Our Immune system vs. Aging

Photo by Rod Long on Unsplash

What if I told you that you currently have a disease…and right now there is nothing really stopping it from killing you.

Introducing…Aging!

But what if we could cure this disease…? As time goes on there will be a larger population that will be “old”.

Let’s look at some stats…

By the year 2030, it is predicted that the 21% of the population will be older than 65.

By the year 2060, nearly one in every four Americans will be above the age of 65! 🤯

With such a high percentage of the population being “old” we have going to have to face its consequences. Hospitals will have to expand, we will need more old age homes and much more! But lets take a step back and look at the biology of aging.

What is aging at the biological level?

Before we get into the aging part we have to know how a cell “grows”.

We all start of as one tiny cell with exactly 46 chromosomes. We get 23 chromosome from each parents. Move forward 5 years. You are a little kid about 3 feet tall running around annoying the people around you. Move forward again 15 years and now you are about 5ish feet and exploring the world. The reason you go from a single tiny cell to a complex organism with 37.2 trillion cells is due to cellular division. Let’s take a closer look at exactly what cellular division is?

Cellular division

This is basically when a parent cell divides into two daughter cells. But the parent cell has 6 main steps to go through before it can split into the daughter cells.

  1. Interphase- this phase consists of three stages, all which are crucial for cellular division. Up first is the G1 phase. This is where the cell gets “ready” and the cell goes under specialized cellular functions in order to prepare for DNA replication. This then leads to the S phase. During the S phase, every single chromosome is replicated in order to maintain the genetic content. Next, during the G2 phase the cell grows a little more to ensure everything is well. Then finally the M phase. It is in this stage the spindles are synthesized. The spindle apparatus is basically the cytoskeleton , “the bones”, of the cell. It’s what keeps the cell together.
  2. Prophase- This is where the nuclear envelop of the cell opens up and the the long strands of chromatin condense to form a chromsome.
  3. Metaphase- At this stage the chromatin is still condensing but as this is happening the chromosomes are making their way to the center of the cell in a linear manner.
  4. Anaphase-Once all the chromosomes are all lined up, and the final signal is activated the cell with very quickly enter anaphase. This quick and abrupt activation is caused by the anaphase-promoting complex. It is also that during this stage the protein securin is broken down which leads to the enzyme separase being released. This enzyme is then responsible for the chromosomes seperating.
  5. Telophase- In this stage the cleavage furrow splits the cells cytoplasm and chromatin.
  6. Cytokinesis- This final stage is the end of cellular division and results in two irreversible daughter cells.

But how many times can our cells split?!?

Introducing Aging

As we know, all cells contain DNA and need to continuously divide in order to keep us alive. But do they ever stop?

YES! This is called cellular senescence. This is called the Hayflick limit. Hayflick was a scientist that found the approximate maximum number of times that a cell could divide before it “died”.

The Hayflick limit deliberates that an average cell has the ability to divide around 50 times before reaching a stage called senescene. As a cell divides the telomeres on the end of the linear chromosome get smaller. Telomeres are like caps on the end of your chromosomes that protect it from damage. They are similar to the plastic that might be on the end of your shoe laces. Eventually these telomeres will no longer be present on the chromosome.

Now after this our body is responsible for getting rid of these cells, since they are no more of value. But sometimes this is not the case… Instead the cells that “escape” stick around and release toxic substances harming the tissue and cells around it. Now this is not a crazy amount of toxicity but just enough to cause harm over time. These escaped cells are called “senescent cells”.

Senescent cells

Although senescent cells can no longer replicate, the are metabolically active. They adopt an immunogenetic phenotype consisting of up regulation of immune ligands, promiscuous gene expression (pGE) and also show to test positive for senescence-associated β-galactosidase.

These are mouse embryonic fiberblast cells. Above is before senescent and after is senescent because of the production of protein β-galactosidase.

Some biomarkers of cellular senescence are p16 protein and the beta-galactosidase protien. But some normal cells also express these proteins such as macrophages and also T-cells. Senescent cells affect tumor suppression, would healing and also play a pathological role in age-related diseases.

Another characteristic of senescent cells is the production of Senescence Associated Secretory Phenotype (SASP) which may consist of inflammatory cytokines, growth factors, and proteases.

Some examples of SASP cytokines are IL-6 and IL-8, and these may cause senescence. SASP have both tumor and anti-tumor effects. They likely support tumor-primed cells instead of shifting healthy cells into transformation. But on the other hand they also aperate as anti-tumor operators. The facilitate the elimination of the damaged cells by phagocytes.

SASP is also related to many age-related disceases like type two diabetes and also atherosclerosis. Researchers are motivated to develop senolytic drugs to kill and eliminate senescent cells to help people live longer. Let’s look at a study by some researchers.

Mice who received a cocktail of drugs that targets these senescent cells were found to live 36% longer and were no longer frail at time of death. Thats crazy!!! Imagine humans living that much longer!! But there is no drug that has been tested and worked in humans yet.

Why doesn’t our body get rid of these zombie cells?

Our body’s immune system is usally suppose to get ride of these zombie cells. But it doesn’t all the time. The senescent cells manage to evade the immune system.

But another problem we face is that as we age, our immune system weakens. Our thymus, an organ responsible for regulating our immune system, dwindles with age and essentially ceases to function properly. This severely constraints the new generation of T-cells. THAT SUCKS! T-cells are one of the most important parts of our immune system! You can think of them like the generals our body. They do a-lot of regulation of what cell signaling molecules and what reactions will take place. Thye are responsible for how much and which certain cytokines are released.

This is unfortunate because our immune system is partly responsible for getting rid of these cells. Without our beloved T-cell, it becomes very hard for our body to get rid of these cells.

Let’s look another scenario when our immune system compromises us.

Cancer.

A disease in which abnormal cells divide uncontrollably and destroy body tissue.

Our immune system is also responsible to regulating these cells. Regulatory CD4+ (Helper T-cells) are responsible for going throughout the body and looking at immune checkpoints. But sadly our immune system sometimes misses these cancer cells.

But there have been promissing solutions to battle cancer. Introducing…CAR T-Cells!

These are basically T-Cells that have been genetically modified to help target specific receptors in the cancer cell. THATS CRAZY AWESOME!

But can we apply this same technique to senescent cells?

Super Hero Immune System

As stated before, our immune system has the tools to be able to get rid of these senescent cells.

The human HLA-E is a non-classical MHC class I molecule that is characterized by a limited polymorphism and a lower cell surface expression than its classical prologues.

The HLA-E is a receptor that is on these senescent cells. Under normal circumstances our immune system uses the NKG2A and CD94 receptor that are on its NK(natural killer cells) and CD8+ (Killer T-Cells) to recognize the HLA-E receptor.

!NK Cell and CD8+ Cell

But as stated previously, our immune system ages. The quality of our T-Cells goes down, or even lost. But what if we gave these T-Cells a reboot.

Similar to how CAR-T cells are made, we could edit the genes of a T-cell from the patient to give it the receptors needed for senescent cell targeting!

Won’t the T-cells already have the correct receptor on them? In short, yes. They should. But they also should be getting rid of these senescent cells.

Why don’t they? As stated before they AGE!

The immune system can not react the same way it does to pathogens as it did before.

They simply can not do the same things as before!

A little about CAR-T cell production

So basically you filter out the T-cells from the patients blood. Give it the specific instructions it need to “grow” the specific protein or receptors. and after allowing them too proliferate, you inject them back into the body.

Imagine doing the same thing to battle aging! Since our immune cells are not as active as before and may not activate an immune response when in contact with a senescent cell when could give them a boost.

After filtering the T-Cells from the patients blood we could insert the genes for the NKG2A and CD94 receptors on the T-Cell. Similar to the CAR-T cell we would then allow it to proliferate. Once we have our desired dose, we could insert it back into the patient. If this works then the newly armed T-Cells should be sufficient enough to eliminate some of the senescent cells. However there are some things to worry about with this procedure. Auto-immune diseases are always a threat. We don’t want too much of an imbalance in our body that our immune system starts doing stuff we don't want it to. It can become very dangerous when there is an imbalance of cytokines in our immune system.

Aging is a problem that needs to be addressed. As a we find cures to other diseases, we will have a population that also grows older. But as of right now, there is no cure to this disease called “aging” .

Tl;DR

  • Right now we all have a disease called aging, and we don’t currently have a cure.
  • Senescent cells have been proved to be a cause of aging and experiments in mice have shown that by eliminating these cells the life expectancy increases by 33%!
  • CAR T cells are immune T cells that have been modified via gene editing techniques to help target cancer cells.
  • We can use gene editing to give our immune cells receptors such as NKG2A and CD94 needed to help target senescent cells!

Aging is a problem that needs to be addressed. As a we find cures to other diseases, we will have a population that also grows older. But as of right now, there is no cure to this disease called “aging” .

Thanks for reading! Feel free to check out my other articles on Medium and connect with me on Linkedin!

If you’d like to discuss any of the topics above, I’d love to get in touch with you! — Send me an email at sbmohammed03@gmail.com or message me on Linkedin!

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living life on the edge

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