Today, we’re going to be talking about a new wave of senolytics that are in development
that can eliminate senescent cells while leaving healthy cells alone.
Things like antibodies that can be tweaked to become intelligent, target-locked missiles that can hone in on senescent cells.
Or the possiliby of a vaccine for cellular senescence.
You’ll want to stick around for this.
I’ve talked a lot on this channel before about senescent cells.
And I’ve talked about therapies to eliminate senescent cells, like senolytics.
But longevity science has advanced to the point where today, I’m going to be talking about second generation senolytics,
and this new wave of molecules is really exciting.
But first, we’ll do a quick recap of just what senescent cells are, and how they impact aging.
When you think about senescent cells, think about zombies. Creatures that are supposed to be dead…but aren’t.
Creatures that go around, turning other healthy creatures into zombies like them.
Senescent cells are a lot like zombies.
They’re cells that have ended the cellular cycle and are supposed to have died, through a natural process called apoptosis,
or programmed cell death. But for some reason, they haven’t died. Instead, they remain metabolically active.
Cellular senescence can be caused by a lot of different things, but the most common is replicative exhaustion.
This is where the cell has divided just about as many times as it can, and it stopped dividing.
Now this is governed by something called the Hayflick Limit and is about 50 to 75 times.
Now cellular senescence can be a good thing and eventually, these senescent cells get cleaned out by the immune system.
Except that some of them don’t, and this is where they really become like zombies.
Senescent cells secrete a variety of pro-inflammatory cytokines, chemokines and proteases…
and they are responsible for a lot of the chronic inflammation that develops as we age.
These are secretions are called senescent-associated secretory phenotypes, or SASPs,
and they can induces neighboring healthy cells to also become senescent, even if they’re nowhere near they’re Hayflick Limit.
And as we age, we accumulate more and more senescent cells.
And it’s believed that cellular senescence lies at the heart of many of the chronic diseases that are synonymous with aging.
Because of their role in aging, over the last decade the senescent cells became the object of intense research.
In quest to prolong human life, scientists had carried out a number of experiments on laboratory animals.
These studies have shown that clearing out senescent cells can successfully delay the progress of age related diseases
and slow down the health decline associated with old age.
So…scientists and researchers have developed a class of drugs called senolytics.
The purpose of these drugs is to eliminate senescent cells.
The first generations of these drugs included dasatinib and navitoclax, both anti-cancer drugs.
It also included fisetin & quercitin which are polyphenols and can be found in many foods.
But there’s a couple of problems with this first wave of senolytics, which have interfered with their effectiveness.
First, each only works on a few classes of senescent cells, not all of them.
And they sometimes have a hard time distinguishing between senescent cells and healthy cells,
meaning that they can sometime destroy both.
In the last few years, the goal of scientists was to come up with a second generation of senolytics
which would target senescent cells specifically, without affecting the healthy ones.
And the results from recent research are starting to look really promising.
It looks like we’ve made some significant breakthroughs.
Now, what’s really interesting is that this new wave of senolytics
seem to use completely different mechanisms to tackle the same problem.
Let's start with grape seed extract.
A group of scientists from Shanghai screened a library of molecules which have been previously reported
to have an effect on senescent cells.
They did a range of trials in petri dishes, testing the effect of each molecule on both senescent cells and on healthy cells.
Their goal was to narrow down the group, finding out which substances killed senescent cells without affecting the healthy ones.
Five substances fulfilled the criteria: fisetin, which was already known to work,
quercetin, curcumin, piperlongumine and grapeseed extract.
Because the strongest results were recorded for grape seed extract,
the researchers naturally decided to focus on that substance.
Now, Grape Seed extract is a mixture of a lot of different molecules,
so the next step was pinpointing which molecule had the biggest impact on senescent cells.
And with help of mass spectrometry, researchers identified the main agent:
a molecule called procyanidin C1, or PCC1.
In small amounts, PCC1 stopped senescent cells from secreting pro-inflammatory SASPs.
In higher concentrations PCC1 can also kill senescent cells, while leaving younger, healthier cells intact.
The next stage was seeing how PCC1 would work in live animals.
The scientists treated aged mice with PCC1 once every two weeks for four months.
Whenever you clear senescent cells, their numbers take some time to rebound.
Because of this, senolytics only be should used intermittently. That’s also a smart way of reducing side effects.
The cohort of mice first treated with PCC1 were two years old,
which is roughly the equivalent of about 70 years old in humans.
The PCC1 therapy increased the lifespan of those aged mice by 9%.
They also had lower levels of cellular senescence.
On top of that, the treated mice also got noticeably fitter, achieving better results on maximal walking speed,
treadmill endurance and grip strength tests.
Encouraged by these promising results, the researchers then gave PCC1 to even older mice,
which in human years would be around 75 to 90 years old. Overall lifespan was improved by 9.4%,
showing the effectives of this molecule, even when administered later in life.
And PCC1 extended the median lifespan of these mice by 64.2%.
The authors concluded that PCC1 decreases the risk of age associated mortality, even when given to older individuals.
They consider PCC1 to be the key to a new anti-aging therapy, which could also help with cancer.
Another approach to second generation senolytics is to design “smart bombs,”
at least that’s what the developers of this intervention are calling it.
Again, the idea is to obtain a drug which would only affect senescent cells while leaving healthy cells intact.
Same goal, but with a different path to get there.
If you’re developing an intelligent weapon, the first problem is how to make it recognize the target, right?
How to recognize a senescent cell when you see one?
Well, you can look at the proteins on the cell’s surface.
Senescent cells have a specific constellation of proteins on their surface, called a surfaceome.
Now, this can be used to identify cells that are senescent. Protein markers like these are used by antibodies to identify germs.
So, what the research did was to make a conjugate of an antibody and a drug,
and it works like a remotely-controlled, highly specific intelligent missile.
Like a “smart bomb”.
In this, the researchers were inspired by cancer research.
In some cancer therapies, antibodies were tweaked so that they can recognize the specific cancer cells and kill them.
The smart bomb approach was similar.
The researchers used antibodies which were modified to recognize senescent cell’s surfaceome,
combining these antibodies with a drub that is toxic to all cells.
When in contact with a senescent cell, the antibody locked into the target and released its toxic cargo, killing the cell.
But, because the antibodies are designed to seek and destroy senescent cells, normal healthy cells are left intact.
This minimizes the potential side effects of the smart bomb drug.
Authors of the study concluded that we now have, for the first time,
an antibody based drug that can be used to help slow down cellular senescence in human beings.
There’s also a third way to tackle senescent cells:
by using a vaccine to hack the immune system so that it will treat senescent cells like viruses.
If you take young, middle-aged and old human cells, and compare them, the older ones show two distinct features:
higher amounts of specific antibodies which are the markers of senescence, and higher numbers of a protein called GPNMB.
This stands for a mouthful: lycoprotein nonmetastatic melanoma protein B.
So we’ll stick with GPNMB.
Now, this protein has multiple roles, but many research studies have linked it to cellular senescence.
It’s upregulated in both humans and mice with atherosclerosis, and its expression in atherosclerosis
is associated with senescence.
Because of this, the researchers wanted to determine if its possible to develop a vaccine which would immunize tissues
to the GBNMB protein and if did, to find out whether or not it would result in less senescent cells.
In standard vaccines, the immune system recognizes antigens from viruses.
This time the marker, instead of being a viral antigen, was the GPNMB protein.
The first step was to create mice with high concentrations of GPNMB.
Because the researchers knew that GPNMB is upregulated in cardiac diseases,
the researchers decided to feed the mice a high cholesterol diet, which led to the mice developing cardiac and metabolic problems.
And it worked. After feeding the mice a diet of essentially junk food,
the mice had developed higher concentrations of GPNMB.
But would giving the mice the vaccine actually result in fewer senescent cells?
Well, turns out, it did.
As a result of vaccinating the mice, GPNMB-positive cells were eliminated.
Both cardiac and metabolic function improved and the mice’s adipose tissue revealed fewer senescent cells.
But here’s the real kicker. Did the vaccine have any positive effect on aging in the mice?
To determine that, the researchers gave the vaccine to mice with progeria, a genetic disease the causes rapid aging.
Using mice with progeria has long been a strategy employed by researchers into longevity.
And the survival rate of the vaccinated mice went up, with male mice surviving longer than the female mice.
So, it looked like the link between the protein GBNMB and senescence was confirmed and that
senolytic vaccination could potentially be used as a successful treatment for aging.
However, one question still remained.
Is vaccinating against cellular senescence really better than the senolytic drugs that we already have?
Authors of the study compared the vaccine to other known senolytics already in use,
such as dasatinib + quecetin or navitoclax.
They all improved markers of senescence, but the vaccine seems to last longer,
up to 24 weeks while the dasatinib + quecetin and navitoclax groups only showed improvements through 16 weeks.
While the results of the study showed that a vaccine that targets GBNMB has the potential to become a new, precision senolytic,
the study raised as many questions as it answered, and a lot more investigation needs to happen
to learn how GBNMB vaccination effects the immune system and it potential role in aging and longevity.
Alright, let’s get real for a moment. How useful is any of this information?
How can you take advantage of any of this new research?
Both smart bombs and senolytic vaccination need a lot more research before we’ll see any new medication reach consumers.
However, grape seed extract is a common supplement that has been is use for a long time and is generally considered to be safe.
Now, as you know, I’m not a doctor and I don’t like to make recommendations.
I only talk about strategies that I might use myself, and I’m thinking that this might be one of them.
The mechanism of action for grape seed extract is fairly well understood.
A dosage of 100 to 300 mg per day has been used in several scientific studies
and it’s prescribed in those same doses in some European countries.
Obviously, don’t take it if you’re allergic to grapes.
If you have high blood pressure of a bleeding disorder, consult with your doctor before starting grape seed extract.
In fact, I would consult with your doctor regardless, before starting any new drug or supplement.
Grape seed extract can also interact with some blood thinners, NSAID painkillers like aspirin
and some heart or cancer medications. So really, check with you doctor first.
Even if this new research is preliminary, it’s exciting to see these advancements in the world of senolytics.
As these second generation senolytics are being developed, it really starting to look like we’re getting closer to finding therapies
which can clear out senescent cells without having any harmful effects on healthy cells.
OK, that wraps up today’s video.
If you’d like to learn more about senescent cells,
then check out this playlist the I’ve created on the topic of cellular senescence and senolytics.
That’s it for me, I’m outta here. Catch ya next time.