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Ever since nicotinamide (NAM) was also shown to cure pellagra, both nicotinic acid (NA) and NAM have been collectively referred to as niacin, or vitamin B3––though they are distinct compounds. For example, NAM is not plagued by the same kind of hot flash reaction. (Facial flushing attributed to niacinamide in some older studies was likely due to a less purified form contaminated with residual NA.)
The relative capacity of NA versus NAM to generate NAD+ is unclear. Neither has been shown to boost sirtuin activity, but both do extend the lifespan of C. elegans. I couldn’t find any longevity trials for NA in rodents. However, NAM was put to the test and failed to prolong the lives of mice. What clinical effects might we expect in people?
Previously, I explored the proven anti-aging effects for topical nicotinamide on the skin, and the remarkable ability of oral nicotinamide to help prevent skin cancer. I also noted it failed to prevent type 1 diabetes, despite promising mouse data, though it may help preserve residual function in people newly diagnosed with type 1 diabetes––but apparently not enough to affect blood sugar control. What about its use as a NAD+ booster?
In those with mitochondrial myopathy, NA raised muscle NAD+ levels, and improved mitochondrial and muscle function. But in healthy individuals, muscle NAD+ levels didn’t budge. However, the average age of individuals in the control group was 50. What about in older adults, whose muscle NAD+ levels might potentially be lower? Four NAD+ precursors were tested in older adults averaging in their 70s: tryptophan, NA, NAM, and NR. All four failed to improve muscle strength or function, failed to affect mitochondrial function, and failed to even nudge NAD+ levels in their muscles. Why not give it a try anyway? Again, side effects.
Like NA, high-dose NAM can cause gastrointestinal disturbances and signs of liver toxicity. However, NAM may result in more issues involving methylation. The first step in breaking down excess NAM is to transfer a methyl group to it, forming methylnicotinamide. Unfortunately, methylnicotinamide is neurotoxic, and can cross the blood-brain barrier. This may explain why NAM can exacerbate Parkinson’s-like symptoms in rats, and why Parkinson’s patients have higher levels of the NAM-methylating enzyme in their brains. And the same with Alzheimer’s brains, for that matter. Excess NAM may also deplete the body’s pool of methyl groups.
If you read the Epigenetics chapter in my book How Not to Age, you may remember that DNA methylation is critical for the regulation of gene expression. Epigenetic changes caused by NAM-induced methyl depletion have been blamed as the reason why rats fed megadoses of NAM suffer from fatty livers and swollen kidneys. But that was at a human-equivalent dose far exceeding what people might take. Is there any evidence that more modest NAM supplementation might affect methylation in humans? Yes, and even with a single dose as low as 100 mg.
Methylation also plays a key role in breaking down fight-or-flight hormones like noradrenaline, and neurotransmitters like serotonin and histamine. Within hours of a single 100 mg dose of NAM, blood levels of all three become elevated, suggesting their metabolism was impaired by the shunting of methyl groups to deal with the excess NAM. Also noted was a significant rise in homocysteine, which is a byproduct of methylation reactions, and a risk factor for cardiovascular disease and dementia.
Another potential problem with NAM is that it’s a sirtuin inhibitor. Wait, I thought the whole purpose of taking NAD+ precursors is to boost sirtuin activity. Sirtuin enzymes use up NAD+ and spit out NAM. This allows the body to recycle the NAM back into NAD+ for further sirtuin use. But it also means the body can use NAM as part of a negative feedback loop. Like a thermostat in the winter that shuts down the furnace when there’s too much heat, the body shuts down NAD+ use by sirtuins when it detects too much NAM. NAM pills didn’t exist when our bodies evolved; so, in the wake of a sudden wave of NAM, the body must think its sirtuins are churning out too much, and dials them back. Perhaps this explains why NAM fails to prolong the lifespans of mice. When the sirtuin-suppressing effects of NAM were first reported 20 years ago, the researchers cautioned that this could potentially lead to “deleterious consequences of long-term nicotinamide therapy in humans.”
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