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Oxidative Species & DNA Manipulation

Oxidative Species & DNA Manipulation

Huge Cause of DNA Mutation and Aging

How cellular functions ultimately lead to DNA destruction…

Are we telling you that you can actually change your DNA? Simply by having a certain “product” in your body?

Yep! We are telling you that.

DNA strand

In case you were wondering, this is not good — to alter your DNA and all.

It actually leads to a lack of longevity (earlier death), as we will see in a little bit.

This is Part 1 of a trilogy. It is the trilogy of reactive oxygen species (ROS).

Now, we mentioned these guys in our last blog post. In case you missed it, you can check it out here.

This is what the National Cancer Institute has to say about ROS:

“A build up of reactive oxygen species in cells may cause damage to DNA, RNA, and proteins, and may cause cell death.” [1]

That doesn’t sound very good, does it? Nope…

So let’s dig into the details and figure out the relationship between ROS, DNA mutation, and longevity (or the lack thereof).

Summary of Part 1

  1. Fast living (more O2 consumption) ≠ fast aging
  2. More ROS production = more mitochondrial DNA damage
    1. The close proximity of ROS production (at Complex 1 of the ETC) directly affects DNA
  3. Antioxidants do not help prevent oxidative damage to DNA
  4. ROS production is not a necessary byproduct of the electron transport chain (ETC)
    1. It seems to be a finely tuned mechanism controlled by mitochondria

Introduction

This week, we looked at one very long research paper… So we broke it up into 3 parts for you.

We hope that makes it easier to follow along. The entire research paper is:

==> The Cell Aging Regulation System (CARS) – conducted by Gustavo Barja at the University of Madrid.[2]

[This Week’s Research File]

Before we get started, we want to make sure you understand something. This is a review article, not a primary source research paper.

That means the researchers here gathered a whole bunch of other research and analyzed it together.

These actually make for great references because they are, essentially, meta-analyses.

That is, analyses with a vastly broad scope. They take in so much information, process it all, and then relay the significance.

This entire paper was written to merge the ideas of the mitochondrial free radical theory of aging (MFRTA) into their review of the cell aging regulation system (CARS).

Now, let’s look at some background information before looking at the article.

Revisiting the MFRTA

You might have heard of “free radicals” before. They are a pretty hot topic. Essentially, they are species with unpaired electrons, so they are extremely reactive.

Free radical

The definition has now broadened to include substances that form radicals really easily, like most peroxides (H2O2).

And usually it is not good to have reactive substances in your body. They change things like your DNA. [34]

This is the basis of MFRTA. The free radicals damage parts of the cell, and the cell dies.

This happens on a very large scale over a very long time — leading to your aging and ultimate death.

Sorry to sound so grim, but studying these things can help with finding cures and preventative measures.

But having said all this, ROS also provide beneficial functions for your cell.[5 , 6] It really is a balance.

The “correct” way to view this stuff isn’t very satisfying:

  • ROS play necessary roles in your body, and that’s why we are programmed to create them.
  • ROS can be very, very damaging to your cells at the same time. They can be pretty bad for the most part.

As you can see, it is not as clear cut as we once thought…

But, there is still a lot of evidence suggesting ROS cause a whole lot of aging and cell damage.

That’s what we are going to focus on today.

So let’s jump into the specifics of the article.

Aging Speeds

So, we know that some species live a lot longer than others. And even within species, some individuals live much longer.

Why is this? What are the common threads between longevity and molecular biology?

This article breaks it down quite nicely. That’s the beauty of a review article.

Moving fast

To make their research credible, they mention how they gathered their studies. They gathered data from short lived rodents, a variety of mammals, and long lived birds.

The birds were especially important because they deviated from an old “law” in the scientific community.

That is Pearl’s Law.

According to Harvard Magazine, “Pearl argued that metabolic rate determines longevity, and the slower the rate of metabolism, the longer an organism will live.” [7]

Pretty much that just means an animal will live longer if its metabolic rate is lower. So, if it has higher respiration (O2 consumption), then it will die sooner.

Fast Living = Fast Dying

Makes sense, right??

Too bad it doesn’t stand up well to recent analyses. Birds (along with bats and primates) debunk this theory.

According to our article, birds have an outrageously high specific rate of oxygen consumption. That means they consume more oxygen per amount of body weight than most species. Yet, they live so much longer than would be expected.

According to the researchers, “Birds have both a high rate of oxygen consumption per gram of tissue and a high longevity. This makes them ideal to solve the problem mentioned above.”

Thus, they concluded that it is not as simple as living faster means your dying faster.

Living longer might be related to slower metabolism, but there must be better correlations to look at, right?

ROS Production and DNA Damage

So, what did they find that was common among ALL SPECIES?

The lack of ROS production was consistently correlated with longevity. Mitochondrial ROS production is a much more sound measure, predictor, and cause of aging than breathing faster.

That is great news because now we have stronger suggestions to what the real cause of aging is. We can tackle the issue head on.

This is the main topic of today’s blog — but only a part of what this entire article talks about.

Chemistry lab

Our article breaks down the importance of ROS production very nicely.

Where Does ROS Production Happen?

First of all, most of the ROS production occurs at Complex I of the electron transport chain, not Complex III like previous thought. (Another study by Yuanbin Liu confirmed this if you’re interested. [8])

They know this because their studies showed inhibiting the flow of electrons back to Complex I (reverse electron transport) decreased the ROS production. That didn’t happen with Complex III.

This location is very important. This is where everything comes together. Remember this:

  • ROS production = bad (in these situations)
  • ROS production happens at Complex I
  • Mitochondrial DNA is situated very close to Complex I

Did you catch that last part? Your mitochondrial DNA hangs out right next to where it’s enemy lives!

Your DNA might even be in contact with Complex I. So your production of ROS is directly affecting your mitochondrial DNA.

We say “might” because no one knows for sure right now. It is an interesting theory, and it would explain a lot…

But that’s for other scientists to tackle down the road. Right now, we see it as a strong possibility.

What Damage They Saw

The researchers for this article did get a little more specific about the DNA damage they saw.

They measured “damaged DNA” by looking at the levels of 8-oxo-dG in the DNA.

It is pretty much just an oxidated line of code in DNA. This helps us define if there was oxidative damage or not.

They found that mitochondrial DNA had much more of this oxidized nucleotide than nuclear DNA had.

Nuclear DNA is what makes you you. It’s the “main DNA” and lies in the cell nucleus.

Mitochondrial DNA is more specific and helps your cells build stuff necessary for respiration and metabolism. Mitiochondrial DNA is the kind that is near Complex I.

Nuclear DNA is far away — it does not get as damaged. Also, the damage it does see is not correlated with longevity.

This suggests that aging really is all about ROS production.

Preventing Oxidative DNA Damage (Anti-oxidants)

You have probably heard of antioxidants before. They are a common thing sold on the market for promoting health.

The U.S. National Library of Medicine says, “Antioxidants are man-made or natural substances that may prevent or delay some types of cell damage.” [9]

==> Keyword here: “may.”

We do not think they’re bad. They might help a little bit. But they don’t help as much as people like to think.

Blueberries - antioxidants

Our researchers actually found a negative correlation between anitoxidant presence and longevity — “a lack of effect of antioxidants on mammalian longevity.”

What?!? Longer living animals actually had less antioxidant in their system?

Yep! But that does not mean antioxidants are causing the aging.

Rather, the researchers suggest that long living animals produce less anitoxidant because they have less ROS production.

It is the reduced ROS production that leads to longevity. As a consequence of less ROS production, their bodies don’t create as many antioxidants.

Makes sense.

But let’s answer the more confusing question. If oxidizing agents are bad (ROS) and cause damage, wouldn’t antioxidants be the natural solution?

Sure! If they actually got there in time!

Remember that mitochondrial DNA hangs out right next to (or even touches) the ROS production site, Complex I.

There is absolutely no way antioxidants can work in time to prevent oxidative damage to DNA. No way.

Anyway, wouldn’t the best “antioxidant” be not creating ROS in the first place? That’s what these researchers suggest.

“To obtain a low level of damage at mtDNA it is much more efficient to lower the rate of generation of damage than to have a high rate of damage generation and, afterwards, try to intercept the generated ROS using antioxidants, or try to repair the damaged already inflicted on mtDNA.”

That pretty much says it’s more energy efficient to never produce ROS in the first place. Let’s focus on that rather than anitoxidants, which can only arrive after the damage is done.

Is ROS a Natural Consequence of the ETC?

Apparently, some researchers think that ROS is something that always happens. It is something that is inevitable.

We don’t know if that is true or not, but this article suggests scientists are viewing it wrongly.

The rate of ROS production varies regardless of the oxygen consumption rate. That means your mitochondria seem to control when ROS is produced.

This seems odd because it is almost like a self-destruct mechanism. They control the rate at which your body is dying.

However, there is evidence to suggest that ROS prouduction is not all bad. [5 , 6So, this phenomenon seems to fit into that narrative. 

There is a balance to everything. After reading this paper, our hypothesis stands that everything requires fine tuning and balance.

Too much ROS production can lead to destruction. Too little can lead to a lack of regulation. Only your mitochondria know best.

Next Hypothesis

But we are convinced there are certain ways we trigger our mitochondria to do carry out destructive measures.

We want to try to eliminate that from happening. So that is why we promote the ketogenic diet.

It is not just a “fad.” It is real science.

This article does not go into the specifics of how ROS is generated, but rather it states the fact that ROS production is directly related to earlier death.

Whether it is the cause or not is up for debate. We think so. The pathway we suggest goes something like this:

 

Process flow of cell damage

 

But this is just our hypothesis – based on our research.

Also, we included some other information that we will be talking about in the next blog! That is the damage done to your mitochondrial membranes.

We just wanted to give a bit of a sneak preview.

There is so much more work to be done in this field, and we are so excited for the future!

Who knows? Maybe you will be the next scientist to figure out the key to slowing down aging…

But for now, we have confirmed 4 things from this article:

  1. Fast living (more O2 consumption) ≠ fast aging.
  2. More ROS production = more mitochondrial DNA damage
    1. The close proximity of ROS production (at Complex 1 of the ETC) directly affects DNA
  3. Antioxidants do not help prevent oxidative damage to DNA
  4. ROS production is not a necessary byproduct of the electron transport chain
    1. It seems to be a finely tuned mechanism controlled by mitochondria.

We hope this was at least somewhat helpful for understanding more about the mechanisms of aging.

Based on all this information, it is yet another reason to promote the ketogenic diet. You might not see why this article leads to that conclusion yet, but we will be going through that on the next posts.

To health, love, and happiness!

References:

[1] National Cancer Institute. 2018. NCI Dictionary of Cancer Terms. [Online]. Available: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/reactive-oxygen-species. Accessed 7 Apr. 2018.

[2] Barja G, et. al. 2017. The Cell Aging Regulation System (CARS)Reactive Oxygen Species 3(9):148–183.

[3] Dizdaroglu M, Jaruga P, Birincioglu M, Rodriguez H. 2002. Free radical-induced damage to DNA: mechanisms and measurement. Free Radical Biology and Medicine. 32(11):1102-1115.

[4] Cadet J, Davies K, Medeiros M, Mascio P, Wagner J. 2017. Formation and repair of oxidatively generated damage in cellular DNA. Free Radical Biology and Medicine. 107:13-34

[5] Li G. 2013. The Positive and Negative Aspects of Reactive Oxygen Species in Sports PerformanceCurrent Issues in Sports and Exercise Medicine.

[6] Scialo F, et al. 2018. Mitochondrial ROS Produced via Reverse Electron Transport Extend Animal Lifespan. Cell Metabolism. 23(4):725-735.

[7] Harvard Magazine. 2018. A New Theory on Longevity. [Online] Available at: https://harvardmagazine.com/2004/11/a-new-theory-on-longevit.html. Accessed 7 Apr. 2018.

[8] Liu Y, Fiskum G. & Schubert D. 2002. Generation of reactive oxygen species by the mitochondrial electron transport chainJournal of Neurochemistry 80:780–787.

[9] Medlineplus.gov. 2018. Antioxidants: MedlinePlus. [Online] Available at: https://medlineplus.gov/antioxidants.html. Accessed 7 Apr. 2018.

3 Responses

  1. […] Another possible mechanism is that lower metabolism leads to higher electron leakage. When you leak electrons backwards through the electron transport chain, you generate oxidative species. Because oxygen is a key player in metabolism, you create “reactive oxygen species” (ROS) that go around and damage everything. We have done several blog posts on why ROS are bad, you can check out a starting point here. […]

  2. […] bring up free radicals or the entire room might burst up in response. In all seriousness, reactive oxygen species (ROS) and free radical species are not good for you in large amounts. ROS decrease life span. They […]

  3. […] We’ve talked about them the last few weeks, so you might not need a reminder. But just in case… you can check out our commentary on the subject here. […]

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