Trance said: My main complaint [on NADH] was insatiable and miserable constant feeling of hunger. My girl friend of the time experienced the same effect
Your experience seems to confirm the research and anecdotal consensus (of forums) that consistent nictinamide use can induce a pronounced insulin resistant state. This insulin resistant state is also likely indicative of the hypoxic state that NAD inducing strategies are designed to ameliorate. Anything that has the potential to produce a state of long term energy deficiency in the cell should be looked at with suspicion, even if it temporarily increases NAD.
We have to parse the strategies that may temprarily upregulate pathways at the cost of long term downregulation and strategies that will cause semi-permanent or permanent increase in, in the case of this model of aging, the NAD/NADH ratio at baseline. SIRT activating strategies seem to fall in the latter category. Niacinamide seems to fall in the former. However, niacin related compounds seem to be varied in action with some being seemingly opposite in their net effect than other similar compounds. Getting to the bottom of the net long term effects on energy metabolism of all relevant niacin related compounds should be a priority.
Nicotinic acid is clearly superior to nicotinamide at inducing NAD production, as it appears the nicotinamide→NAD pathway is saturated at low doses. The level of extracellular nicotinic acid that maximises NAD production is a fairly moderate 5 µm. 500 mg of immediate release nicotinic acid produces plasma peaks of 40-48 µm, above 5 µm for almost 2 hours:
It would be interesting to know what the NAD/NADH ratio was, after return to homeostasis, in relation to the prior baseline.
Nad+ is thought to drive SIRT activation. Here's an article to add some more context:
http://www.ncbi.nlm....les/PMC3764375/
excerpt:
Sirtuin enzymatic activity requires NAD+ as a cofactor whose levels increase by energy stress which occurs, e.g., during fasting, CR, and exercise. Thus, NAD+ mediates the adaptive response to low energy by activating sirtuins and their downstream targets. Sirtuins transform NAD+ to nicotinamide, which acts as a competitive inhibitor of sirtuins by a negative feedback mechanism. The other breakdown product of NAD+ is O-acetyl-ADP-ribose.
So, we can see here how niacinamide supplementation may act as such a potent SIRT inhibitor and likely a potent downregulating agent for NAD+.
Interestingly, NAD+ levels greatly increase during CR in muscle and white adipose tissue
Nicainamide is the 'anti-calorie restriction' mimetic and likely a strong net inhibitor of NAD+.
Other relevant excerpts:
... administration of antioxidant vitamin C and vitamin E severely impairs the insulin-sensitizing and beneficial effects of exercise in humans ...
Hormesis-stimulating compounds act by eliciting an adaptive stress response, which in turn conveys resistance to subsequent higher doses of the same agent ...
SIRT3 may also play a role in the response to consumption of ethanol. The oxidative metabolism of acetaldehyde (derived from ethanol) is facilitated by mitochondrial aldehyde dehydrogenase 2 (ALDH2), which is also an NAD+-dependent enzyme (Marchitti et al., 2008). Interestingly, significant acetylation of mitochondrial proteins is observed in liver tissues of mice fed high ethanol diets (Fritz et al., 2012). Remarkably, 30 min after acute ethanol treatment of human aortic endothelial cells (HAECs), the mitochondrial NAD+/NADH ratio decreased by 65%, thus potentially limiting the activities of NAD+-dependent enzymes such as SIRT3. Additionally, a decrease in the acetylation state of ALDH2 upon overexpression of SIRT3 suggests ALDH2 is a target of SIRT3; however, additional studies must be performed to confirm this interaction (Xue et al., 2012).
Aside: revisit L-Serine and caffeine as a method to improve the NAD+/NADH ratio.
Surprisingly, CR reduces neurodegeneration in animal models of both PD and AD, possibly via upregulation of SIRT3 (Zhu et al., 1999; Mattson, 2000). Furthermore, overexpression of SIRT3 has been shown to significantly increase neuronal lifespan (Weir et al., 2012). ...
the effect of resveratrol on Sirtuin expression remains controversial. In one study, mice on a 30% CR diet exhibited increased Sirt3 mRNA levels, while treatment with resveratrol did not affect Sirt3 expression levels. In light of this finding, resveratrol may be ineffective in mimicking CR-mediated health benefits (Tauriainen et al., 2011). However, not all hope is lost for the polyphenol compounds. A recent report found that a resveratrol derivative, trans-(-)-ε-viniferin, is able to increase SIRT3 expression and provide protection in cell models of Huntington’s disease (HD). Specifically, viniferin treatment of striatal precursor cells overexpressing mutant huntingtin resulted in increased SIRT3 expression, increased the NAD+/NADH ratio, reduced intracellular ROS accumulation, and decreased acetylated MnSOD levels. Additionally, treatment with viniferin increased levels of activated AMPK and decreased acetylated LKB1, effects which were shown to require the presence of SIRT3. Thus, Sirt3 is required for viniferin-mediated neuroprotection in HD models
This has all mostly been prior discussed or alluded to at sometime or another, with the exception of maybe viniferin, but it's worthwhile to rehash in light of Sinclair's research.
Edited by Michael, 30 July 2017 - 10:05 PM.
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