What causes us to age, and to get all these aging-related diseases and symptoms, and to eventually die?
There are some fundamental, primary causes of aging, which then lead to secondary causes of aging.
Some important fundamental, primary causes of aging are:
- Epigenetic alterations
- Loss of proteostasis
- Mitochondrial dysfunction
- Genomic instability
- Telomere attrition & shortening
- Advanced Glycation End Products (AGEs) and other crosslinks
These fundamental, primary causes of aging lead to secondary aging mechanisms in our body, such as:
- Senescent cells
- Stem cell exhaustion
- Altered intercellular communication
- Deregulated nutrient sensing
- Other reasons why we age
Of course, various other aging mechanisms will likely be discovered in the future. But these mechanisms described here are a good start
1. Why we age: Epigenetic alterations
The epigenome plays an important role in aging. The epigenome determines which genes are switched on or off.
When we get older the epigenome becomes more dysregulated, leading to genes that are switched on that should be switched off, like pro-cancer or pro-inflammatory genes. And vice versa: aging leads to genes being switched off that should be switched on, like repairing or housekeeping genes.
All this activation of the wrong genes, and silencing of good, healthy genes leads to our cells functioning less well. Given the importance of the epigenome in aging, let us go a bit deeper into the epigenome.
What is the epigenome?
The epigenome consists of 3 “layers” or parts:
One way the epigenome can switch off genes is by methylating them. A gene is a part of our DNA. When methyl groups are placed on DNA, a gene is switched off. Methyl groups are small molecules (consisting of a carbon atom and three hydrogen atoms). When a gene is covered by lots of methyl groups, the cellular machinery (specific proteins) cannot reach this gene anymore to translate it into proteins (proteins are the building blocks and machinery of our cells). DNA methylation can also switch on genes by methylating a gene or region of the DNA that otherwise would switch off another gene.
Histones are little balls of proteins around which our DNA strands are winded. Just like yearn is rolled up around a spool or bobbin, histones are the proteins around which DNA strands are winded. If DNA strands are tightly rolled up around histones, then the genes that are part of this DNA cannot be accessed by the gene-reading machinery, effectively silencing or inactivating those genes.
Chromatin is all the DNA in our cell. It’s how the DNA appears when looking at the cell nucleus – the nucleus contains the DNA. The DNA on a chromatin level is condensed (wrapped up) in specific ways. For example, it can form chromosomes, which are large structures of condensed DNA.
The organization of the epigenome is quite a feat. All the DNA in our cells is around 2 meters (or yards) long! So a 2-meter-long strand of DNA needs to be folded in such a way it can fit in a tiny nucleus with a diameter of around 10 micron (a micron is a thousandth of a millimeter).
However, by rolling up the DNA around millions of histones and then organizing these histones and strands our cells manage to fit 2 meters of DNA into the minuscule cell nucleus. Even more, our cells can duplicate all this DNA with relatively little errors during each cell division, creating two new cells with each 2 meters of DNA.
If we would unravel the DNA from all our cells in our body (about 40 billion cells) and string this DNA together into one big strand, it would stretch for about 67 billion miles or 108 billion kilometers, or twice the diameter of our solar system. We contain a lot of DNA!
The epigenome is very important for the proper functioning of our cells.
After all, all our cells have the same DNA (except for red blood cells, they don’t have a cell nucleus containing DNA).
So despite our cells having the same DNA, there are around 200 different types of cells in our body, such as muscle cells, neurons, gut cells, liver cells, skin cells, and so on.
All these cells contain the same DNA, or the same set of instructions to build about 20,000 different proteins, which carry out most of the functions of the cell.
In other words, a liver cell is a liver cell and not a muscle cell or nervous cell, despite having the same DNA and same genes.
A liver cell is a liver cell because the epigenome switches off all genes that the liver cells do not need, like heart cell genes or stomach cell genes and thousands of other genes.
The same in other cells. The epigenome in skin cells makes sure the skin-cell genes are active, while the epigenome in brain cells turns on the brain-related genes (and switches off the skin, gut, or liver-related genes).
So the epigenome determines the identity of each cell, and by this also its fate.
After all, some cells live much longer than other cells. For example, brain cells can become as old as a human, like 80 years or older, whereas a skin cell only lives for about 4 weeks. This despite that brain cells and skin cells have the same DNA! It’s the epigenome that determines not only how cells look, but that also determines their lifespan and fate.
Aging and the epigenome
Given the enormous amount of (tight) organization of the epigenome, it’s not surprising that as the years of our lives pass this system becomes more and more dysregulated, contributing to aging.
This dysregulation of the epigenome leads to “bad” genes being turned on which normally should be turned off, like cancer-promoting genes (increasing the risk of cancer as we get older), pro-inflammatory genes and other genes that impede the proper functioning of the cells.
The opposite is also happening: during aging, “good”, beneficial genes are switched off, like repair genes, housekeeping genes, anti-inflammatory genes, and many other genes that keep our cells healthy and young.
This malfunction of the epigenome is an important contributor to aging. Luckily, various substances exist that can help to better maintain the epigenome, and scientists are exploring ways or reprogramming the epigenome back into a younger, more youthful state.
2. Why We Age: Loss of Proteostasis
Each cell in our body contains millions of proteins. Proteins are the building blocks of our cells. Proteins are also the working horses given they carry out most of the functions in our cells.
For example, there are proteins that form channels (gates) in the membranes of our cells to let substances in and out of cells. Muscle proteins inside muscle cells can contract, so the muscle cells become shorter and our muscles can contract. Proteins in the membrane of brain cells transmit electrochemical signals or pump out neurotransmitters. Proteins in our gastric cells produce gastric acid. Long protracted proteins form beams that give cells their shape, or anchor them to other cells. Collagen and elastin proteins outside cells provide elasticity of skin and ligaments. Other proteins accelerate chemical reactions (these proteins are called “enzymes”), like breaking down the sugar and the fat you eat.
In other words, proteins are the building blocks of life.
Our DNA mainly contains the instructions to build proteins. A gene is a piece of DNA containing the code to build a specific protein. Our DNA contains thousands of genes to build about 20,000 different proteins.
Our cells contain millions of proteins. Most of these proteins are continuously produced and recycled.
So proteins are continuously created and broken down. Our cells contain intricate machinery (also mostly built of proteins) to break down and recycle proteins. This maintenance of proper protein metabolism happens via different mechanisms, such as (R):
Proteins and other waste materials are engulfed in vesicles and then transported to the lysosomes which break their contents down. The lysosomes are little sacs in the ells that contain enzymes (proteins) that break down proteins and other substances. One can consider the lysosomes as the incinerators of the cells.
There exists micro-autophagy (used to clean up small cell parts), macro-autophagy (often used to clean up larger cell parts) and chaperone mediated autophagy (to clean up very specific parts of our cells).
The ubiquitin-proteasome system
This cellular machinery looks like a tiny cylindrically-shaped “grinder” that breaks down proteins. In fact, small proteins called ubiquitin stick to specific proteins, tagging them for destruction. These ubiquitinated proteins are then transported to the proteasome, which breaks them down (the proteasome actually looks like a meat grinder).
Proteins and aging
The recycling processes we just discussed are very intricate, but they are not perfect.
During aging, our cells become less and less able to properly recycle their proteins. Proteins start to accumulate inside and outside our cells. This hampers the function of the cells. They are becoming “old”.
In other words, during aging, the proper maintenance of all the proteins inside and outside our cells (this proper maintenance is also called “protein homeostasis” or proteostasis”) becomes dysfunctional.
Proteins are not broken down and recycled properly, and start to accumulate everywhere inside and outside our cells. Also, various other waste materials in our cells start to accumulate during aging because the “biological incinerators” of the cell start to become dysfunctional.
We see that protein accumulation plays a role in many aging-related diseases. For example, in Alzheimer’s disease specific proteins (and likely others) such as tau protein, beta-amyloid protein and TDP-73, start to accumulate. This hinders the proper functioning of brain cells, eventually even causing them to die off.
In aging blood vessels, specific proteins start to accumulate, making these blood vessels more frail and prone to breaking.
In an aging heart, proteins accumulate in heart cells, impeding their function. Proteins accumulate in the blood vessel walls, making them more stiff and prone to breaking. Protein accumulation in lung tissue also contributes to more stiff and “old” lungs.
3. Mitochondrial dysfunction
The mitochondria are the powerplants of our cells. They generate the energy cells need to function properly. The reason why you need to eat food and breathe oxygen is mainly to keep the mitochondria going. The sugars, fats and amino acids from your food, and the oxygen you breathe, are used by the mitochondria to generate ATP, which is a small molecule that provides most of the energy to keep our cells going.
ATP makes things work by attaching it to other proteins, changing their shape so they can perform their function. For example, when ATP attaches itself to muscle proteins, they become a bit shorter and when this happens in billions of muscle proteins at the same time, your muscle contracts.
When ATP attaches itself to a channel protein, the protein opens up, letting specific substances inside the cells. And so on.
So the mitochondria are pivotal for proper cellular functioning. Without mitochondria, complex cells, and complex life would not be possible.
Our mitochondria are in fact very ancient bacteria that about two billion years ago got engulfed (eaten) by larger bacteria. Instead of being broken down, a symbioses originated, in which the smaller bacteria (the mitochondria) would generate energy for the larger bacteria (which would become “eukaryotic cells”, which are the cells all mammals are composed of).
This also explains why the mitochondria have their own DNA (bacteria have their own DNA).
However, when we get older, our mitochondria start to decline. There are many reasons for this. During aging:
– The DNA in our mitochondria gets damaged by free radicals and other substances (caused by the many chemical reactions that take place in the mitochondria)
– The DNA in our mitochondria gets damaged every time when the mitochondrial DNA is copied given the copying process is not perfect and small errors are made.
– The membranes of the mitochondria get damaged during aging (e.g. cardiolipin fatty acids that make up part of the mitochondria).
– Damaged mitochondria evade proper breakdown (mitophagy) and keep lingering on in the cells, not producing sufficient energy for the cell. Over the course of time, “natural selection” of such dysfunctional mitochondria happens, causing more and more of these dysfunctional mitochondria to take over the cell (R).
These aging processes cause the mitochondria to deteriorate. Decade after decade our mitochondria become more damaged and dysfunctional. This leads to our cells functioning less properly, making them “old”.
Damaged mitochondria do not produce enough energy for the cells, which hampers their function. Damaged mitochondria secrete substances and signaling molecules that negatively impact the cell. DNA that leaks out of damaged mitochondria activates the STING pathway, which causes inflammation in the cells.
One one to stay younger for longer is by preserving mitochondrial function as long as possible, and by reversing mitochondrial damage.
4. Genomic instability
Our DNA contains the building instructions to build our cells, and so our body. The DNA is the instruction manual for how to build a human.
More precisely, DNA contains the code for making thousands of different proteins, which build up our cells and carry out most of the functions in our cells.
Most cells in our body contain 3 billion base pairs (“letters”) that make up our DNA. However, during aging our DNA becomes more and more damaged.
Our DNA gets damaged in myriad of ways:
– Chemicals, free radicals, toxins, UV radiation, and many other metabolites and substances in the cell can react with the DNA and damage it.
– Each time when DNA is replicated (during cell division) some errors (mutations) happen given the process of replication is very accurate but not perfect. Over time, more and more mutations accumulate in the DNA.
As the decades pass, more and more DNA becomes damaged. Our cells have intricate mechanisms to repair a lot of this damage, but these mechanisms are not perfect, and cannot work everywhere in the cell.
Damaged DNA leads to the cells functioning less properly. Damage or mutations in regions of the DNA that encode for important proteins can make that these proteins are not properly produced or are damaged themselves. This for example can lead to cancer (for example when tumor-suppressing genes become damaged).
Damaged DNA also activates all kinds of DNA-damage responses, which can further worsen cellular functioning.
5. Telomere attrition & shortening
Telomeres are the “caps” on our DNA. Just like shoestrings have plastic caps to protect them from unraveling, our DNA strands have telomeres that need to protect them against unraveling.
However, the problem is that each time when a cell divides, these protective caps (telomeres) become shorter. Until they are so short they cannot properly protect the DNA, which then leads to damaged DNA and the activation of all kinds of DNA damage mechanisms that further hamper proper cellular functioning.
Also, telomeres (and the protein complexes surrounding them) can become damaged or dysfunctional during aging, leading to cellular dysfunction.
There exist a lot of misconceptions about telomeres.
The first one is that telomeres do not play an important role in aging given there exist many cells in the body that hardly divide (so their telomeres do not become shorter during each cell division), but still age. Examples are brain cells or muscle cells.
However, the cells surrounding brain cells and muscle cells often divide a lot, and their telomeres become shorter. For example, each neuron in our brain is surrounded and nourished by around 10 glial cells. These cells divide and their telomeres become shorter, which makes them dysfunctional, and which lead to less proper maintenance of our brain cells, and causes damage to them.
Another misunderstanding about telomeres is the following: mice contain telomeres that are about ten times longer than humans, but mice only live for about two years. So telomere length and telomeres in general do not play a significant role in aging.
However, despite that mice have much longer telomeres, their telomeres become shorter much faster compared to humans. So it’s not only telomere length that plays a role in aging, it’s also the rate of shortening of telomeres.
There exist also various tests online to measure your telomere length to measure your “biological age”. However, we are skeptical about these tests because they only look at one type of cell (white blood cells and not many other tissues that also age), and because they mainly measure telomere length of white blood cells. White blood cells have the ability to lengthen their telomeres briefly (for example, during an infection when they have to multiply themselves a lot). This (and many other factors) make their telomere length not very reliable to measure your “biological age”.
Nonetheless, telomeres do play a role in aging, especially in fast dividing tissues like gut cells, hair cells, skin cells, red blood cells, immune cells and stem cells.
Some people are born with very short telomeres, and they suffer from various diseases that have symptoms that we also see during aging, like depletion of their white and red blood cells, baldness, skin wrinkling, and so on.
Providing mice with extra telomerase (the enzyme that can lengthen telomeres) extends their lifespan and healthspan (R).
Mice born with extra long telomeres also live longer (R).
How to lengthen telomeres?
In an interesting study, the telomeres in mice were extended (R). One reason why we age is our telomeres becoming shorter. The telomeres are the little “caps” on the ends of our DNA strands that protect them and get shorter with each cell division; then also can get damaged when getting older, leading to genetic instability, DNA damage and activation of stress pathways in cells, which ages them, can make them senescent or cancerous.
Lots of people (including some scientists and doctors) still think that lengthening telomeres automatically leads to an increased risk of cancer (given cancer cells need long telomeres to keep dividing), but as I explain in the part about telomeres, this is not the case.
Interestingly, in this study, telomere lengthening increased lifespan by a whopping 41 percent. The metabolism of the mice also improved (glucose tolerance) and did physical performance. Body mass loss and loss of fur was also prevented. Aging-related deterioration of the mitochondrial structure was halted too.
Of course, these are mice studies. Mice have much longer telomeres than humans, but they shorten much faster too. It remains to be seen if such results can also translate into humans. However, we see that improving telomere length and health could be one way to keep our cells, especially cells that have to divide a lot, like stem cells, healthier and younger for longer.
Various studies show that it’s possible to length telomeres via a healthy diet, exercise and supplements (R,R,R).
6. Advanced Glycation End Products (AGEs) and other crosslinks
Crosslinks are connections (“links”) formed between the building blocks that make up our tissues.
For example, sugar molecules can form a crosslink between proteins like collagen that make up our skin or blood vessel walls. When lots of our collagen is crosslinked or “glued together” by sugar-crosslinks, the tissues become more stiff. Crosslinking of collagen and elastin proteins in the skin is one of the reasons why the skin becomes less flexible and more stiff and wrinkly. Crosslinking of the collagen and elastin in our blood vessels makes them more stiff, which leads to “hardened” blood vessels, increased blood pressure (hypertension), and makes blood vessels more prone to break, which can cause a bleeding in the brain (a stroke) or other organs like the gut.
Crosslinking of proteins in the lungs makes the lungs more stiff. This crosslinking of the lungs is one of the reasons why our lung function declines. This process also makes the lungs more prone to infections, which contributes to the much increased risk of dying of pneumonia in the elderly.
There exist many different kinds of crosslinks in the body, such as:
– Glucosepane: this is the most common crosslink in our tissues
– And many others.
Often, these crosslinks are called AGEs, which stands for Advanced Glycation End products.
Many crosslinks are formed by sugar molecules sticking to proteins and linking them together. People with type 2 diabetes often have high levels of glucose circulating in their body. This drastically increases the crosslinking in their blood vessels, kidney, nerves and other tissues, leading to a dramatically increased risk of heart disease, kidney failure, nerve damage (neuropathy), eye problems we see in diabetic people.
Besides crosslinks caused by sugars, other substances can also cause crosslinks, such as lipids and amino acids.
7. Senescent cells
As we age, senescent cells arise everywhere in our body. Senescent cells are cells that are damaged but refuse to die. Despite their damage, and their malfunctioning, they keep lingering on. Some scientists call them “zombie” cells, because they should normally be death bit they keep living on.
Senescent cells are very damaging to their environment. They secrete many substances that promote inflammation or malfunctioniàng in neighboring cells and tissues. The pro-inflammatory, damaging substances they secrete can even travel far and wide via the blood to other tissues, causing inflammation or damage there.
Examples of these detrimental substances that senescent cells secrete are pro-inflammatory molecules like IL-6, IL-1, IL-8, TNF-alpha that cause inflammation in neighboring or far away cells. Senescent cells also secrete pro-coagulation substances that can make the blood coagulate faster. They also secrete substances that break down the extracellular matrix, which is the gel-like glue that glues together all our cells. A more loose extracellular matrix makes other cells behave not as they should (like stem cells, which need a thightly regulated extracellular matrix to be embedded in), or makes it for cancer cells much easier to spread (metastasize).
During aging, senescent cells arise in the skin, contributing to wrinkles. Senescent cells in the blood vessels contribute to atherosclerosis (the clogging up of our blood vessels). Senescent cells in the lungs make the lung tissue more stiff and prone to infections (like pneumonia). Senescent stem cells are less able to generate new cells to replenish our tissues, contributing to a decline of these tissues.
In other words: senescent cells are bad. They play a major role in aging.
How do senescent cells arise? They mainly arise due to damage they accrue. Normally, if a cell becomes too damaged, it kills itself. However, senescent cells evaded this, and they keep existing. Also, normally, the immune system clears away lots of senescent cells, but during aging the immune system becomes less able to clear senescent cells.
Senescent cells arise due to many of the causes we discussed before, such as epigenetic dysregulation, DNA damage, mitochondrial dysfunction, proteotoxic stress (due to protein accumulation) and so on. So fundamental aging processes contribute to the formation of senescent cells.
Senescent cells can also be caused by other kinds of damage, like exposure to UV light or radiation, specific toxic substances, including some medications, pressure, and so on.
How to clear senescent cells?
Scientists are trying to find many ways to kill senescent cells.
One way is creating a peptide that “frees” up an important protein called p53 (to be more precise, the peptide prevents p53 binding to FOXO4, another protein). P53 is an “alarm” protein, that kicks into action when a cell becomes damaged. When p53 is activated, three main outcomes can happen: the DNA damage is repaired (when there is not too much damage), or the cell becomes senescent (when there is more damage), or the cell kills itself (when there is too much damage) By liberating more p53, senescent cells are killed. Destroying senescent cells this way, led to some rejuvenation in mice (R). It restored fur density, fitness and renal function in both fast aging mice, and in naturally aging mice.
Other ways to clear senescent cells is via small molecules (drugs) that target anti-apoptotic pathways (these pathways prevent senescent cells from killing themselves), for example by xxxx
or by creating molecules that are specifically targeted to senescent cells (for example by attaching a senolytic drug to an molecule that likes to attach to receptors that are often found on senescent cells), or by creating senolytic vaccines, which are substances that want to induce the immune system to specifically kill senescent cells (R).
An important aspect to clearing senescent cells, is making sure the intervention is sufficiently “specific”, meaning it kills only senescent cells, not healthy cells. Many small molecules that are called “senolytics” are not specific enough, in the sense they can also damage healthy normal cells, including stem cells. So with senolytics, one has to be careful to not use substances that can damage too many healthy, non-senescent cells.
There are various “senolytics”, like quercetin, fisetin, piperlongumine, and so on. However, I would still be cautious about taking high amounts of these substances in order to “clear” senescent cells, given there.
8. Stem cell exhaustion
Every second you produce two to three million red blood cells. This means that in a day your body has produced around 200 billion red blood cells.
These red blood cells are continuously created by hematopoietic stem cells in your bone marrow. Each day, your hematopoietic stem cells also create billions of white blood cells (which are part of your immune system) and around 400 billion little platelets, which enable your blood to clot in case you are wounded.
Besides hematopoietic stem cells there exist many other types of stem cells in your body. Stem cells in your skin replace your skin cells every month. The same goes for the stem cells in the gut that replenish your entire gut lining every few weeks. Stem cells in your bone generate bone and cartilage cells, and liver stem cells renew your liver regularly.
What are stem cells?
Stem cells have two powerful and important characteristics: they can renew themselves (creating other stem cells) and create new differentiated cells. Differentiated cells are non-stem cells. These are the ordinary cells (also called “somatic cells”) that make up most of our tissues, like fat cells, skin cells, bone cells, gut cells, neurons, muscle cells, and so on.
Stem cells are undifferentiated cells that give rise to differentiated cells. For example, mesenchymal stem cells give rise to bone cells, cartilage cells, and fat cells. Liver stem cells create liver cells, gut stem cells produce various types of gut cells. Hematopoietic stem cells create red blood cells and white blood cells.
Stem cells can divide symmetrically and asymmetrically. When a stem cell divides asymmetrically, it creates a new stem cell and a differentiated, somatic cell (like a skin cell or a liver cell). When it divides asymmetrically, it creates two new stem cells or two differentiated cells.
There exist different types of stem cells. Everywhere in our body we can find multipotent stem cells: they can give rise to only a few different types of differentiated cells, like mesenchymal stem cells being able to create fat cells, bone cells and cartilage cells, but not gut cells or kidney cells. In general, multipotent stem cells are very rare and difficult to find in our tissues. For example, it’s estimated that less than 1 out of 10,000 cells is a mesenchymal stem cell.
Then there are pluripotent stem cells. These are cells that can give rise to all the different cells that occur in an adult’s body. A pluripotent stem cell can give rise to fat cells, kidney cells, neurons, skin cells, and so on. Pluripotent stem cells are “super stem cells”. Examples of pluripotent stem cells are embryonic stem cells or “induced pluripotent stem cells” (IpSCs are made of normal cells – I explain more about iPSCs later on). An adult’s body does not contain pluripotent stem cells, they are found when we are still an embryo.
There are also “super super stem cells”, called “totipotent stem cells”. These stem cells give rise to all cells that occur in an adult’s body but also to extra-embryonic tissues. Extra-embryonic tissues are the tissues that surround and support the embryo in the womb, like the placenta and the umbilical cord. The prime example of a totipotent stem cell is the fertilized egg cell (zygote), which after fertilization creates the embryo and the extra-embryonic tissues. While totipotent stem cells are the most powerful stem cells, it’s the pluripotent stem cells that are in fact most interesting for research, regeneration and longevity.
So in summary, we have the following main types of stem cells:
Totipotent stem cells: can create all cells in an adult plus extra-embryonic tissues like the placenta and umbilical cord
Example: fertilized zygote (egg cell)
Pluripotent stem cells: can create all cell in an adult but not extra-embryonic tissues like placenta or the umbilical cord
Examples: embryonic stem cells, induced pluripotent stem cells (iPSCs)
Multipotent stem cells: can create specific types of differentiated cells
Examples: hematopoietic stem cells creating red blood cells and white blood cells, liver stem cells creating liver cells, mesenchymal stem cells producing fat cells, bone cells and cartilage cells.
Stem cells and aging
Stem cells are pivotal for longevity and health, given they renew, replenish and maintain our body day in and day out. A young person has a lot of stem cells, which are very healthy and vigorous, replenishing the tissues at a very high rate, giving the skin its youthful thickness and glow, making organs function at their prime, and tissues be able to be quickly repaired and renewed.
Unfortunately, during aging, our stem cells start to decline. When we get older, in some tissues, stem cell numbers go down by stem cells that die off. In other tissues, stem cells do not decline (sometimes they even increase in numbers), but they become dysfunctional.This means they generate less cells to maintain the tissues. In fact, some stem cells focus too much on reproducing themselves, creating other stem cells, instead of creating differentiated cells, which are needed to replenish and maintain our tissues. This is also called “clonal expansion” of stem cells, which can lead to tissue dysfunction (not enough tissue cells are replaced and maintained) but can also lead to cancer (when stem cells start to divide uncontrollably). Other stem cells become senescent during aging, causing harm to other cells.
What causes this stem cell dysfunction? Mainly the hallmarks of aging we have discussed here. As the decades pass, our stem cells suffer from epigenetic alterations, mitochondrial dysfunction, protein accumulation, DNA damage, telomere shortening, crosslinking of the extracellular matrix in which they are embedded, and so on. This leads to our stem cells becoming dysfunctional. And when our stem cells do not function properly, our tissues are not replenished and maintained: our skin becomes thinner and more frail, our organs and muscles cannot regenerate properly, wound healing is delayed, our teeth start to fall out (there are dental stem cells in our mouth), our brain starts to function less well (our brain cells are supported by surrounded dividing cells, like glial cells or the cells that make up the blood vessels), our immune system starts to decline (because our stem cells regenerate less new and functional immune cells).
9. Altered intercellular communication
Cells can communicate with each other in various ways. They can have close contact with each other by anchoring to each other via various types of anchoring proteins, like gut cells or skin cells that need to keep close contact to form a barrier. They can also secrete substances like proteins, peptides, inflammatory substances in close vicinity. They can also secrete various messenger substances into the blood stream, reaching cells far and wide in the body.
During aging, this communication between cells goes awry. Cells start to secrete the wrong or damaging substances. For example, cells become senescent cells, secreting pro-inflammatory substances, or substances that damage the extracellular matrix that embeds our cells, or pro-aging factors. Also, when we get older, our gut becomes more leaky, leading to toxic substances (like pro-inflammatory lipopolysaccharides from the gut bacteria), leaking into our body, causing damage everywhere, including in our brain. Also, during aging, retrotransposons and other pieces of “unruly” DNA start to make copies of themselves and insert themselves everywhere in our DNA, causing cells to be in a pro-inflammatory state. Crosslinking of the extracellular matrix that embeds our cells leads to our cells changing the way they communicate with each other. Damaged mitochondria in the cells leads them to secrete “alarm” proteins and other substances that can impede the function of other cells. To make a long story short, when we get older, our body becomes more inflamed and levels of damaging substances increase in our blood and the fluids that surround our cells, which fan the flames of aging.
How to address altered intercellular communication?
There could be various approaches to address altered intercellular communication.
This also explains why “heterochronic parabiosis” works so well. In these studies, young blood is administered to old mice, for example via infusions, but sometimes also by sewing a young and old mouse together so that they share the same blood circulatory system; leading to also young blood flowing through the vessels of old mice. Studies show that these old mice get “rejuvenated” in the sense that their tissues and organs can regenerate better again (unfortunately, the young mice get older when exposed to the young blood).
This led to a vigorous search by scientists to identify substances that can rejuvenate mice, or which can make them older. However, more recent
AMBAR Alzheimer study
10. Deregulated nutrient sensing
When we get older, our bodies, and our cells specifically, become less able to deal with nutrients. Each day, most of us consume sugars, amino-acids (from proteins) and fats. These need to be properly processed by our body. But as the decades of our lives pass, our cells become less able to process nutrients.
For example, our cells become more insulin resistant during aging. This means that cells become numb to insulin, which is an important hormone that makes cells take up the sugars that circulate in our blood after a meal. When these sugars are not properly taken up by specific cells (especially the liver and muscle cells) then they can damage other cells (such as brain cells, nerve cells, kidney cells and the cells in our retina).
When people suffer from serious insulin resistance, this is called type 2 diabetes. But during aging, everyone becomes more or less insulin resistant. This explains why so many people sooner or later get a beer belly, or love handles, or have more and more difficulty losing weight, while still eating in the same way as they did when they were younger.
If you are young, your body is still very insulin sensitive and can deal much better with these overloads of fast carbs, unhealthy fats or loads of red meat. But the older we get, the body becomes less able to deal with these nutrients.
As we get older, the body becomes less able to deal with not only sugars, but also with fats and proteins. Fats start to redistribute all over the body. Normally, healthy fat is stored under the skin (this is called “subcutaneous fat”). But during aging, fats end up in many places it should not be, like in the liver (contributing to liver steatosis or “fatty liver”), the pancreas (damaging beta cells which produce insulin, contributing to type 2 diabetes), muscles, our artery walls (contributing to atherosclerosis), between our organs (leading to a beer belly), and even our bone marrow. It’s as if fats start to find their own way, crawling and accumulating everywhere in our body.
This fat also becomes unhealthy on its own. Due to the large accumulation of fat such as around the organs (forming a beer belly), fat cells are being pressed to each other, leading some of them to die off or become damaged and become senescent cells. Dying fat cells and senescent fat cells secrete various proinflammatory substances that travel throughout the body, causing inflammation in the blood vessels (further contributing to atherosclerosis) and in the brain, which increases the risk of Alzheimer’s disease and in many other tissues, which also increases the risk of cancer (cancer cells love a pro-inflammatory environment).
In other word, nutrient sensing deregulation leads to our bodies to be less able to deal with the foods we eat, resulting in weight gain, insulin resistance, type 2 diabetes, beer bellies and a dysregulated metabolism in general, further increasing our risk of heart disease, cancer and Alzheimer’s disease.
11. Other reasons why we age
We listed some major reasons why we age. Of course, there are other reasons why we age, and likely many others will be discovered. For example, a decline in the transcriptome also contributes to aging (leading to problems with RNA, such as the accumulation or dysfunction of mRNA and lncRNA and tRNA or splicing).
During aging, our gut microbiome also changes. The gut microbiome contains about 40 000 billion bacteria that continuously secrete substances of which many enter the bloodstream and contribute to our health (and disease). During aging, the gut microbiome becomes less diverse, and also more toxic and detrimental.
Lingering viral and bacterial infections could also contribute to aging, such as herpes and CMV. Many people are infected with these, and they could contribute to the risk of Alzheimer’s, cancer and other diseases.
Transposons jumping around in our DNA also contribute to aging. Transposons are “rogue” DNA sequences that can make copies of themselves and insert themselves at other random places into our DNA, leading to genetic instability, intracellular inflammation (by activation of the STING pathway) and cancer (for example when a genetic sequence inserts itself into a gene encoding for a tumor suppressing gene).
In the future, we will likely see many other interesting mechanisms being discovered that contribute to aging, and the many aging-related diseases we all will eventually get.