Note: If you haven’t already, please read Part 1 of this post prior to this one, for a better understanding of Aging.
Doug: Hey Molly, I was so excited to learn about gene expression and cell biology last time around that I’ve been telling all my friends about it. It’s so cool to know that even though every cell in the body has the same DNA, the reason a skin cell is different from say a kidney cell is the fact that different genes get expressed in each cell.
Molly: Yep it is! And that is the field of epigenetics - changes in gene expression without changes in the DNA sequence. So if you think of DNA as the hardware, epigenetics is the software that regulates the DNA - it is how cells control gene activity. We also touched upon how epigenetic modifications such as DNA methylation and histone acetylation can lead to abnormalities in gene expression which is associated with aging.
Doug: Yes, yes, can you please tell me more about these epigenetic modifications and their association with aging.
Molly: Do you really want to discuss DNA Methylation by this campfire at Yosemite?
Doug: Yes I do!
Molly: Alright then. It’s campfire story time.
Long, long time ago, some 1,000 years ago, there lived a King who ruled over an island called Caputi. Caputi was a small island with no resources of its own, but it had something very special. That is, the control of the Sea of Caputi. You see, Caputi was flanked by two of the largest trade nations at that time - Perulia and Tapooca. Perulia and Tapooca were constantly engaged in trading goods and they would send ships back and forth across the Sea of Caputi. Turns out, there was no way for Perulian and Tapoocan ships to reach each other without crossing the Sea of Caputi. And crossing the Sea of Caputi meant that they paid royalties to Caputi each time. These royalties are how Caputi made money.
Apart from his big ego, King Caputi (he renamed the island to be named after him, hence the big ego) was an otherwise benevolent ruler who used the royalty money for the benefit of his citizens. Having plenty of resources and not much work to do, the citizens of Caputi engaged in music, dance, and art. They lived a life of leisure and opulence.
But something terrible happened one day. King Caputi fell in love with an elegant lady named Rosanna. Now, now, of course, falling in love was not terrible. It was beautiful. In fact, Rosanna married King Caputi and they had two babies together. Here comes the terrible part.
One day, Rosanna woke up and claimed to not be feeling too well. She had contracted a disease called aging. Over the days, her situation got worse and the next 10 years were heart-breaking. Rosanna was bed-ridden, her hair turned white, she could barely speak, and she became a shadow of her former self, before eventually finding her way to the heavens.
King Caputi broke war. He roared, he moaned, he cried. But he was not one to give up. “I will murder Rosanna’s killer,” he said. The next day, an announcement went around:
“I, King Caputi, have declared war against a disease called aging. I ask: Why do we age? Whoever can figure out the culprit of aging and bring that bastard to me will be handsomely rewarded. I command the lands of Perulia and Tapooca to engage their best scientists and detectives on finding this culprit. If they do not comply, all trade will be stopped and the Sea of Caputi will no longer be open to them.”
The announcement created havoc. Everyone gasped. No one had dared ask the question “Why do we age?” before.
Priests came out and said, “God wants us to age. It is a sin to even ask the question.”
Philosophers said, “Control your thoughts. Learn to be stoic. Do not worry about aging. Embrace death.”
Economists said, “If we didn’t age and die, there would be shortage of food for the growing population.”
But King Caputi would not listen to anyone. His command was final: “I have declared war against aging.”
Perulia and Tapooca were forced to comply otherwise their trade would be shut off. They ordered their best scientists and detectives to work on the question. Months passed by but no culprits were found. Then one day, a man named Khalesh reached King Caputi’s court and declared, “Your majesty, I have found the killer.”
Khalesh’s clothing was torn, his face grummy, and he looked like he was about to die of starvation.
King Caputi roared, “You have found Rosanna’s killer? Who are you? You look like a poor beggar. Go away, don’t waste my time.”
“But Your Majesty, I beg you to believe me. Give me a chance. I swam all the way across your holy Sea of Caputi to deliver the message. I’ve been working on your question ever since your announcement got around. You see, I lost my father to the same bastard called aging and I too want to find the culprit. My father was my only family.”
Upon hearing that, King Caputi softened up. “So this murderer called aging has not only taken Rosanna’s life, but he’s out on the loose killing others too? He must be caught! Alright, tell me what you have to say.”
“Thank you, Your Majesty. I have been spending hours searching for this murderer and I think his name is DNA Methylation.”
“Guards, go find this bastard DNA Methylation and bring him to me.”
The next day:
DNA Methylation is presented in front of King Caputi.
“You son of Satan, who are you?” the King shouted.
DNA Methylation casually responded, “I am an epigenetic modification to your DNA. I am a process that involves the transfer of a methyl group on to the C5 position of your cytosine leading to gene silencing. I am catalyzed by enzymes called DNMTs, three of which have been identified in mammals.”1
“Speak English, you devil! Are you insulting me in your murderer speak? Tell me, did you kill Rosanna or not?”
“Kill Rosanna? No, far from it. I tried to help her.”
“You liar. Khalesh says that you killed Rosanna and his father and many more.”
“No, Your Majesty. You have the wrong information. In fact, I have an important role in helping you. I regulate your gene expression. You see, ~45% of your genome consists of viral elements and toxins. And you know what I do? I silence these toxins23.
“Khalesh, is this man speaking the truth?”
“Your Majesty, he is lying. He has a strong role to play in aging, inflammation and even cancer,” Khalesh responded meekly.
“Guards, kill this man called DNA Methylation. What an ugly name, anyway,” fired King Caputi.
DNA Methylation coolly replied, “Your Majesty, if you kill me, you will die too. Who will silence your toxic genome then? You see, Khalesh only has half the information. I help you by silencing your genes, as I said. But over time, something happens. Something I don’t like either and that is, umm..I start to change.”
“What do you mean you start to change?”
“Just like you have changed over time from being a child, to King, to lover, to warrior, I change too. But for some reason, these changes do not serve me well. Sometimes, I lose energy and this causes me to go into hypomethylation4 mode. And other times, I am in hypermethylation5 mode. And when that happens, genes that should be expressed in you don’t get expressed or vice versa where say cancer genes that should not be expressed, start to get expressed. And when gene expression is changed for a long time, cells begin to lose their identity, become senescent and die, all resulting in aging. The point being that any alterations and changes in me are not good6 and these changes summon the disease called aging that you are after,” said DNA Methylation.
“Okay, but why are you changing then if you don’t like it?” The King was getting impatient at this point.
“Your Majesty, I don’t know what is causing me to change, I don’t have a full answer and I am trying to figure it out. But I believe you and your people could be a reason.”
“You bastard, now I’ve had enough. You are telling me that we cause you to change and bring about our own death? You know how ridiculous that sounds. I’m going to behead you.”
DNA Methylation pleaded for the first time. “Your Majesty, please don’t. I am no scientist. I am only telling you what I have learned. I hear there are these people who do aging research and some of them say that changes in me summons DNA Damage, which over time causes aging. And your unhealthy lifestyle is causing changes in me7.”
“What’s unhealthy about my lifestyle?”
Majesty, that cigar in your mouth. The toxic chemicals in the air. Radiation. The stress you faced after Rosanna’s death. Your whiskey. You sitting on your throne all day long. You eating lavishly and consuming cakes. You sacrificing sleep for the dances you organize. All of this can add up over time resulting in changes in my methylation profile which is associated with aging8.
“DNA Methylation, now I know what’s going on! You can’t trick me. You are a spy from the island of Tapooca and want to figure out the secret to our opulence. All the things you mentioned show how wealthy we are.”
“Your Majesty, your wealth is not helping your health.”
“Shush, you poet! Guards, kill him.
“Majesty, before you do that, I have some good news for you. Preliminary studies show that it might be possible for you to reverse or slow changes in my methylation profile. Recently, these aging scientists conducted a small study where 8 weeks of a lifestyle that involved a diet of plants and fish, exercising, breathing exercises, and proper sleep reversed the biological clock used to measure me by a little over 3 years!”9
“What do you mean by a clock that measures you? You can be measured?” asked King Caputi.
“Yes! Your Majesty, I hear someone named Steve Horvath designed these clocks to measure changes in me and indicate both your biological age and how long you have till death. I don’t know too much more about it. You will have to ask him.”
“Okay, I’ll give you one last chance. If we find Steve and he verifies what you’re saying, maybe you can be saved. Until then, you shall be imprisoned.”
“Guards, find this Steve guy for me!” ordered the King.
Molly: That’s it for now, Doug. I’m sleepy and the fire is out. Let’s go into the tent.
Doug: What? You can’t leave me hanging like that. Did they find Steve? Did they find a way to measure DNA Methylation? How else can we slow changes in DNA Methylation?
Story to be continued…
DNA Methylation also serves other important functions including embryonic development, chromosome stability, X-chromosome inactivation. https://www.nature.com/scitable/topicpage/the-role-of-methylation-in-gene-expression-1070/
Loss of methylation in sites that should normally be methylated. Linked to aging and diseases such as cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873040/
Silencing genes due to methylation that should not be silenced. Again, linked to aging and diseases. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791695/
The precise regulation of DNA Methylation is also important for normal cognitive functioning. When DNA methylation is altered as a result of developmental mutations or environmental risk factors, such as drug exposure and neural injury, mental impairment is a common side effect.