Oxidative Stress and aging

Oxidative stress is the major pillar of the theory of aging. As a joke, I often say in my classes that we get old because we have the bad habit of spending our whole life breathing oxygen. Basically it is the oxygen that makes us live, but it is also the one that kills us little by little, that is, that makes us grow old...
And what is the relationship between oxygen and aging? The answer boils down to two words: oxidative stress! Sporadically, there are O2 molecules that transform into reactive oxygen species, most of which are neutralized by our antioxidant defenses (more information on this subject here). However, there are always some reactive oxygen species that can bypass our defenses and consequently can cause minor damage to some of our biomolecules. Although these damages do not have much biological significance, when evaluated isolated, as we grow older, they accumulate, and these cumulative damages begin to translate to the loss of some functionalities. Examples are loss of skin malleability, joint stiffness, loss of sensory ability, etc.

Therefore, everything that can accelerate our metabolic rate has the potential to make us age faster because it increases the production of reactive oxygen species. In this context, the effect of emotional stress is particularly evident! For example, people who have jobs and activities of high stress, age at a much higher rate than those who have a much more relaxed life.
Finally, I would like to make it clear that oxidative stress is not the only factor responsible for aging, but it is certainly one of the main ones, so if we want to age more slowly, we have to ensure an adequate balance between the pro-oxidants and the anti-oxidants!

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Oxidative stress and cellular respiration

During cellular respiration, electrons are transferred from NADH or FADH2, along 4 protein complexes in the inner mitochondrial membrane, to an O₂ molecule (read more about this subject here). In the last stage of the process, the electrons are transported one by one, that is, they will reach the oxygen one at a time. 

This situation, which may seem only a detail to many, has, in fact, very important implications for our biochemistry, because it means that all O₂ molecules are, even temporarily, transformed into a free radical, the superoxide anion. This means that, literally, at every instant we are producing large quantities of reactive oxygen species. However, this situation, which is potentially very dangerous, does not have, under normal conditions, dramatic consequences for cells, mainly for 2 reasons:
1. There are mechanisms that prevent the superoxide anion from diffusing from complex 4 before it is completely reduced to water. That is, the free radical is formed, but remains in place and quickly receives another electron, ceasing to be free radical.
2. As there are always some superoxide anions that can escape the first mechanism, we have other defense mechanisms, and in this context, the most important is the presence of a mitochondrial enzyme called superoxide dismutase. This enzyme, which also has a cytosolic isoform, will cause dismutation of the superoxide anion, converting two of these molecules into hydrogen peroxide.
Of course there will also be superoxide anions that will be able to escape from superoxide dismutase, but under normal conditions these are very few. In addition, we still have several other antioxidant defenses waiting for them...

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Oxidative stress - Advantages and disadvantages

Oxidative stress results primarily from an imbalance between molecules potentially dangerous to our cells, the so-called reactive oxygen species, and molecules that protect the oxidative integrity of our cellular structures, as discussed in another post (more information here). When this imbalance favors the former, or disadvantages the latter, we have the condition called oxidative stress.
Oxidative stress is the mainstay of the aging theory, because although we have several antioxidant defenses to protect us, there are always reactive oxygen species that can bypass these defenses, causing little damages that start to accumulate. Furthermore, in the case of smokers, there is permanent oxidative stress, especially at the level of lung cells, since tobacco smoke contains large amounts of reactive oxygen species (and reactive nitrogen species, but I will not talk about them today), which causes the antioxidant defenses in the lungs to be unable to cope completely with the aggressions from tobacco smoke.
But not everything is bad news, because our biochemistry is full of examples where even the most dangerous situations/molecules can be converted into an advantage, at least in some contexts... This is what happens with oxidative stress! Although it is a potentially fatal situation for cells and therefore, most often, is a situation we should avoid, there is a context where oxidative stress is beneficial to our body. I'm talking about the inflammatory response...

In a simple way, when there is an invading microorganism (or other types of stimuli), our organism detects that something is not well, and initiates the inflammatory response. One of the most important cellular components of it is neutrophils, a class of white blood cells. One of the ways neutrophils act, is related to their contact with invading microorganisms. In response to this situation, neutrophils increase their metabolic rate, and the reason is simple: they want to overproduce reactive oxygen species, that means, they want to induce oxidative stress. Of course, this is a controlled process, that is, the stimulation of oxidative stress occurs at a level that can still be effectively eliminated by our antioxidant defenses, but most microorganisms will no longer have this capability. Thus, neutrophils induce oxidative stress, at a level still tolerated by most of our cells, but not tolerated by most microorganisms. In this way, the invasion is controlled and ideally does not cause significant damage to our body.
Therefore, even oxidative stress can be advantageous, as long as properly controlled. It is another notable example of how fascinating is the World of Biochemistry ... ;)

Oxidative stress - Antioxidants

Recently I have made a post about oxidative stress (you can read it here), in which, of course, I gave some prominence to the reactive oxygen species. Well, today I'm going to talk about the "good ones", that is, the antioxidants...
The word "antioxidant" is probably the word most often heard in social media ads, whether in the context of food, cosmetics, etc. And, in fact, we can (and should!) ensure a high exogenous supply of antioxidants, being this an important issue in different contexts. What possibly fewer people know is that we already have several internal antioxidants. Therefore, we can already divide the antioxidants into 2 categories:
- Exogenous antioxidants, which are those that we obtain mainly from the diet;
- Endogenous antioxidants, which are those that we produce in our cells and that, under normal conditions, are always present in them.
Another possible classification is as follows:
- Enzymatic antioxidants, which are enzymes that we produce and whose function is to eliminate reactive oxygen species. For example, there is an enzyme, called superoxide dismutase that catalyzes the conversion of 2 superoxide anions (that are free radicals), to a hydrogen peroxide molecule (which, although being a reactive oxygen species, is not a free radical). Another example is catalase (you can read more about thisenzyme here), which converts hydrogen peroxide into two products potentially harmless to our biomolecules, water and oxygen.
- Non-enzymatic antioxidants, which are molecules that function as antioxidants because they react with reactive oxygen species, promoting their inactivation. In the background, they are molecules that "generously" put themselves at the forefront of the battle against the pro-oxidants. Therefore, these pro-oxidants will react with them, promoting their oxidation. This situation is beneficial, because it is the antioxidants that end up getting oxidized, sparing our biomolecules from oxidative damage. These non-enzymatic antioxidants often have in their composition benzene rings which stabilize the presence of a possible unpaired electron, and may also react with one another so that their unpaired electrons become paired. 

Within this class we have glutathione, for example, which is an endogenous antioxidant very important for red blood cells (and for other cell types...) and that reacts with peroxides undergoing oxidation. When it undergoes oxidation, it dimerizes with another oxidized glutathione. We also have some molecules that are exogenous antioxidants, namely vitamin C and vitamin E, which are very important antioxidants for our plasma and for our membranes, respectively. Note that there are many vitamins that do not have antioxidant function, that is, this characteristic can not be generalized to all other vitamins. There are also several antioxidants that are not indispensable to our metabolism, but they contribute to its good functioning, belonging to the class of bioactive compounds of the diet. Flavonoids or lycopene from tomatoes are good examples of this.
Therefore, if we look at the two classifications, it is easy to see that the exogenous antioxidants are always non-enzymatic, and that the endogenous antioxidants can be enzymatic or non-enzymatic. Regardless of the class where they are inserted, they are extremely important molecules and if we can guarantee an adequate contribution of them, surely we will be better prepared to deal with oxidative stress.

Cartoon about free radicals (2)

Oxidative stress (general considerations)

Today I decided to make a post on a very important topic, oxidative stress. This subject is often referred to in biochemistry classes (and not only!), but it is not always clear to the speaker or to the audience, what it actually represents.
Nevertheless, the idea is simple to understand ... As I say many times in my classes, we have a bad habit, which kills us slowly, without exception: we spend our lives breathing oxygen! And this molecule, so important for our biochemistry, in particular for aerobic metabolism, is what kills us slowly, and makes us grow old. And do not hesitate, if we do not die of an accident, or of some illness, we will die because we have been breathing O2 during our life! :)
So, what does oxygen contain that makes it so dangerous? Basically nothing, that is, the molecule itself is harmless to our molecules/cells. The problem is in its susceptibility to suffer partial reductions, that is, to capture electrons. In fact, we are continually forming the so-called reactive oxygen species, which are essentially 3: the hydroxyl radical (free radical), the superoxide anion (free radical) and hydrogen peroxide. Of these 3, the first two are more aggressive because they are free radicals. Free radicals are molecules that have an unpaired electron (which is why they are represented with a black speckle, which is that unpaired electron).  

The electrons have a serious problem, they do not like to walk alone, so they will look for "companionship" in the first molecule that appears ahead, be it a lipid, a protein or a nucleic acid. That is, reactive oxygen species are highly reactive molecules, they are powerful oxidizing agents, which will react with our biomolecules, removing an electron and altering/destroying them. And the problem is that although the free radical ceases to be when it picks up an electron, the molecule with which it reacts becomes a free radical, giving rise to a destructive chain process.
To counteract this, our cells have several defenses, called antioxidants. Therefore, oxidative stress arises when we have an imbalance between the pro-oxidants (reactive oxygen species and reactions that produce them) and the antioxidants (processes that prevent the formation and/or action of the pro-oxidants), favoring the first, or disfavoring the seconds.