Why do we age? Layman’s overview of the hallmarks of aging, pt.1
Let’s play a guessing game: I’m going to give you two patients’ medical data from their last blood test, and then ask you a question I’d like you to answer.
Bob’s files show an overnight fasting blood glucose of 4.4 mmol / L, and his blood contains 35 % white blood cells (you want them!), which help fight infections, as well as 0,015 mg/L of the C-reactive protein, an inflammatory marker (you don’t want that).
Karen, on the other hand, has an overnight fasting blood glucose of 8.0 mmol / L, while her blood contains 25 % white blood cells and 0,080 mg/L of the C-reactive protein.
Can you tell me which one of Bob or Karen is younger? Feel free to take some time to look at the charts and think about it. Did you answer Bob? Looking through his files, it would sure seem that way. But if you interpreted the question as being one of chronological age, then you’d be wrong: Bob is a 55 year-old Okinawan while Karen is a 38 year-old non-so-health-conscious American. (It appears Bob’s parents liked typical English names.)
Why did Bob’s files lead us to think he was the youngest one? Well, clearly, Karen’s blood report doesn’t look too good, she’s got inflammation, lowered white blood cell count and very high blood sugar, while Bob on the other hand displays only minimal signs of damage. And there we have it: damage. That truly is the keyword to recognize aging, NOT time as is commonly thought.
It makes sense, then, that the way we can describe aging scientifically is also through measured of damage. In other words, we look at what changes for the worst within our cells as time passes. Those changes, many of which are believed to be causal, are the hallmarks of aging. Today we’ll be looking at a few of them, and then maybe I’ll make a part 2 for the rest.
Genomic instability
Genomic instability simply is the propension of the genome, or DNA, to lose information due to all sorts of internal or external agents. Information loss is an obstacle to your body working properly, since the genome is like the set of instructions on how to make the proteins that are essential to keep you healthy. As you can guess, without all the instructions, the fabrication of proteins doesn’t go as well and sometimes, doesn’t happen at all.
This causes many of the symptoms of aging, some benign like white hair, and others very serious like muscle wasting. This is all due to the lack of some or part of the information necessary to make a protein.
In the field of longevity, agents are often described as being DNA damaging or, on the contrary, as being something that prevents DNA damage. Now you know why we mention those things and the impact it has on our aging. And since I’m talking about them now, I’ll give you a couple examples of DNA-damaging agents, so that you can better recognize them and avoid them, and I might have a whole article dedicated to that in the future.
Free radicals are probably the most well-known cause of DNA damage, as they snatch electrons from atoms in your DNA and most importantly, have been heavily publicized by the antioxidant trend. Now there’s truths and myths within that trend, but it is true that some antioxidants seem effective at slowing aging down.
Other causes of DNA damage include:
- Replicative damage through telomere shortening (we’ll cover that in an instant)
- Certain chemical compounds like polycyclic aromatic hydrocarbons (from car exhaust)
Telomere attrition
The next hallmark of aging on the list is telomere attrition, or shortening. Telomeres are like the protective end caps to our chromosomes, like those on shoelaces. For what we know, they don’t contain any important information and their sole role is to prevent DNA damage through replication.
The DNA polymerase responsible for DNA replication doesn’t have the capacity to read a chromosome completely. For this reason, the beginning and the end of the chromosomes (where the telomeres are) will be lost in the process. The cells this division gives rise to will have shorter telomeres than the ones before.
Eventually, the cell will reach a point called the Hayflick limit, where it can no longer divide properly because all of its telomeres are gone. If it were to divide in this state, it would suffer significant DNA damage of about 50 pairs of nucleotides, and eventually become cancerous.
So that Hayflick limit is a bit like a crossroad. From there, 4 things can happen.
Ideally, the cell would die then and there, and a new cell, created thanks to a stem cell, would replace the old one and everything would keep working properly. Stem cells are cells that are like cell factories. They exist in your body to create new cells to replace the ones you lose. When they divide, they create one cell to replace the old one (which could be a blood cell, a skin cell, or pretty much anything else depending on the type of stem cell), and they also create a copy of themselves, so another stem cell is created to replace the one that divided. Unfortunately, this ideal way can’t always happen, because stem cells aren’t immune to telomere attrition either. We will cover this a bit later, but at some point, we say they become exhausted and cannot do their jobs anymore, so there’s no more cell to replace the one that died.
So sometimes, and increasingly often, the cell will simply die without being replaced. Unfortunately, this leads to decreased tissue cell count, which weakens our muscles and organs and overall bodies. This is part of the cause of osteoporosis.
A third thing the body can do with the cell that can’t divide anymore is to send that cell into senescence. Senescent cells are covered a bit later in this article, but you’ll learn that too much of them is harmful. You can see that our options for the cell aren’t great at all if you can’t replace it, but unfortunately, there are worse ways to deal with a cell with short telomeres.
The fourth and final possibility, if neither cell death nor senescence happens, is that the cell will eventually become cancerous as the division proceeds to cut off some of the genes responsible for cancer suppression, such as p16, p21 and p53.
Basically, there is no good answer for the cell when its telomeres are gone, if it doesn’t have well functioning stem cells (which loose their telomeres too).
Cellular senescence
A senescent cell is a bit like a zombie cell: not totally alive, but not totally dead either. That’s because alive cells are actively participating in maintaining organismal health, and dead cells are just not there. They get cleared out and (hopefully) replaced.
Senescent cells, on the other hand, are both alive and dead. Dead, because they don’t serve their functions anymore, and alive, because they do release some chemicals. Harmful chemicals, for the most part.
Those chemicals are called chemokines and cytokines, and basically mean inflammation. Through the activation of some particular cellular pathways that have to do with free radicals production, they can cause DNA damage to other neighboring cells. This nicely illustrates the fact that aging accelerates over time, and that it is a vicious cycle.
Stem cell exhaustion
Stem cell exhaustion is a result of stem cells dying for all sorts of reasons exposed above, such as reaching the Hayflick limit or becoming senescent.
When too many of our stem cells are not working anymore, they cannot produce more cells to replace the ones that die, because they are somewhat dead themselves.
This means the cell count in some of our tissues decreases with age, making us vulnerable to many diseases. For example, stem cell exhaustion results in muscle weakening and muscle loss, a condition known as sarcopenia. Muscle tissues can also stop responding properly to injury. The brain can lose neurons, contributing in cognitive decline and dementia, as well as loss of control over fine muscle movements (Parkinson’s disease). The thymus can shrink, leaving you more vulnerable to infectious diseases as fewer immune cells are produced.
Hard not to see aging as a disease.
Epigenetic alterations
Last for definitely not least, according to many longevity experts. It’s also one of my favorite topics to write about. The epigenome is basically the way our genes are expressed. All our cells have the same genome, but an eye cell is obviously very different from a skin cell. That is thanks to the epigenome, which is essentially like a set of on and off switches for genes, which will allow cells to have different properties even though they have the same DNA.
Now, our cells need to express the characteristics of their own cellular identity, such as “skin” or “neuron” for our body to work properly. For example, a brain cell needs to be able to receive neurotransmitters through its receptors, but a scalp skin cell rather needs to be able to grow hair.
But when the epigenome becomes deregulated, cells lose their identity. For example, a heart cell may get somewhat transformed into an eye cell, for example, as the genes it would express would be closer to those of that type of cell. You probably understand how this is no good news for our hearts.
Nor is it good news for any of our body parts when too many cells lose their identity.
Cells that cannot accomplish their functions create tissues that cannot accomplish their function, which create organs that cannot accomplish their functions, which causes organ failure and death.
Conclusion
On that merry note, I want to end by stating I hope I could demystify aging a little in this article. It’s important to understand that the aging process isn’t some sort of immutable and inevitable law of the universe, but rather a combination of physical processes over which we can potationally have control, if we research it enough.
(That’s what folks at the Buck Institute and LEV Foundation are trying to do, you can donate to them.)
If you want to learn about more of the pathways to aging, keep an eye out for part 2 of this articles series. In the meantime, be well, be healthy, I’ll see you in the next one.
Sources
The bulk of the article is from this paper by Cell. It’s a great and very detailed paper which I encourage you to read if that’s something you’re interested in. https://www.cell.com/cell/pdf/S0092-8674(22)01377-0.pdf
The other things here and there:
https://youtu.be/AvWtSUdOWVI : fun talk by Aubrey De Grey, founder of SENS and LEVF.
