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Well, he ruined his teeth on his 30s by eating tons of wheat germ oil. I don't think that is any better than a little derailed metabolism. Also he took 1kg of pregnenolone for a year (and had luck nothing bad happened as consequence). He said he used to drink up to 10 strong coffees a day.
What I mean, I doubt moderate is the best word that defines him.
However, we found no changes in body weight, fat mass and fasting blood glucose and insulin.
. We found no pronounced increase in hepatic lipid storage. Instead, NAM increased lipid content and decreased glycogen content in skeletal muscle.
Together, it can be concluded that NAM-induced insulin resistance in nonobese mice was associated with skeletal muscle lipid accumulation. In this work, the possible explanation for skeletal muscle lipid accumulation is that NAM reduced the capacity of exogenous FA oxidation and increased TAG esterification.
Fast twitch muscle can be good. How much can be explained by just this switch from slow-twitch to fast-twitch?Additionally, we found that NAM selectively increased the mRNA levels of myosin II (IIa, IIb and IIx, fast-twitch fiber) and made a nonsignificant reduction in myosin I (slow-twitch fiber).
He admits that fast-twitch muscle fibers have lower mitochondrial mass, but he makes it sound like a bad thing. This can probably explain the differences in mitochondrial DNA found in the muscles of high-niacin-fed rats.A possible explanation for NAM to induce insulin resistance and lipid accumulation could be that muscle fiber-type switching reduced lipid utilization and mitochondrial mass.
But total weight was identical and the liver was normal:As type II myofiber has lower mitochondrial mass than type I myofiber (oxidative muscle fibers), our results are quite consistent with the skeletal muscle data in that NAM impairs mitochondrial function and reduces mtDNA content.
. This study did not explain why lipid accumulation occurs only in skeletal muscle but not in liver.
In the muscle, some genes associated with reduced metabolism were decreased but some were increased. Adenosone monophoshate kinase α₂ was increased, but he does not talk much about this:Most metabolic genes implicated in glucose and lipid utilization, including CPT-2, TIGAR, TBC1D1 and PRDM16, were reduced in the NAM-treated mice, while expression of PDK4, LKB1, AMPKα2, Cidea and UCP3, was increased (Fig. 2H–K).
You can make this high-dose niacin sound either good or bad depending on your biases. The slight decrease in total insulin sensitivity could simply be the result of decreased mitochondrial capacity of type II fibers.The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, and modulation of insulin secretion by pancreatic beta-cells. –Wikipedia
So this happens directly, without niacinamide even becoming NAD⁺.NAM inhibits SIRT1 deacetylase activity by binding to a conserved pocket adjacent to NAD⁺ and blocking NAD⁺ hydrolysis, rather than by increasing the NAD⁺ level or [NAD⁺]/[NADH] ratio.
But somehow, a certain dose of niacinamide works in the opposite way on SIRT1. Maybe lower doses do this by increasing NAD⁺ (substrate)? He draws on two citations which show opposite effects on SIRT1. Perhaps there are differences in the study protocols that might explain this. He did measure the acetylation level on one mitochondrial protein (p53). But notice the increase in actin:Contrarily, SIRT1 activity in the absence of NAM is enhanced by an increase in the NAD⁺ level or [NAD⁺]/[NADH] ratio. Interestingly, 5 mM NAM but not higher concentrations causes SIRT1 activation in fibroblasts, as demonstrated by decreased acetylation level of histone H3 and p53.
Very interesting. I didn't know that.The niacinamide also shifts methyl groups from methionine. This is probably a necessary result of taking niacin without folate. In natural foods, these are found in balanced proportions. This is a good thing to keep in mind. Effectors of methyl balance now officially include B₁₂, folate, methionine, and niacin.
Very interesting. I didn't know that.
@haidut - his posts might interest you. You guys have so much in common, both can solve a 11*11*11 Rubik's cube in 5 min, on congested days.
But it seems to raise homocysteine. Niacinamide Increases HomocysteineThanks. Yes, niacinamide is a methyl sink,
Wow. This makes perfect sense. But I would think with a low-methionine diet, general niacin-induced demethylation wouldn't create a pathological level of homocysteine. The Japanese have lower homocysteine levels, on average.But it seems to raise homocysteine. Niacinamide Increases Homocysteine
I vote methionine to be amino acid public enemy #1, with tryptophan a close second
Thanks. Yes, niacinamide is a methyl sink, so in higher doses it acts similar to methionine restriction (known to prolong maximum lifespan more than restricting any other nutrient, including tryptophan). But in depleting methyl groups too much may create a problem with adrenaline deactivation, which depends on methyl groups. So, there is a sweet spot for niacin and niacinamide dosing and Hoffer thought that 1,500mg niacinamide daily is that sweet spot for lifespan extension. Same with methionine restriction - lower is better but no less than 2mg/kg methionine daily as less than that creates issues.
@nathan10000Thanks. Yes, niacinamide is a methyl sink, so in higher doses it acts similar to methionine restriction (known to prolong maximum lifespan more than restricting any other nutrient, including tryptophan). But in depleting methyl groups too much may create a problem with adrenaline deactivation, which depends on methyl groups. So, there is a sweet spot for niacin and niacinamide dosing and Hoffer thought that 1,500mg niacinamide daily is that sweet spot for lifespan extension. Same with methionine restriction - lower is better but no less than 2mg/kg methionine daily as less than that creates issues.