Aging: the What, the Why, the Fix (Part 1)
Cell Biology Basics: Cell division, DNA, RNA, Proteins, Genes, Epigenetic Aging
Hi everyone! Before we move on to some riveting cell biology, a few announcements:
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And now, onto the final announcement. This post is Part 1 in a series of posts on Understanding Aging - what it means, theories on why we age, longevity pathways in the body, and mechanisms to reverse it. But before we dive into the intricacies of aging science, it’s best to cover some cell biology basics in this post. Trust me, it’s super cool, so here we go! :D
Doug: Hey Molly, what is all this hype about NAD+ and how it can reverse aging?
Molly: Aha, I’m glad you asked Doug! I indeed had planned on explaining the role of NAD+ in aging, but we first need to cover some foundational cell biology.
Doug: Nah, that’s boring. Basics are for kids. Please just tell me what NAD+ is and what to do to not get grey hair.
Molly: Alright then. NAD+ is a co-factor that is essential for the activation of sirtuins, enzymes that instruct histone spooling proteins to bind up the DNA tightly, and by removing the chemical tags on histones, sirtuins help prevent transcription factors from binding to genes, converting euchromatin into heterochromatin. By doing so…
Doug: Woah woah stop! I don’t get a word of it..
Molly: Well, I just explained to you the role of NAD+ in preventing aging..that’s what you asked for..
Doug: Okay Molly, you’re right. It might be better to cover some foundational material first.
Molly: Yes Doug. Don’t worry we will get to NAD+ eventually and in a fun manner that’s actually understandable! If we go step-by-step, you will understand a lot more about cell biology and aging than most people, and the foundations will serve you well!
Doug: Let’s go! I’m ready!
Molly: You remember how we spoke about cells having a different birthday, right? We discussed how aging is essentially occurring at the cellular and molecular level. We touched on how DNA damage can cause cells to become senescent which leads to Inflammaging. That was great to introduce you to the concept of aging occurring at the cellular level and what senescent cells are. (on another occasion we will dive deeper into senescent cells) Now that you have a better understanding, it’s time to drop the “advanced stage bomb” on you. So in the next few conversations I’m going to tell you about a particular theory of aging (the informational theory of aging popularized by David Sinclair in his book Lifespan), the hallmarks of aging, the very important co-factor NAD+ that you just asked me about, the very important enzymes / genes called sirtuins, the main longevity pathways that have been studied so far and certain actions you can start to take now to activate these pathways.
Doug: Wow, I’m about to learn so much!
Molly: Yes! Let’s begin. We established when we made you take your biological test how your cells have a different birthday, which is to say that aging is occurring at the cellular level. So if cells are so important to our survival and reproduction, I thought it might be a good chance to understand some of the basics of cells and genes and cell biology. After all, cells are the fundamental units of life.
I know, I know you found biology boring in school, but schools and textbooks have this weird property of making the most interesting stuff to be boring. In fact, it’s super cool to understand the encoding activity of your genes once you know the basics. Each and every cell is truly amazing.
Doug: What’s so cool about cells?
Molly: The first super cool fact: Even though we are an aggregate of 10^3 cells in the human body, we have been generated by the cell division of a single cell! This single cell, believe it or not, is the vehicle for all of the hereditary information that defines each species. And that is because each cell has the same DNA.
Doug: Dumb question, but uhh what exactly is our DNA? I know people throw it around a lot, but what’s the function?
Molly: Not dumb at all - I had the same question! Well, structurally speaking a DNA is a double helix chain, formed of the same 4 types of nucleotides (adenine, cytosine, guanine, and thymine). But I won’t go into those details. What’s important to know is that all living cells store their hereditary information in the DNA - the information you get from your parents is stored in the DNA of each cell. Also note that I mentioned how each cell has the same DNA. Now, cells replicate by dividing into 2 daughter cells. When they divide, the daughter cells get the same DNA as the mother cell, which is to say that with some rare exceptions (mutations in your DNA), each cell has the same DNA.
Doug: Hmm..so does my DNA determine my destiny?
Molly: It can dictate it, but it’s far from determining it! To see that, let’s learn how this hereditary information gets played out. We have established that the hereditary information of cells is carried in the DNA. Just because the DNA carries the information, it doesn’t mean it can express it. This is where RNAs and proteins come in to allow the expression of the DNA.
Doug: So just like - I may possess the talent of singing inside me, but to express it I have to bring my voice and mouth into play. Here the talent is the DNA, and the voice and mouth is the RNA and proteins?
Molly: Yes, great example! Through a process called transcription, the DNA creates RNA molecules which translate into protein synthesis. Proteins are the main molecules that put the cell’s genetic information into action and they direct the vast majority of the chemical reactions within cells.
DNA -> RNA -> Protein Synthesis ->action molecules
Doug: I see. So each cell has the same DNA which stores the hereditary information we get from our parents, and for the information to be expressed, the DNA forms RNA which create proteins, and these proteins are the molecules that are responsible for all the action going on in our cells.
Molly: Bingo! You’re great at summarizing1, Doug!
Doug: Hold on though. I’m confused about one thing. If each cell has the same DNA, why then are cells different? For example, why is a liver cell different from a skin cell?
Molly: Very important question. The simple answer is that not all genes get expressed in each cell2, and they can be switched on and off by external and internal protein signals. Okay, so what is a gene? Essentially, if you divide the DNA into different segments, each segment is called the gene3.
To ensure that each cell is carrying out the function that it’s supposed to (for example, a liver cell doesn’t just express itself as a kidney cell), genes get expressed differently in each cell. In a liver cell there may be certain genes that are turned “off”, while those same genes may be turned “on” in the kidney cell. While it may seem that there is a lot going on, gene expression regulation is usually surprisingly stable, at least in our youth.
DNA -> RNA -> Protein Synthesis -> Gene expression
Doug: What do you mean by “at least in our youth”? What happens as we age?
Molly: Yes, so this is where I want to touch upon how gene expression is linked to aging. Sometimes, the regulation and expression of genes can go haywire and abnormal and one such reason is when there is a change in the chemical structure of the DNA. For example, sticking methyl groups (DNA Methylation) or acetyl groups (Histone Acetylation) to the DNA changes its chemical structure, and thereby the expression of genes.
Doug: And what causes DNA methylation, for example?
Molly: Lifestyle factors are a big reason9. When we smoke or eat junk food, it could cause DNA methylation which results in aging. But the good news, as I’ve said earlier, is that it’s also reversible.
Doug: So Molly, I get that changing the chemical structure of DNA (DNA methylation and histone acetylation) can obviously change the expressions of genes. But how does the change in expression of genes result in aging?
Molly: Again, great question and that’s a topic for next time! I’ll touch upon a theory known as the informational theory of aging (popularized by David Sinclair in LifeSpan) which talks about how this DNA Damage (DNA methylation and histone acetylation) can cause aging. And I’ll discuss your favorite co-factor NAD+ too!
Doug: Hmm thanks..and you will discuss what can be done to reverse aging too, right?
Molly: Of course, Doug! One step at a time! I believe that if you understand what’s causing aging it makes it much easier to implement the lifestyle actions needed to reverse it.
Doug: I agree with you! Also, you’re right, cells are kinda cool and I’m glad I finally understand the basics of DNA and genes.
Molly: I’m glad too! It will be helpful in understanding epigenetic aging next time around.
For further reading, a great summary of DNA, RNA, Proteins and Gene expression can be found in the introductory chapter to Matt Ridley’s book Genome.
Other reasons why not all genes are expressed in each cell: (1) RNA molecules transcribed from the same DNA segment can be processed in different ways to give rise to different / alternate versions of proteins, thereby results in different genes being expressed. (2) Regulatory DNA binds to special protein molecules and controls for the rate of transcription, ultimately affecting gene expression. (3) If we write down the DNA sequence, we can know what amino acids will be produced and how they will be stitched together. But knowing how the protein will assemble itself, and what final shape it will adopt is a very hard problem. And the shape of the protein also determines the function it plays out, thereby changing gene expression. Further, pathways (such as NRF2 pathway touched on here) can also change the shape of the protein, affecting gene expression. (4) Changes in the chemical structure of the DNA (DNA Methylation and Histone Acetylation discussed) change the expression of genes.
Remember that each segment transcribes into different RNA molecules which further translate into different proteins. Which is to say that each gene codes for a different protein depending on the DNA sequence.
The DNA double helix is wrapped around histones, another kind of protein. Histones prevent the DNA from getting tangled and protect it from DNA damage. They also play a role in gene regulation and DNA replication.
Epigenetic age is a measure of biological age based on testing for DNA Methylation patterns.