Senolytics: The “Magic” Drug to Live Another 100 Years
Might sound surreal, but guess what? The future is now.
By Michelle Sandels
I’m sure you’ve heard of “The Fountain of Youth”, supposedly letting us live forever. Most people would say it’s a myth. I wouldn’t.
I just believe it comes in a different form. Instead of eternal life, (I mean, would you really even want to live forever?) extreme, prolonged life. And instead of bathing in a magical fountain, swallowing a simple pill.
Sounds too good to be true, but trust me, science is so damn advanced.
Before we dive into the pill, some backstory.
Every year, on my parents’ birthdays, I ask them if they're excited to be a whole year older. And every year, they say the same old thing, “No”. I always reply with the usual “What?! Why not?! You can do so many cool things! You can explore the world so much more!” — You know, the typical response from a kid.
But this year, I pushed beyond the simple image of the freedom of being old and wondered… why. Why? What was the actual reason they were scared to get older? Was it because the sags and wrinkles would take over? Was it because they were one year closer to dying? In the back of my mind, that’s what I always assumed. Death. Appearance. What else could there be? So I asked them.
Chronic pain. Checking off another year means you’re one year closer to the exhausting chronic pain that comes with age.
On average, humans spend the last 10 years of their lives in chronic illnesses. And, guess what… it’s not fun! Cancer. Alzheimer’s. Diabetes. Dementia. Arthritis. Countless days laying in bed, wishing for it all to go away. Wishing for an escape from the pain. Worrying surgeries, but oh you have a 94% chance of seeing another day. Bottles and bottles of therapeutic drugs. In and out of hospitals. Piles and piles of medical bills and debt. Extreme fatigue of energy. Mentally and physically not being able to do what you once loved. Slowly inching closer and closer to death, knowing there’s nothing you can do. But exist. Exist in pain. Extreme mental stress not only on you but everyone else around you. Your loved ones, worried for your life, wondering when the last family dinner with you will be, when the last midnight stroll will be, when the last hug will be, when you’ll be gone forever.
It’s tough.
Fortunately, humans are natural problem solvers. And this problem’s no different.
This is where the incredibly fascinating branch of science, longevity, comes in. You might’ve guessed from the name — longevity is the branch of science trying to literally increase our lifespan. A lot of people have this conception that living another 100 years would just mean more sick days in bed, in pain, in misery. Why would anyone want that? But that’s not the goal. The goal is all about increasing the healthy lifespan (or health span) of a person. This means more years exploring this world, creating everlasting memories, and experiencing everything life has to offer. Decreasing that fear of checking off years. Healthspan.
Fun fact: While the average lifespan for males is shorter, their health span is actually longer!
So, the solution? If we can prevent or delay these illnesses, we can prolong our healthspan… by a lot (aka living another 100 or more years).
And to do that isn’t by finding a cure for each and every condition, it’s by tackling one disease — the disease called aging.
“Aging is a disease, and that disease is treatable” — David Sinclair
So, how do you go around just… increasing the length of a healthspan? That sounds, well, complicated. And it is! It definitely is. But science is frickin cool. And we can do stuff we never thought would be ever possible. First, let’s understand why we even age in the first place.
The heartburning question — Why do we age?
Science has gotten to a state so advanced we’ve been able to label “The 9 hallmarks of aging”. The 9 reasons we age. Damn, science is crazy. Knowing these hallmarks allows us to study aging as a whole (how to limit, stop, or even reverse aging!) and why aging increases the appearance of certain diseases, allowing ways to prevent them and elongate our healthspan.
Pretty cool stuff, right?!
I won’t go into each reason as it’s not the focus of this article, however, they’re really interesting so if you want to learn more about why we age, definitely do a bit of research!
What we’ll focus on is one of the most major hallmarks of age-related diseases — cellular senescence.
Senescent cells
Senescent cells (the outcomes of cellular senescence) grow in number as we age and are cells in your body that just exist, often referred to as “zombie cells”. They don’t replicate (kind of a cell arrest sort of situation), look a bit funky wunky, but still have metabolic action going on.
Cells become senescent when they can no longer function in a healthy manner. A few leading causes of senescent cells are:
- Genomic instability — Mutations and genetic errors cause the cell to make the wrong proteins and miss the right ones, failing to keep the cell functioning normally. This can be detrimental and is a leading factor in cancer. So, to prevent all that, cells become senescent.
- Telomere shortening — Every time our cells divide we lose a bit of DNA bases at the ends of our chromosomes. Luckily we don’t lose our precious genes as we have telomeres, which are basically “useless” DNA bases that get sacrificed instead. They get more and more cut off in each division and eventually, run out. If our cells start losing important genes and continue replicating without them — disaster will happen to say the very least. So, to prevent that disaster, once telomeres get to a dangerously low length (also known as the hayflick limit), they become senescent.
- Epigenetic changes — Throughout our DNA, we have epigenetic markers (in the forms of methylation and histones) that tell our cells which genes to read and thus, determine which proteins are created and how our cells function as a whole. If these markers are placed wrong (which occasionally they are) then cells read and produce the wrong proteins, which leads to them being confused about who they are and what they should be doing. This means a skin cell could start reading genes encoded for a brain cell, ultimately disorientating it completely from doing its tasks to survive. Or even worse, a brain cell can start reading genes for a skin cell. That’s scary. When these cells become so disoriented they can’t function properly anymore, they become senescent to prevent cell division from occurring and the confusion carrying on.
- There are also a few other factors like oxidative stress, free radicals, and loss of proteostasis.
Senescent cells release pro-inflammatory molecules, in the form of cytokines, immune modulators, growth factors, and proteases, collectively known as the senescence-associated secretory phenotype (SASP), that inflame surrounding cells and tissue. The inflammation spreads like a virus, inducing damage to surrounding cells and forcing them to also become senescent. Some well-known consequences are cancer, cardiovascular diseases, atherosclerosis, type 2 diabetes, and rheumatoid arthritis.
A mini-summary of all that: When a cell is stressed or damaged, it locks itself into senescence (a state of no replication), preventing it from reproducing its faults. Senescent cells cannot divide and secrete SASPs that secrete dangerous inflammatory molecules.
So if senescent cells do all these horrid things, why do we even have them?
The Biological Purpose Of Senescent Cells
The 2 main purposes of senescent cells are:
- Tumor prevention: As listed for the reasons above, over time cells can get cellular damage. Words cannot express how terribly devastating it would be if these cells continued to replicate and live on. They would continue to replicate these faults and alongside creating lots of other conditions, create tumors. A cell that can’t divide, can’t form a tumor.
- Healing injuries: Senescent cells are extremely present in wounds or other injuries. The molecules released (in the SASP) tell the immune system that there is damage and to come to clean it up. This allows for wounds and other damages to be fixed. (If we didn’t have senescent cells our immune system wouldn’t know about our injuries and thus, all our wounds would go unnoticed and get much worse, inflamed, and painful.)
Once the wounds are noticed and healed, and the tumor is blocked, we don’t really need these “zombie” cells anymore. There’s no need for us to have inflammatory proteins just spreading around, inflaming other cells for no reason, causing them to join this massive cycle that, quite ironically, results in age-related diseases like cancer.
But our bodies usually have a nice way of keeping everything in check, so what’s the solution to this one?
Simple, we have special immune cells, called cytotoxic T and Natural Killer (NK) cells, that recognize and kill senescent cells (also known as apoptosis) once we no longer need them! Then, through the process of phagocytosis, cells from the innate immune system, ingest them. Boom — senescent cell gone, tumor avoided, wound healed! So… the problem?
As time goes on, more and more senescent cells accumulate, becoming too prevalent and impactful for our poor immune systems to handle. The non-treated inflammation spreads like wildfire, making other cells undergo senescence, dramatically damaging tissues, resulting in lots of age-related diseases like cancer, Alzheimer’s, dementia, arthritis, and so on.
Once we get those diseases, our health span ends. We’re then in those last 10 tortuous years of life.
So, the way to live an extra 100 or more years? The way to increase our healthspan and live happily in health? Kill those senescent cells that the immune system cannot. If we can kill those cells, then we can prevent the inflammatory molecules that cause those age-related diseases, increasing our health span, and thus, our lifespan by a lot.
The pill that makes us live another 100 or more years? They do exactly that.
Senolytics
Senolytics are drugs or compounds that selectively force senescent cells to undergo apoptosis (programmed cell death). Senolytics have such a massive potential to change our lifespans, it’s full-on crazy.
How do these (literally) life-changing pills work?
There are two ways for a cell to undergo apoptosis: Intrinsic pathways and extrinsic pathways.
Intrinsic pathways
On our mitochondrial membranes, we have two sets of proteins called anti-apoptotic pathways and pro-apoptotic pathways. Pro-apoptotic pathways want apoptosis; they create pores in the membrane that leak out harmful substances which end up killing the cell (I’ll get more into later). But when cells are healthy and functioning properly — they don’t want that! They kind of want to live! Which is why we have anti-apoptotic pathways. Anti-apoptotic pathways basically chill on the surface of the membrane, binding to the pro-apoptotic pathways, preventing them from forming pores — so when they are together nothing happens.
Mini-note: Both, anti and pro-apoptotic pathways are comprised of many types of proteins (ex — one anti-apoptotic protein, called Bcl-xL, binds with one of many pro-apoptotic proteins, Bax).
But when there’s cellular stress or damage and cells are signaled to perform apoptosis, cells upregulate pro-apoptotic proteins.
When all the anti-apoptotic pathways are blocked, the extra pro-apoptotic proteins can come together and form pores. Through the pores, cytochrome c leaks out.
The leaked cytochrome c binds with APAF-1 to form a complex called the apoptosome. The apoptosomes then bind with procaspase- 9s. Together, they go around and activate caspase- 9s. The caspase-9s go on to activate effector caspases which to put it in simple terms, tear apart the whole cell — all the DNA, all the organelles, everything. This is known as, in my opinion, one of the most satisfying phrases to say, *drumroll* the caspase cascade!
There are 2 groups of caspases involved in apoptosis. First the effector caspases (caspases -3, -6, and -7) and second the initiator caspases (caspase-2, -8, -9, and -10), which activate the effector caspases.
Once everything is completely torn apart and ruined, the phagocytosis immune process removes the remains.
And that’s the intrinsic way of how to kill normal cells!
But we want to kill senescent cells. So, what makes senescent cells resistant to this process?
Senescent cells upregulate anti-apoptotic proteins so even when the cell produces more pro-apoptotic proteins to kill itself, they just inhibit a few of the many anti-apoptotic ones, preventing apoptosis from really happening.
Cancer cells often express a lot more anti-apoptotic proteins than pro-apoptotic to keep apoptosis from happening. Meanies.
Senolytics work by upregulating pro-apoptotic proteins, and/or downregulating anti-apoptotic proteins, allowing for more pro than anti-apoptotic pathways, essentially opening up the membrane pores and allowing everything to smoothly crash after that.
And this isn’t just a theory, it’s real. For example, a molecule, ABT-199, was invented to inhibit the BCL-2 anti-apoptotic protein and dispaces pro-apoptotic proteins, allowing for them to come together to form pores and execute apoptosis. This senolytic drug is used to treat certain blood cancers, especially chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML).
Cool, right?
Extrinsic pathways
Important note: Current senolytic treatments don’t use the extrinsic pathway to combat senescent cells, however, the extrinsic pathway is a huge part of maintaining life, it’s how our immune system naturally kills these age-related disease-causing cells! So, if you’d like to know how our immune system forces them to kill themselves — read this part.
The second-way cells perform apoptosis is by external signals. These signals are given by Natural Killer (NK) cells or CD8-positive Cytotoxic T lymphocytes (CD8+ T cells).
On the extracellular surface of NK and CD8+ T cell membranes, are lots of proteins called Fas Ligands (FasL) that bind to the Fas Receptors (FasR) of our damaged cells.
How do NK and CD8+ T cells know which cells are damaged and which ones are healthy? Well, on the membrane surface of our cells, we have Major Histocompatibility Complex (MHC) class I molecules. On normal cells, these are inhibited by self-antigens but on damaged cells — they aren’t! When cells are damaged they also produce stress-related ligands that bind with receptors on NK and CD8+ T cells. So, basically, senescent cells, express a few different ligands than the ones on healthy cells, which NK and CD8+ T cells recognize and bind to.
When the FasL and FasR bind together, activation of a protein, the Fas Assioted Death Domain (FADD), occurs. When FADD is activated it binds a similar protein (the FADD Adapter Protein) consisting of another FADD plus a Death Effector Domain (DED) with it.
Then another protein comes along — a procaspase -8 or -10 linked with another DED.
The DED attached to the procaspase links with the DED of the FADD Adapter Protein. This entire complex is known as the death-inducing signaling complex (DISC).
Once all that happens, the procaspases break their large and small subunit apart. These subunits come together to form active caspases -8 and -10.
Now, caspases -8 and -10 can’t just break apart the entire cell, they’re way too few of them to actually do it. That’s why these are our initiator caspases.
Because procaspases -8 and -10 are the only procaspases that can attach with DEDs, they are the only ones that can break apart their large and small subunits to form an active caspase. These active (initiator) caspases then go around breaking the bonds between the large and small subunits of effector caspases, and those new caspases break the bonds of other inactive ones, and the cycle keeps repeating.
As I said earlier, when the initiator caspases activate other caspases, they create the caspase cascade — the crazy cell state where caspases are everywhere, activating more and more other caspases, destructing and tearing apart everything in their way. Just like in the intrinsic pathway, the phagocytosis immune process removes the remains — and boom! Senescent cell gone!
So, where do senolytics come into play with this? They don’t. But, who knows, in the future, maybe using the extrinsic pathway could be the key!
Senolytics In The Real World
Senolytics aren’t some fairy tale pill, they’re pretty real! And changing this world. For example…
- Mayo Clinic used senolytic drugs, dasatinib and quercetin, to remove senescent cells in mice, eliminating tons of age-related diseases and increasing their lifespan by 30%.
- UNITY Biotechnology is using senolytics to inhibit an anti-apoptotic protein, Bcl-xL, with UBX1325, treating diabetic macular edema (DME) and in general, age-related diseases of our eyes.
- Cleara is using senolytics to remove senescent cells found in several chronic diseases and late-stage cancer in humans.
The applications are just begging to emerge — we still have a whole sea full of the coolest fish to dive head-first into!
Summary
- Longevity is all about increasing our healthy lifespan
- Senescent cells release pro-inflammatory molecules that suppress tumors and notify the immune system to heal injuries
- But, as we age, our immune system can’t keep up with cleaning them, and the molecules start dangerously damaging surrounding cells and tissues, causing lots of age-related diseases
- Senolytics are drugs or compounds that kill the excess senescent cells either by upregulating their pro-apoptotic pathways or deregulating anti-apoptotic pathways
- With the extra pro-apoptotic proteins, pores in the mitochondria are formed, leaking out cytochrome c
- Cytochrome c binds with apaf-1 and procaspase 9 to make the apoptosome
- The apoptosome triggers the activation of effector caspases, creating the caspase cascade and ultimately tearing apart the whole cell
- Senolytics might just be the key to living much, much, much longer!
Before you go:
- Hey, I’m Michelle, a 14-year-old, biology, psychology, and philosophy enthusiast!
- If you enjoyed, give a quick clap and let me know your thoughts in the comments!
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