Ever wonder what happens to the cells in your body once they reach the end of their life-cycle?
OK…probably not. Most of them just die and get recycled.
But some of them don’t die.
Instead, they become…ZOMBIE CELLS!
In today’s video, we’re going to take a look at how that happens,
and examine some drugs called senolytics,
that have been developed to eradicate this infestation of the undead.
As you grow older and cellular damage begins to accumulate,
an increasing number of cells in your body enter into a state known as senescence.
Once they enter this state, they stop doing a number of things that active, living cells do.
Things like…dividing and creating new cells, repairing and supporting the tissue that they’re a part of.
Instead, they start secreting harmful chemical signals that can cause damage,
such as causing healthy, neighboring cells to also enter the state of senescence.
In addition to reducing tissue repair, this can cause an increase in chronic inflammation
and a rising risk of cancer and other age-related chronic diseases.
Cellular senescence can be caused by a number of different things.
Mitochondrial dysfunction, a decrease in sirtuin levels, different types of stress, such as oxidative stress,
and damage to the DNA.
And the most common genetic damage stems from telomere erosion,
the leading cause of cellular senescence.
In the nucleus of every cell, lie the genes, which are made up of long spirals of DNA.
At the ends of these spirals are a section of the DNA that does not encode for anything.
These non-coding sections of DNA are the telomeres,
and they act like those little plastic caps on the ends of shoelaces.
They protect the spirals of DNA from unraveling and becoming damaged.
Every time a cell divides, a little bit of DNA is lost off the end of the telomeres.
So there’s a limit to the number of times that a cell can divide
before the protection that the telomere provides is gone.
This limit happens to be called the “Hayflick Limit” and it’s about 50 divisions of the cell.
Once a cell has reached the “Halflick Limit”,
it’s telomeres are gone and the DNA in it’s genes start becoming damaged.
At this point, one of only two things can happen:
either the cell dies and is recycled, or it enters senescence.
“Apoptosis” is the programmed death of cells,
and it’s what most of your cells do when they reach the “Hayflick Limit.”
Once they die, their molecular material is recycled through a process called “autophagy.”
And this is a good thing…this is what we want to happen.
Once a cell is no longer doing it’s job, we want it to be removed and recycled, right?
But some cells don’t die, instead they enter a state of senescence.
In addition to a bunch of pro-inflammatory chemical signals,
senescent cells secrete pro-survival genes which make them highly-resistant to apoptosis.
So, they don’t die, and instead of being a productive member of their society,
the tissue that they’re a part of, they become a detriment.
Senescent cells provoke a variety of different types of damage.
They produce an array of inflammatory cytokines and chemokines,
immune modulators, growth factors and proteases; all falling under the heading of SASP,
also known as senescence-associated secretory phenotype.
And SASPs can do a lot of damage.
They can cause chronic inflammation,
they can encourage nearby healthy cells to also become senescent.
And in an effort to survive,
senescent cells can even cannibalize surrounding cells to utilize their resources to stay...
well, not exactly alive but certainly not dead.
Which is why they’re also called “zombie cells.”
Now, normally, senescent cells don’t accumulate because they’re scoured away by the immune system.
Senescent cells are one of the things that the immune systems was designed to remove.
But as we age, the immune system goes into decline,
and more and more senescent cells escape this process and begin to accumulate.
And there’s this weird feedback loop going on between the immune system and senescent cells.
While an accumulation of senescent cells can be caused by a failing immune system,
senescent cells are one of the things that cause the immune system to go into decline in the first place.
This can be demonstrated by the fact that a declining immune system
can be improved by taking something called a “senolytic.”
OK, so, what is a “senolytic?” Quite simply, it’s a drug that selectively kills senescent cells.
Turns out, killing cells is pretty easy to do with a large assortment of drugs.
But selectively killing just one type of cell…that's much more difficult.
So senelytics have been developed to do just that…only attack senescent cells.
And how they do that is pretty interesting.
Remember those pro-survival genes that I talked about earlier,
the ones that all senescent cells emit and that make them so resistant to apoptosis?
Senolytics target those genes.
And once those pro-survival genes are no longer protecting senescent cells,
apoptosis can take over and kill them, like it’s supposed to.
So, that’s what senolytics do. They ignore healthy, living cells and only kill senescent cells.
Or at least in theory, that’s what they do.
In practice, most of the senolytics that have been developed have turned out to have…
varying degrees of efficacy. Most of them only kill a few of the many types of senescent cells that exist.
So, let’s turn this discussion to an examination of some of the available senolytics.
The first of these is quercetin.
Quercetin is a natural pigment called a flavonoid,
and it can be found in vegetables, fruits, grains, tea and wine.
In addition to being a mild senolytic, it’s also an anti-oxidant.
It’s been shown in the lab to be somewhat effective at remove a few, but not all, types of senescent cells.
But it has poor water solubility, chemical instability and poor bioavailabity,
making it unrealiable in senolytic therapy.
Next up is dasatinib.
Dasatinib is a drug that is used in a targeted therapy to treat certain cases of leukemia, and it’s quite toxic.
But it’s been shown to be a fairly effective, if somewhat limited, senolytic.
In fact, that’s how it’s utilized in leukemia treatments.
But, because of it’s toxicity, it can only be used by prescription and under the care of a physician.
Interestingly, combining quercitin with dasatinib
has been shown to be more effective than using either of them alone.
Now, the next senolytic that we’re going to talk about is fisetin.
Fisetin is also a flavonoid and it’s found in strawberries, apples, persimmons, onions and cucumbers.
In animal trials, fisetin apparently proved to be just about as effective as quercitin plus dasatinib.
However, the jury’s still out because so far as I know, there have been no human trials.
Now, the biochemistry of mice is quite similar to humans when it comes to cellular senescence,
and other senolytics that have proved successful when used on humans
have worked equally well when used on mice.
Another compound that has proved to have senolytic qualities is piperlongumine.
Piperlongumine is a natural constituent of the fruit of the long pepper,
which is a pepper plant found in SE Asia and southern India.
In addition to being a senolytic, it also may have some anti-cancer properties.
Piperlongumine appears to be a promising senolytic
because it’s less toxic and more orally bioavailable than other senolytics.
But the mechanism with which it can selectively kill senescent cells is not understood,
and an understanding of this is critical if piperlongumine or any of it’s analogues
are ever going to be developed as an effective senolytic.
Now, it can be used as a senolytic now, I think that it’s going to be much improved in the future.
Another interesting candidate is FOXO4-DRI.
It’s a peptide, and it stands for FOXO4 D-Retro-Inverso. It’s a protein produced from the FOXO4 gene.
This peptide is the mirror image of regular FOXO4,
and because of this, it’s not processed in the normal way by cellular metabolism,
and the effect of that is that it sabotages the survival efforts of lingering senescent cells in old tissues,
causing them to self-destruct.
Now, this is a fairly new protocol, and it’s also fairly complex and possibly illegal,
so I would leave this one on the shelf for the time being.
Now, if you’re interested in it, there’s a link in the description to a great article that I recommend
by a guy who goes by the handle of “Reason”, who has a longevity blog named “Fight Aging”.
It’s well researched, and has quite a bit of detail about this protocol.
Finally, there Navitoclax. This is another senolytic drug that’s also used as an anti-cancer drug.
But it’s so toxic that the costs outweigh the benefits, in my opinion.
Researchers are experimenting with various protocols to make it less toxic,
but that’s a ways off, so this is another senelytic that I would shelve for the time being.
Now, there was a paper that was published on May 12 of this year, just a couple of weeks ago,
about a senolytic that's currently being called SSK1.
This senolytic uses the same pathway that other senolytics use, targeting the pro-survival genes.
SSK1 is a prodrug,
which is a compound that is therapeutically neutral until it encounters a chemical trigger in the body.
In this case, the trigger is an enzyme produced by one of those pro-survival genes,
the ones that are emitted by all senescent cells.
Once activated by the trigger,
SSK1 releases a compound that induces apoptosis, killing the senescent cell.
Since it’s only activated by pro-survival enzymes released by senescent cells,
it completely ignores healthy cells, focusing only on senescent cells.
SSK1 was developed in China, and in early testing, it proved to be one of the best senolytics yet,
because it has a much more broadband effect,
killing more different types of senescent cells than other senolytics,
AND because it also has been proven to be much less systemically toxic.
Now, SSK1 is still a long ways from being made available,
but the future of senolytics is really starting to look pretty bright.
I hope you enjoyed this discussion of senolytics,
and if you’re interested in more information on cellular senescence,
check out this other video that I did on the topic about a year ago.
That’s it for me, I’m outta here. Catch ya next time.