Elimination of too many free radicals can be damaging

[gaoli]

Hello Dr Yechiel

I've been slowly working my way through your topical formulations articles.  A lot of what you say I have come across before, though in much less detail.  It's illuminating, if not a bit of a wake-up call to me to see it all pulled together - so thanks for that.

However one point you make, in your article "Anti-Oxidants, Oxidative Stress, and Cellular Aging", is quite radical for me, especially considering how anti-oxidant formulations are such a major player in the anti-aging market.  You say "free radicals are bioactive molecules which the body generates by design to be used in some metabolic processes and in defense mechanisms."

and your summary
"Reactive Oxygen Species and anti-oxidants are major players in bio-systems. Because of their high reactivity, the unclear and narrow borders between their “good” and their “bad” effects, and the limited understanding of their roles in living systems, much caution is recommended. Elimination of too many free radicals can be as damaging as the presence of too many free radicals. Until more is known, it is best to stick to anti-oxidants which are well known and be very cautious when exploring new anti-oxidants."

Can you elaborate on this, or point to any research proving this or is it purely theoretical at this point?   

I suppose what I'm also looking for is some practical guidelines or specifics which might indicate at what point you are eliminating too many free radicals, using which anti-oxidants and at what percentages?  If any of that might be known.

Thank you in advance
gaoli

(BTW sorry if this is in the wrong category - I can't see one for discussing general concepts)

[DrYechiel]

Hello Gaoli,

I have read your posting and your questions with interest and I browsed the literature again to make sure that I am updated with more current articles, as some time passed since I wrote the antioxidant article in our Journal Of Topical Formulations. Because the issues are vast and the arguments have to be organized, I decided to answer your question in two parts.

Part 1 which is this posting includes the verdict which is, indeed, the oxidation process is the basis of life and you can overload your system with antioxidants to the point of disrupting the natural oxidative pathways. There are antioxidants which are more meaningful in combination with each other and some which are more prone to disturb the biosystem’s natural oxidative pathways; not all anti-oxidants are created equal.

Part 2 will include the explanations to support Part 1 and I will need another week before I can put these arguments together in a coherent way to show how this can be known. I will also explain the role of pro-oxidants.

Thank you for your questions and comments.

[gaoli]

Thanks so much for replying Dr Yechiel.

I can understand it is a *vast* area like you say, which is why I am so looking forward to seeing if you can put together Part II.  That will be quite a feat.

Gaoli

[DrYechiel]

This is Part II of my answer.

Most free radicals are generated by our own body’s biochemistry. Many biological free radicals, like many things in life, have an immediate, short-term effect of supporting life and long-term effects of damaging the very life they bring about. Just like the effects of some chemicals which prevent immediate danger from food poisoning may in the long run weaken the body. Free radicals are known to be involved in an ever-increasing number of signaling pathways in the body, immune activities, detoxification in the liver, and in many other life-supporting mechanisms. In addition, if a large quantity of our free-flowing electrons were removed, or the mechanisms which generate them would be blocked, we'd literally die, and rather instantly. Too many anti-oxidants can also cause fatigue due to reduction in energy generation or utilization. Extreme overload of anti-oxidants may even impair the basal metabolic rate. The ultimate dilemma is reflected in the activity of free radicals: they save biological entities from imminent and fast death, but they also contribute to an accumulated biochemical deterioration which results in shortening life. The secrets are two:

1. Balancing the amounts of anti-oxidant and,
2. Controlling the identities and relative quantities of the antioxidants we consume, and consuming them in a smart combination.

Free radicals are a normal byproduct of breathing, in which biosystems use oxygen to generate energy. The process of energy generation, “oxidative phosphorylation”, is based on electrons which are passed down a reactivity slope from molecule to molecule and in the process positive ions are pushed across the inner mitochondrial membrane via specific portals, due to an electric potential between the two sides of the membrane. This electric potential is further utilized by the cells to generate chemical energy as ATP, the energy-molecule which gives and maintains life. ATP is generated from ADP when the protons push their way back through the inner membrane via the specific portals. This passage of protons is coupled with a mechanism which creates chemical energy in the form of ATP from the electrical energy.

Free radicals can damage cell membranes and genetic material and contribute to the development of cancer and heart disease. However, there are also very well known specific ailments which occur from overdose of specific anti-oxidants. For example, selenium, which is a common dietary supplement, and an antioxidant, and is very helpful in the removal of harmful free radicals. Many of the benefits of selenium are related to its role in the production of glutathione peroxidase (GP), an anti-oxidant enzyme that helps detoxify the body. However, too much glutathione-peroxidase activity contributes to development of type II diabetes. A study at Cornell University suggests that increased levels of a selenium-containing enzyme could promote type 2 diabetes due to increased precursors of the disease. The same “good” selenium becomes “bad” if it is overly consumed. In addition, some level of free radicals appear to be needed to regulate insulin sensitivity to receptors, which is a major problem in type II diabetes. 

Butylated hydroxytoluene (BHT) is a common anti-oxidant used in foods and oils. It was discovered that BHT and also butylated hydroxyanisole (BHA) can directly interact with the mitochondrial oxidative phosphorylation structures and reduce their effectiveness in two ways:

1. They act as uncouplers, uncoupling phosphorylation (phosphorylation is the generation of ATP by adding a phosphate group to ADP) from the oxidation process by permeating the mitochondrial inner membrane with protons. This means that the protons flow freely through the membrane and they don’t have to pass through the special portals which are coupled to ATP generation (uncoupling). This is not very different from a short-circuit in electricity.

2. They also directly interact with the structures in the electron transport chain on the inner side of the membrane, preventing the generation of  an electric potential across the membrane and thus inhibiting respiration.

Overdosing on BHT can result in low energy levels, frequent tiredness and fatigue, and higher susceptibility to various ailments.

To mention a few more antioxidants which act as uncouplers: Quercetin, a flavonoid that has been shown to act to uncouple mitochondrial respiration via inhibition of the Mitochondrial Membrane Permeability Transition (MMPT). Conjugated linoleic acid (CLA) has been reported to increase the expression of the uncoupler UCP2 in the mammary gland, brown adipose tissue, and white adipose tissue of mice, and also the levels of the uncoupler UCP3 in skeletal tissue. Olive oil feeding created a very high rate of expression of mRNA for UCP1, UCP2, and UCP3 in rat brown adipose tissue; the uncouplers in brown adipose tissue are supposed to generate heat instead of chemical energy.

So far, it appears that lipid-soluble anti-oxidants have more deleterious effects on mitochondrial function than water-soluble antioxidants. However, this may just be the tip of the iceberg. It is well know that Vitamin C, which is highly water-soluble, can regenerate Vitamin E, which is very oil-soluble. This can suggest that water-soluble anti-oxidants can affect oil-soluble anti-oxidants for the better; the question of whether they can also do it for the worse remains open. It is also possible that water-soluble anti-oxidants can directly interfere with metabolic pathways, but because they are eliminated from the body quite rapidly they appear to be less of a threat than oil-soluble anti-oxidants, which can stay in the body for many days. It is also possible that even in a short stay in the body of an overdose of water-soluble anti-oxidants, some metabolic pathways may be negatively affected. Overdosing on Vitamin C, the very well known and safe vitamin even in very high doses, was also reported to be associated with tiredness and fatigue. The connection so far is not proven nor understood.

Research is now focused on finding a way to reduce reactive oxygen species (ROS) which are generated in the mitochondria during the “resting phases”, (since ATP is generated at state-3) when ATP is not generated and the activity of anti-ROS will not significantly affect the energy generation in cells. Uncoupling is thought to be important in protecting against ROS under "resting conditions," wherein ATP generation is not essential, thereby directing electron transport toward uncoupling, or alternatively to work independent of ATP generation, so that ROS will not accumulate due to altered flow-rates or unconsummated flow of electrons (flow can be affected if protons passage through the membrane is restricted, which is the case when ATP is not generated) and therefore generate ROS. It was also reported in one study that at state-4, (where ATP is not produced) there is 4 times more production of ROS than during state-3, when ATP is produced. However, uncouplers which were used at state-3 did not reduce the ROS formation levels. If a method will be developed to quench ROS generation during resting states so that they don’t interfere with the ATP generation state, it could provide a better targeted means to rhythmical-dosing (rather than constant-dosing) in the utilization of anti-oxidant.

Many natural anti-oxidants in the body exist or are utilized in very different concentrations, some, at an orders of magnitude more than others. To learn the natural state of concentration of each anti-oxidant and how they are related to each other or react with each other is the very knowledge base people are usually ignoring. Anti-oxidants are not made equal and many have physiological attributes other than just acting as an anti-oxidant. When an anti-oxidant interacts with its target, it becomes itself a pro-oxidant. This can be reversed by additional action from another anti-oxidant on it. For example, Vitamin E becomes a pro-oxidant after it protects a membrane lipid from oxidation; then Vitamin C will regenerate Vitamin E into its natural state as an anti-oxidant while the Vitamin C will turn into a pro-oxidant. Some pro-oxidants are mild and water-soluble and don’t require more recycling before they exit the body. Some will recycle by natural mechanisms which in themselves utilize metabolic energy for the recycling process.
 
The bottom line is that taking the right amounts of the right anti-oxidants is very important; too much is too much. In the long run, modulating ROS generations in the mitochondria during resting states may be one more avenue to healthy life and even to a prolonged lifespan.

[gaoli]

Thanks for taking the time to put together such a detailed explanation.

I think most people are aware of 'vitaminosis' or overdosing on supplements, but I have quite a simple question though the answer won't necessarily be so easy.

Most of your conclusions here are drawn from studies of oral anti-oxidants - can you really apply that directly to dermatology?  I've always imagined the metabolism of the skin to be quite different to the metabolism of say, the liver.  I was really hoping you could give more examples relating to topical anti-oxidants.  So, is your answer directly applicable?

It seems to me it's very difficult to put together any completely tested anti-oxidant combos unless they are in ones and twos; like LA and Vit E or Niacinamide and Kinetin; because that's what studies tend to prove (online at least - I don't know about professional sources), never more.

If that's the case how can any formulator ever really know whether their anti-oxidant formulation containing a mix which hasn't been studied is truly effective and not counterproductive at all, apart from an educated guess?

Thanks again, gaoli

[DrYechiel]

Thank you, however, my comments were not really about overdosing on vitamins. Many vitamins have more functions than just being anti-oxidants and that is where you can overdose on vitamins. “Overdosing on antioxidants” is another issue; this is the issue I have discussed and it is definitely not a well-known issue, even by many profesionals. I was talking about dismantling the ReDox potential in cells and its relation to cellular and organ functions. An extreme case of such activity is the example of the poison cyanide, which kills in seconds by destroying the ReDox potential. I must also emphasize that oxidation is a physiological need, as is anti-oxidation; they are not “the good and the bad”, they are both only good if they are well balanced. Most studies are in tissue cultures and there are more oral than topical studies for reasons which I will not further deviate from the topic to discuss. However, there are means of performing topical studies with reasonable accuracy. Of course, many of these studies are developed by specific companies (no FDA general guidelines have been developed about “anti-oxidative dosing”, neither for topical nor for oral consumption) and they would prefer to keep it a secret from competitors. The main problem is not so much to estimate a safety range of an anti-oxidant as to estimate absorption which differs with every product line and every product within a product line. Example: you can coat your entire skin with vitamin E and only feel greasy as a result but no side-effects as you may feel if you swallow it. It is because plain vitamin E does not absorb.