it does. The biochemistry is not in dispute at all.

What NAD+ actually is

Nicotinamide adenine dinucleotide is a coenzyme present in every living cell. It has two jobs, and they are both central.

The first is electron transport. NAD+ accepts electrons during glycolysis and the citric acid cycle, becoming NADH, and delivers them to the electron transport chain where ATP is produced. Without adequate NAD+, cells cannot convert fuel into usable energy at a normal rate. This is not a marginal pathway — it is the pathway.

The second is as a substrate. Sirtuins, the enzyme family associated with DNA repair and metabolic regulation, consume NAD+ to function. So does PARP, the enzyme family that repairs DNA strand breaks. Both are competing for the same limited pool.

Why levels decline

Tissue NAD+ concentrations fall with age. The measured decline is substantial — the commonly cited figures suggest levels in middle age are roughly half those in youth, though the exact number varies enormously by tissue and by measurement method.

Two things drive it. Synthesis declines, and consumption rises. PARP activity increases as accumulated DNA damage rises, and PARP is a heavy NAD+ consumer. Chronic inflammation drives CD38 expression, another significant consumer. The result is a pool that is being drawn down faster while being refilled more slowly.

Precursors versus direct NAD+

Most oral NAD+ products are not NAD+. They are precursors — nicotinamide riboside or nicotinamide mononucleotide — which the body converts. That conversion is real, and oral precursors do raise measurable blood NAD+ metabolites.

The argument for injectable NAD+ is bioavailability. The NAD+ molecule is large and poorly absorbed orally, so subcutaneous administration skips the first-pass problem entirely. The argument against is that the intracellular delivery question is still not fully settled, since NAD+ does not cross cell membranes freely either.

What is not in dispute is the subjective difference. People who have run both almost universally report that injectable NAD+ feels like something and oral precursors do not. Draw your own conclusions about what that means.

The flush, and why it happens

This is the part nobody warns you about properly. Push a subcutaneous NAD+ dose too fast and you will get a distinctive cluster: chest tightness, flushing, a wave of nausea, sometimes a headache and an urgent need to sit down. It arrives within a minute and resolves within a few.

It is dose-rate dependent, not dose dependent. The same total amount delivered slowly produces almost none of it.

Two rules solve it. Start lower than you think you need — meaningfully lower — and inject slowly. Not "reasonably slowly". Slowly. If you feel the chest tightness begin, stop pushing and wait; it will pass, and you can continue.

The flush is not an allergic reaction and it is not dangerous at sensible doses, but it is unpleasant enough that a lot of people abandon NAD+ after one bad first attempt that was entirely avoidable.

How it is typically dosed

Protocols vary widely. The general pattern is a low starting dose with a slow ramp over several weeks toward a maintenance level, then either continuous low-dose administration or periodic loading blocks. Your provider sets the actual numbers based on your labs and how you respond to the first few doses.

The lyophilised presentation needs reconstituting with bacteriostatic water; the ready-to-use liquid at 200 mg/mL does not. If you are new to injections, the liquid removes an entire category of things to get wrong.

What to stack it with

NAD+ is about substrate availability. SS-31 is about mitochondrial membrane efficiency — it binds cardiolipin on the inner membrane, where the electron transport chain actually sits. Those are complementary rather than redundant, which is why the pairing is so common.

MOTS-c is the third piece people add, and glutathione typically runs underneath the whole thing as the redox buffer. That combination — NAD+, SS-31, glutathione — is what most people converge on after a year of experimenting.

What to measure

This is the slowest-feedback category we run. You will not feel a dramatic change in week one, and if you do, be suspicious of it. What moves first are markers, not sensations.

Get a baseline panel before you start and repeat it at month four. Without those two data points you are guessing, and guessing is expensive in this category.