If my NAD levels are down a little, temporarily or permanently, does that actually impact anything?
Is "good enough" good enough, or is a miss as good as a mile?
TL;DR: No one knows.
For most of the 20th century it was thought that the 15 mg of vitamin B3 (niacin) that is sufficient to prevent Pellagra was all you needed. But now we know that greater supplementation provides greater benefits:
For most of the 20th century, [15mg of niacin] was considered optimal [to sustain NAD levels]. It is now known that NAD+ levels decline with age and that raising levels back up to or even above baseline provides a surprising number of health benefits in a wide range of organisms, from yeast to rodents.
So more is going to be better for some people in some circumstances. But how much is enough, and how much is too little?
What Happens When You Run Low on NAD+?
Is it like running out of oxygen, and if you go four minutes without oxygen your body suffers catastrophic, irreversible damage?
Is it like running out of water, where your body slowly starts to wilt, and there are increasing signs of distress, but you could last a number of days without any permanent damage?
Is it like running out of food, where your body switches to alternate sources, and you can go weeks or months without much more than discomfort, because your body stores backup fuel -- first glyogen, then fat?
Another question is whether the results of an NAD shortage are temporary, like not being able to exercise as long today, or whether things actually break that might not get fixed, like wrinkles in skin that do not get unwrinkled?
We don't know for sure, but let's see what we DO know.
Measuring Your NAD Levels
One reason it's difficult to know is that your body does not have a just a single, master NAD level. Instead, different tissue types each have their own level, and some burn through and replace half their NAD in 15 minutes, whereas others might take 60x longer than that.
NAD fluxes vary widely across tissues (t1/2 15 min to 15 hours)
Even within a single cell, there are different NAD levels in the nucleus, the mitochondria, and the cytosol. So the simple act of measuring whether you are running low -- overall, or in a particular type of tissue, or in one part of a single cell -- is not simple at all.
Still, we want to get some sense of it. And given that NAD levels are central to everything your body does, it would seem intuitively that running short could cause real problems, and your body would want to regulate this very tightly, the way it keeps body temperature within a narrow range.
It's not at all clear that that's how it works, though.
On the one hand, it appears clear that cells a quite sensitive to NAD levels:
NAD+ is a substrate for sirtuins and poly(adenosine diphosphate–ribose) polymerases and even moderate decreases in its cellular concentrations modify signaling of NAD+-consuming enzymes. (emphasis added)
On the other hand, researchers deprived mice of 85% of their muscle NAD without much immediate impact:
Mice with a drastic (~85%) reduction in skeletal muscle NAD+ content have surprisingly mild phenotypes into early adulthood, and increasing skeletal muscle NAD+ content is almost without effect in young adult animals, requiring a prolonged exercise training regimen to tease out differences in performance.
Probably some processes are resilient to minor NAD shortages, like cell respiration, whereas other processes, like the activity of sirtuins and PARPs are more sensitive:
These values suggest that enzymes such as...dehydrogenases of the Krebs cycle...should be able to function unless a substantial degree of depletion occurs, whereas some NAD+ consumers, such as sirtuins...and PARP1...may be more responsive to small changes in NAD+.
So there ends up being a different answer for every process, and also for every tissue. The liver can probably handle 50% NAD depletion, but even that assumes that the liver is not particularly stressed during the time of depletion.
The available evidence suggests that the liver can maintain basal function with up to ~50% NAD+ depletion, but is more sensitive to NAD+ loss under stress.
Other types of cells are not so resilient:
In projection neurons, adult neural stem cells, Schwann cells, immune cells, and retinal pigmented epithelial cells, [blocking NAD production] leads to overt dysfunction or death.
But there is a big difference between completely blocking NAD production versus modest declines, maybe 10% or 20%, which are routinely seen in aging tissues. It's just hard to know. When they dropped the mice's muscle NAD levels by 85%, there wasn't much sign of harm for a while. Myopathy -- a neuromuscular disorder -- did not appear until after 5-7 months. Then the myopathy was rescued by replenishing NAD with NR, but the amount of NR needed to rescue the myopathy did not bring the muscle NAD levels anywhere near to 100% of normal:
Skeletal muscle specific Nampt KO mice have an approximately 85% loss of NAD+ and have almost no observable phenotypes as young adults. Although they develop myopathy by 5-7 months of age, this can be reversed by a nicotinamide riboside supplementation regimen that only modestly increases skeletal muscle NAD+ content, leaving the rescued animals with much less NAD+ than is present in aged wild type mice.
One way to think of this data is that muscle NAD levels can drop significantly before harm develops. Another way to think of it is that if your NAD levels are low, just a little bit of replenishment can make a crucial difference.
One study noted that mouse neurons died when NAD synthesis was completely blocked, but even just partial restoration of the NAD synthesis capability was enough to prevent neural degeneration:
Restoration of as little as 25–50% of NMNAT2 activity can prevent degeneration of the axon
But this research does not tell us what more subtle things might have been going wrong from the NAD deficit, or what additional benefits might have been had from greater NAD replenishment.
Another possibility that researchers have considered is that young tissues are more resilient to NAD declines than older tissues, and there is some evidence for that:
Aging skeletal muscle was reported to exhibit an NAD+-dependent “pseudohypoxic state” that was not observed in young muscles depleted of NAD+, again suggesting age- or time-dependent differences in the consequences of NAD+ deficiency
Can NAD be stored for use later? Can it be shared among cells. There is some evidence for it.
NAD+ can be released from the mitochondria into the cytosol and nucleus through specific permeability transition pores during conditions of apoptosis or necrosis. Therefore, high starting mitochondrial levels of NAD+, which are an order of a magnitude greater than cytosolic levels, are necessary to maintain optimal redox function. [emphasis added]
All of this data suggests gradual transitions between adequate and depleted NAD storage states, with partial effects.
But perhaps that weighs in favor of stronger replenishment. One of the most important cellular functions that is powered by NAD is DNA repair. If the cell is short on NAD, there will be less DNA repair activity. If the DNA repair is simply delayed until tomorrow, when your body gets a fresh batch of dietary NAD precursors, maybe that's okay. But if some of the work never gets done, that seems like it would not be okay.
The flip side of that is that if NAD is aggressively routed to DNA repair, then there will be a severe limitation of NAD+ availability for other functions.
It has been demonstrated that extensive DNA breaking can dramatically reduce intracellular NAD+ content up to 20–30% of its normal level, resulting in severe limitation of NAD+ availability for other NAD+-dependent enzymes.
-- Antioxidants, February 4, 2023
When the demand for NAD suddenly exceeds what is available, some function is going to draw the short-straw for NAD use, and that function will get performed late or not at all. How bad is that? We don't know.
You don't want to run out of air for even a short time, and there are limits to how long you can go without water before things go badly awry. NAD is central to so many functions in so many cells that it is impossible to calculate when NAD levels drop exactly what goes wrong when and under what circumstances. And we do not have the data to drive the calculation anyway.
But the data we do have suggests that cell metabolism is surprisingly robust in the face of NAD shortages, and that the obvious bad effects do not appear right away, at least not in muscle cells. On the other hand, some cellular functions are more sensitive to NAD levels, including sirtuins and PARPs that that protect the cell.
We don't know how much NAD depletion is too much, or how long a period is too long. There is no reason to think that having extra NAD does much for you. On the other hand, running short on NAD will likely cause problems, sooner or later.