AOR said,
If these in vitro results pan out in vivo, then the use of idebenone would result in increased mitochondrial free radical production, accelerating the aging process. Therefore, while the apparent clinical benefits of idebenone in some disease states may make its use a sensible calculated risk for victims of those pathologies, it seems an extremely foolish gamble in the case of an otherwise healthy life extensionist.
adamp2p replied,
Well without sounding insulting, every single nootropic drug has, in one study or another, been shown to decrease intelligence; so would you then conclude that because a single study gave such results, that those results are reproduceable?
First, like David, I don't believe that any study of the classic/true nootropics (pyroglutamate analogs) has ever been shown to have any negative effect on intelligence. But even if I did, that would not be an analogous case. One must base one's judgements on the balance of available evidence. If many studies showed cognitive benefits from a substance and just one study showed a negative effect, the balance of evidence would still favor the supplement.
In this case, by contrast,
all of the studies which I have found have either reported that idebenone increases mitochondrial free radical production, or related findings which suggest the same conclusion. The abstract extracts which I previously posted were just the "low-hanging fruit" which I selected for posting purposes because their abstracts are clear and do not require much background knowledge to see the implications.
These results build on a previously-established body of work, such as:
Arch Biochem Biophys. 1996 Jun 15;330(2):395-400.
The interaction of Q analogs, particularly hydroxydecyl benzoquinone (idebenone), with the respiratory complexes of heart mitochondria.
Esposti MD, Ngo A, Ghelli A, Benelli B, Carelli V, McLennan H, Linnane AW.
Idebenone is ... clearly a poor substrate for ... complex I. Indeed, idebenone is a strong inhibitor of both the redox and proton pumping activity of complex I, showing effects in part similar to those of coenzyme Q-2. However, the mechanism of idebenone interaction with complex I may be different from that of Q-2 because of its different sensitivity to inhibitors. The possible relevance of the present findings to the therapeutic use of idebenone is discussed.Now, to many that might sound innocent enough -- just a bunch of biochemical babble. But it seems more sinister if one is familiar with the way that free radicals are produced in the mitochondria. And in the full text, the authors elaborate:
Idebenone promotes a redox bypass of complex I, allowing NADH to be oxidized and enhancing the concentration of quinol substrate for complex III, and at the same time functions as an excellent substrate for succinate oxidation. Both of these effects could result in a potentiation of the bioenergy production of the respiratory chain. ... Nevertheless, our biochemical data suggest that the clinical use of idebenone should be exercised with caution, especially because idebenone could stimulate oxygen radical production in mitochondrial electron transport. Our results also indicate how idebenone may ameliorate mitochondrial defects due to functional impairment of mitochondrial complex I as in the case of LHON [Leber’s hereditary optic neuropathy] (LHON).The abstract of the following article mentions neither idebenone nor mitochondrial free radical production:
Biochim Biophys Acta. 1998 May 6;1364(2):222-35.
Inhibitors of NADH-ubiquinone reductase: an overview.
Degli Esposti M.
This article provides an updated overview of the plethora of complex I inhibitors. The inhibitors are presented within the broad categories of natural and commercial compounds and their potency is related to that of rotenone, the classical inhibitor of complex I. Among commercial products, particular attention is dedicated to inhibitors of pharmacological or toxicological relevance. The compounds that inhibit the NADH-ubiquinone reductase activity of complex I are classified according to three fundamental types of action on the basis of available evidence and recent insights: type A are antagonists of the ubiquinone substrate, type B displace the ubisemiquinone intermediate, and type C are antagonists of the ubiquinol product. But in the full text appears:
Short-chain quinones such as Q-2, Q-3 and octyl-Q function both as substrates and inhibitors of NADH oxidation in mammalian mitochondria. These quinone analogues accept electrons from complex I and become inhibitory once reduced, a suicide-like action that seems to derive from semiquinone instability, since it increases oxygen radical production in complex I. The hydroxydecyl Q analogue idebenone is more potent than Q-2 and specifically inhibits membrane potential, which raises some worries for its use as a nootropic drug .shapeshifter asked,
To AOR support:
The article you submit is interesting, but frankly, I don't undertand it very thoroughly. There are lots of terms I don't even recognize. Terms such as "Complex I", "Complex III", "N2" and many more.
The mitochondria generate energy by feeding electrons through a series of "pumps" in its membranes, each of which is referred to as a "Complex" and numbered sequentially (Complex II doesn't fit this pattern). This process builds up a "reservoir" of protons which are then released through a "turbine" called Complex V. (See the discussion and diagrams here:
http://www.r-lipoic....tochondrion.htmBasically, the main source of free radical production in mitochondria comes from the "fumbling" of electrons being carried by CoQ from Complex I to Complex III. "N2" is an iron-sulfur cluster in Complex I where this "fumbling" usually occurs. The short-chain CoQ analogs are more vulnerable to this "fumbling" than CoQ itself -- and idebenone is by far the worst of the lot.
But I understand that the basic finding is that one in vitro study suggests that idebenone increased mitochondrial free radical production. But what about the claim that idebenone is a very potent antioxidant: could it also be that, in vivo, those free radicals are soon to be neutralized by idebenone itself?
Not overall: if it were, your mitochondria would never produce superoxide and we would all live forever
. Despite the fact that it can act as an antioxidant, CoQ in its electron-shuttling role
is a free radical (ubisemiquinone). Indeed, the CoQ or analog has to be reduced (to have accepted an electron) in the first place in order to form this radical and then do its damage by mistakenly passing the electron on (via N2) to oxygen, forming superoxide. This already happens "normally" with CoQ
in vivo; by taking idebenone, you are displacing some CoQ with a substance which (in these
in vitro studies) is clearly much more "butterfingered" with the electrons in its charge.
I think it's quite logical that a substance that is known to increase cellular energy production also increase free radical production (simple analogy: more burning means more smoke).
That isn't the mechanism, as outlined above. It's not that you're pressing harder on the accelerator: you're replacing your spark plugs with cheap substitutes which make your engine burn less cleanly.
Personally, I'd rather advise heightened caution than to advise not to take idebenone based on one in vitro study (while numerous other studies do not come up with this possible risk).
But how would you exercise that caution, aside from by prudently refusing to take the risk in the first place? This is not a case like high-dose niacin, where one can take the supplement but exercise caution by undergoing regular liver enzyme tests. There is no way to monitor your own mitochondrial free radical production. The best that I can imagine doing is making sure to take plenty of R(+)-lipoic acid. In this case, it seems more sensible to simply refuse to risk one's health and chance at bootstrapping one's way into engineered negligible senescence, since after all (in answer to cosmos' earlier question) there are only marginal data supporting its benefits in normal, healthy organisms to begin with -- and to the best of my knowledge
no evidence of benefit in normal, healthy
humans.
It would seem best for life extensionists who are already fundamentally healthy to give special weight to studies suggesting a negative effect -- especially on a fundamental mechanism of aging, such as mitochondrial free radical production. It is one thing to take a risk when one is in an immediately crippling health disaster like Friedrich's ataxia; it is quite another when one has little to gain and much to lose. There would be little more bitter than to spend years pursuing extended youth, health, and longevity, only to discover that one has actually been poisoning oneself with the very substances which one has been swallowing in hopes of extended lifespan.
To your health!
AOR
