Aging as progressive pseudohypoxia?
We have already come across the concept of hypoxia here, it is a state of lack of oxygen. Every healthy cell can prepare for this condition just in time, can turn on and off the necessary genes, and can easily survive a short-term or moderate lack of oxygen. But what is pseudohypoxia? We can imagine it so that the cell receives a signal that there is not enough oxygen and starts the necessary mechanisms. But in reality, this signal is false and can thus damage the cell. The same phenomenon is also referred to as aerobic glycolysis or, according to its discoverer, as the Warburg effect.
The authors of one study arrived at these considerations because they noticed a striking similarity in the behavior of aged cells and cells exposed to a lack of oxygen. But let's look at another study first.
How does lack of oxygen manifest itself, what does hypoxia do to metabolism?
This study investigates the effect of hypoxia on fat metabolism.
Several interesting insights can be gleaned from the graphs above. MCAD and LCAD enzymes are the basic machines for breaking down fatty acids in the mitochondria, LCAD mainly breaks down long unsaturated and MCAD long saturated fatty acids. Even the intermediate product HIF-1α itself has an effect on the activity of these enzymes and thus on fat metabolism (on the graph, sh1a means its removal and the removal of the effect of hypoxia), which I already wrote about here. This can be stabilized, as we already know, only in the presence of hydrogen peroxide, which is a product of superoxide dismutation by superoxide dismutase (SOD) and which is degraded by glutathione peroxidase (GPx) during the conversion of reduced glutathione (GSH) to GSSG. Thus, the peroxide level increases with higher SOD activity and decreases with higher GPx activity and increases with GSH deficiency. The upper graph clearly shows that the stabilization of HIF-1α, so hypoxia, not only limits the breakdown of fats, but also activates the formation of new fats (enzymes FASN, SCD1 etc.). It is entirely secondary whether the stabilization of HIF-1α occurs due to a real lack of oxygen or just false signaling.
This brings us to the heart of the matter. Namely, the problem of how false signaling of hypoxia is caused even when there is enough oxygen? See the previous post. For example, a lack of reduced glutathione (GSH) in an environment of excess free fatty acids (FFA) in the blood is sufficient for this.
And now we can go back to the first study that looked at aging mice and concluded that the pseudohypoxia associated with aging is due to a lack of NAD+. If you've ever watched a YouTube video on life extension efforts, you've probably come across the idea that missing NAD+ needs to be replenished with various supplements such as vitamin B3 (niacin, NA), NAM, NAC, NR, NMN, and more. It is clear that the ratio of NAD+/NADH levels changes during metabolic problems. It is actually an excess of NADH fuel due to insufficient combustion (oxidative phosphorylation), insufficient function of the electron transport chain (ETC), i.e. one of the mitochondrial complexes I to V. However, few people deal with the real causes of this condition.
In this study, they found that there is a decrease in the expression of mitochondrial enzymes that ensure the production of energy with the help of oxygen. Moreover, they confirmed that this is caused by a lack of NAD+ in the cell nucleus and this deficiency can be partially corrected by supplementation and this leads to the restoration of mitochondrial enzyme activity and also the correct labeling and removal of the HIF-1α hypoxia signal. So this supplementation might seem to extend life. But there is no evidence for that yet, and maybe there won't be.
Let's review how does a cell get NAD+? The main source is the electron transport chain, i.e. obtaining energy by combustion with the help of oxygen. Other smaller, i.e. supplementary, sources are the fermentation of glucose to lactic acid (lactate) and also higher desaturation of unsaturated fatty acids, specifically linoleic acid. So if lactate production is increased in a state of pseudohypoxia, it is actually a defense, a negative feedback and a way to restore NAD+ levels.
The sequence of causes can therefore be the opposite, so how is it? Is NAD+ deficiency a cause or a consequence of pseudohypoxia? Isn't the lack of NAD+ caused at first rather by a lack of adaptation to real hypoxia, by not starting the fermentation that would easily restore NAD+? A lack of NAD+ could then cause changes in gene expression and pseudohypoxia even after the oxygen level is restored. The main regulatory signal could then be the HIF-1α signal. Let's repeat again how it breaks down, because insufficient breakdown will cause a state of pseudohypoxia and thus aging, and excessive degradation could trigger this state.
The transcription factor HIF-1α is always synthesized. In order to be removed in normal situation, it must be labeled with the OH tag, but not in hypoxia. Other enzymes like VHL (Von Hippel-Lindau) then ensure its removal when labeled. However, it is necessary to take into account the results of another study, in which the authors found that even this degradation can be influenced very strongly. They found that with enough hydrogen peroxide, no degradation of HIF-1α could occur even if it is properly labeled. Or, on the contrary, high activity of glutathione peroxidase can erase the reaction to hypoxia, HIF-1α is broken down even at a very low oxygen level. This will definitely cause a lack of NAD+, because oxidative phosphorylation will not take place, but fermentation will not start. And here's the catch, if we supplement NAD+ in a state of high glutathione peroxidase activity, induced by a high level of free fatty acids, after the reserves of reduced glutathione are depleted, i.e. in a state of insulin resistance, gain we something? So where is the cause of pseudohypoxia?
I am afraid that supplementing with NAD+ alone is not enough. In addition, it has been found that, for example, vitamin B3 (niacin, nicotinic acid, NA) works in the short term, but in the long term it increase the level of free fatty acids, but then we get to the initial state or a state even worse than before. Can't really recommend it. I don't know how the other substances used to supplement NAD+ specifically affect fat metabolism, but since the authors of the studies are not at all interested in the level of free fatty acids, they do not measure them, then I would be skeptical and cautious.
There is one other interesting supplement called melatonin. I haven't studied enough information yet, so I'll just mention what the authors of this study found. They succeeded in slowing the growth of lung tumors in a mouse model by restoring the activity of the mitochondrial complexes of the electron transport chain and thus restoring the production of energy by combustion with the help of oxygen. They reduced the fermentation of glucose to lactate and also clarified the processes that cause it. And that's just by supplementing with melatonin, that sounds very promising, doesn't it?
References:
Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation
Polyunsaturated Fatty Acid Desaturation Is a Mechanism for Glycolytic NAD+ Recycling
Role of pseudohypoxia in the pathogenesis of type 2 diabetes
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