What am i talking about?
There's someone we need to talk about!
In our daily lives, bombarded with information,
we've forgotten, we've overlooked someone!
And that someone is aging.
Imagine an hourglass you want to stop.
It's in your hand, and you truly want it to stop.
Now, imagine it slipping from your hand and shattering.
What we're doing to ourselves is unsustainable.
We need to talk about us.
12
The number of things that happen to us as we age
Metin Sokmen, MD
Genomic Instability
About 150 years ago, we discovered that there was a code within us. Soon, we saw that this code was made up of four letters. We were excited. How hard could it be to crack this code? It took us 150 years just to read the entire code, let alone crack it. You might remember or imagine the excitement when the Human Genome Project was announced in the early 2000s. We thought we would be able to press the keys on the keyboard ourselves. But that didn't happen. In the last 20 years, our DNA reading technology has truly advanced. However, we have only just begun to intervene. This is a long journey.
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This structure that we can just barely touch gets damaged every day. It happens because of the sun, the food you eat, the medicines you take, or simply as a result of the normal life of a cell. We have repair mechanisms to fix the mutations that occur, but they can't keep up. As the unrepaired parts accumulate, THE CAR STOPS.
Telomere Shortening
I assume you've heard of telomeres. If you have, you've definitely encountered the shoelace analogy. I wish I could use a different analogy, but none fits better. Yes, our telomeres are like the protective plastic tips at the ends of shoelaces. They protect the lace (chromosome). However, there is a problem. Otherwise, why would you visit a site like this and read these articles? The problem is that this structure shortens with each cell division.
You might hope this starts at 60, 70, or even 90 years old. But it doesn't. It begins at the very moment the sperm and egg cell merge to form us. In fact, during the early stages in the womb, this shortening is quite significant due to the rapid cell division.
I can almost hear you wishing this shortening didn't happen. Well, there are cells where this doesn't happen, but they are not pleasant. Cancer cells do not experience telomere shortening as they divide. This is the PRICE of uncontrolled growth. Clearly, we don't want that. For now, simply slowing down the shortening can be beneficial.​
Epigenetic Alterations
I believe this is the most underrated topic in the exciting agenda of today's world. Many of the issues we still debate over DNA can actually be answered here. It can be said that the concept of 2-dimensional DNA, which was put forward 150 years ago, took on a 3-dimensional form 70 years ago with epigenetics.
We had a common curiosity in biology classes: How can organs with such different functions be found in the human body, which consists of the same 46 chromosomes from a single cell? This is made possible by epigenetics. Through some marks placed on DNA, decisions are made on whether genes are turned on or off. In simple terms, genes that form cells enabling your ears to hear are active, while the genes in your eyes use those allowing you to see. Unnecessary parts are not only redundant but also mean energy waste and chaos. Organizing DNA is vital.
But it's not over yet. If you got excited up to this point, here comes the punchline. You may remember a man named Lamarck who claimed that the material of inheritance changes with our way of life. He became generally regarded as an insignificant figure in science because this was incorrect for DNA. However, we can reconsider this with epigenetics because there is a trace left in you from your grandmother's smoking or your father's sedentary lifestyle. Epigenetics is the report card of your life, and this report card is passed on through inheritance.
Loss of proteostasis
The main function of genes (in fact, we could say their only function) is to encode the information necessary for protein synthesis. Additionally, this information needs to be passed on to future generations. Why? Because you are giving your children the recipe for the proteins that allow you to survive. They should make the same proteins and survive as well.
Some people call genes selfish, thinking that genes do not consider us, but are passed on solely to keep themselves alive. I hope this is not the case, as it would be a relationship devoid of the allure of emotions. Anyway, let's continue.
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The produced proteins need to undergo additional processing. You can think of this as adding spices to a dish. If you don't do this spicing process correctly, the dish will be ruined. Incorrect folding is like this. The consequences don't leave us hungry; they cause us to forget what we ate last night.
One of the first factors identified in the formation of Alzheimer's disease is these misfolded proteins. Misfolding and the inability to clear these harmful clumps not only damage the cell but also trigger inflammation. Drugs that clean up these misfolded origamis are the latest treatment for Alzheimer's. However, this process also occurs to varying degrees and forms in our other cells. As we age, one of the burdens we carry is these useless proteins.
Deregulated Nutrient Sensing
Is there anything better than eating a good meal? Bon appétit. However, if you attend Longevity 101 class, you definitely won't be treated like this. When you enter the classroom, you'll see posters that say "No Eating Allowed."
Yes, if there's one thing we've known for 100 years that extends lifespan, it's calorie restriction. Moreover, this knowledge dates back to ancient Greece. A moderate lifestyle adds years to your life. So why is this? Couldn't our bodies be more pleasure-seeking? Actually, this is a misunderstanding. Maybe one day we can explain this to our cells. The signals created by hunger are clear. This topic can become vital. The genes that activate in preparation for battle help us live longer.
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The pathways that activate these genes wear out as we age. Worn-out pathways leave the body unprepared for battle. Resilience is lost, and a new concept emerges: frailty.
Mitochondrial Dysfunction
Mitochondria is one of my favorite topics. Together with epigenetics, I expect a big breakthrough from here.
Imagine an organelle within the cell that transferred from another organism in the early stages of life and established eukaryotic dominance on Earth. It's a miracle! Science is like that; it writes books about a word you've never used in a sentence in your life. Mitochondria deserve this attention because life is energy. Every energy requires a source. More precisely, the potential energy in a source needs to be released and converted into a usable form.
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Before we existed, and even before we became engineers, all rivers flowed naturally. Then we came and built hydroelectric power plants. We used the potential energy of water at high elevations to light our bulbs. That's what mitochondria do. They convert the energy in an apple into ATP that our cells can use. Think about the importance of this: energy. Everywhere, people talk about healthspan and lifespan, but I think the real issue is this. I even coin a new term here: energetic longevity... The proof of our lives is the energy we produce.
Cellular Senescence
We've come to cellular senescence. Some textbooks categorize aging mechanisms under this heading. Indeed, it is more of an outcome than a cause. If only cells had a voice, imagine what they would say. After all they've been through, they eventually become damaged. To prevent the domino effect of proliferating damaged cells that could destroy the entire organism, they make a sacrifice. They give up the pleasure of proliferating. Here, we can also show good examples of our selfish genes.
These cells are often referred to as zombie cells. But why call them zombie cells instead of dead cells? Because despite their sacrifice, they do one more thing. They secrete certain substances. These substances trigger inflammation. Why do they support this pathway, which causes deadly damage in muscles, the brain, and blood vessels?
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Actually, we have recently found that this too can be a physiological call for help. However, as we approach the species-specific lifespan limit, it seems to do more harm than good.
Stem Cell Exhaustion
In presentations, it is recommended to avoid expressions that create misleading emotions for the audience. Are you feeling exhausted? But we must continue; we have just started the second half.
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This field is also fascinating. If you are excited about epigenetics and mitochondria, I suggest adding this topic alongside them. Each of you carries incredibly talented cells within you. Yes, every cell has indispensable functions, but some are different. We can explain this with the analogy of worker bees and the queen bee. This is actually a very fitting analogy because, as you know, the future and strength of the hive are determined by the queen bee. The ancestors of these cells formed you. As long as you live, they live too. Actually, it’s the other way around. As long as they live, you live. However, they get exhausted. You age.
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A similar situation, known as the Hayflick limit, occurs in somatic cells. Every cell has a division capacity, and this limit is set by telomeres. If you have read about stem cells, telomeres, and telomerase before, this is where the confusion starts. In biology classes, stem cells were defined as cells with unlimited division capacity. But it doesn’t work that way. Time wears everything down. This means that each division leaves a mark on the stem cell. Genetic damage, microenvironment changes, epigenetic alterations, and a bit of telomere shortening and inflammation (it touches everything, including here) shatter the dream of stem cell immortality.
Now, let me tell you a secret. We have started to erase some of these marks. Can you imagine? A youth elixir for our cells called "epigenetic reprogramming" has been found. But it’s not ready for you yet. Should you be excited? I think so!
Altered Cellular Communication
This topic is rarely discussed anywhere. It is indeed the hardest to define as it encompasses other areas. Let's go through a few examples.
As you age, your neurotransmitter levels change. This is why depression is so common in old age and why Parkinson's disease occurs. In old age, insulin signaling deteriorates. This is the reason for the insulin resistance and type 2 diabetes I see so often in my clinic. The changes in our skin's structure and the programmed cell death also bear its mark. As I said, it's a vast field, but we can see the loss of organizational skills.
It's like an army where the general and high-ranking officers are shirking their duties, leaving us vulnerable to attacks on the battlefield.
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I don't want to appear shallow by constantly using war examples, but the topic at hand is a real battle. It's a battle where evolution has put us at a disadvantage, but one where we have managed to advance with our exceptional skills. However, if you insist, for the white-collar workers among us, I can compare it to a company without a CEO, COO, CFO, CIO, CMO, or CTO.
Inflammaging
Inflammation is a very special topic. It might be the most frequently mentioned word in longevity discussions, but rest assured, very few truly understand this area. Don't end your longevity talk without using a trendy term like "inflammaging."
In its simplest form, it's a low-grade but persistent fire. It doesn't create an overt clinical scenario like a pneumonia, which is why it was overlooked until the last few decades. (In fact, when we used to refer to the "Hallmarks of Aging" as the "Nine Hallmarks" ten years ago, this concept was missing.)
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We are an organization, and like any organized system, we need to limit external interventions and intrusions. Our inflammatory cells are like law enforcement, maintaining order and preventing foreign invaders. However, partly because they can't mount the strong responses they did in youth, and partly due to the prodding of senescent cells, they are constantly alert. When you see elderly people who eat very little, think of how you lose your appetite when you're sick. Who wants to eat in the middle of a fire, right?
Disabled Macroautophagy
Life inherently contains some errors. This is natural. These errors can be corrected. The purpose of autophagy is precisely this: to clean up the waste and eliminate mistakes.
However, as this process continues over many years, some errors inevitably slip through, creating stress within the cell. One of the main sources of intracellular stress is increased ROS levels due to mitochondrial dysfunction. This stress further disrupts cellular organization. Then there's the lysosome issue, the organelle responsible for cleaning. The decline in its functions leads to the path of programmed cell death.
As seen, this is not an isolated topic. It is closely related to deregulated nutrient sensing, mitochondrial dysfunction, and senescence. Indeed, as you delve deeper into the field of longevity, you become intrigued by the quest for a Theory of Everything, much like in the field of physics.
Microbiome Dysbiosis
We've reached the last and most popular topic. Almost everyone who says at least two sentences about this topic mentions that the number of microorganisms in our gut exceeds the number of cells in our body. Let me not break this rule either.
But this field deserves to be popular. Two aspects of it are very important in my opinion. First, it is a topic that we can intervene in. If we have the economic means to decide on the quality of the food we eat (at least whether it's ultra-processed or not), part of the control is in our hands. The other important point is that our gut guests also have control over our eating decisions. Calling them "guests" is incorrect. The truth is, we form a whole together.
Over the years, a change similar to the Ship of Theseus occurs. Some microorganisms lose dominance while others take over. These kinds of changes also have an inflammatory response in our blood. We know the results of this. The existence of mice whose lifespan has been extended by fecal transplants makes the situation even more interesting.
Still, we can't quite digest the idea. In such a human-centric world, how can organisms living on our surfaces have a say in our lifespan?