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This week, I thought I’d try something different.
As you may suspect, I try to keep up on the latest news in the field of longevity.
Occasionally, I come across news that I know you guys would be really interested in,
but there’s not enough here to make a whole video.
So, once a month I’m going to combine a few of these news items into a single video.
As it turns out, there’s recently been a lot of discoveries in a single field.
Normally, I think I'll be doing the news on a variety of subjects, but this month it’s all about cellular senescence.
OK, so this first item comes from a study that was published on the 18 of June, this summer.
I’ll put a link to it in the description below, as well as all the rest.
Now, this first study talks about using senescence-associated secretory phenotype, or SASP,
as an indicator of both biological age and medical risks.
As you may know, once cells enter senescence, they start secreting an array of pro-inflammatory cytokines,
chemokines, immune modulators, grow factors and proteases.
Collectively, these are known as senescence-associated secretory phenotype…and they can do a lot of damage.
They not only cause chronic inflammation, they can encourage neighboring cells to also enter senescence.
This new study used 7 of the factors in SASP to form a biomarker for aging and health.
Now, in order to be clinically useful, biomarkers need to be both accurate and cost-effective.
But these 7 factors can be sampled through a simple blood draw,
and then diagnostic equipment can both test for their presence and determine the level of senescent cells.
By knowing how much of a burden a person is carrying from cellular senescence,
it should be possible to determine a person’s biological age
as well as any potential health risks associated with senescent cells.
It could also be useful in determining how well senolytic therapy is progressing
by measuring the reduction in senescent cells.
I recently did a video on testing for biological age
in which I review several different tests that analyze such things as methylation, telomere length
and mitochondrial dysfunction in order to determine your biological age.
This is one more test to add to your toolbox to get as accurate a read as possible on your true biological age,
the state of your health and the risks you’re facing from age-related diseases.
The next item comes from a study that was published on the 3rd of July.
In the study, the researchers took a look at Naked Mole Rats, which are a particularly long-lived rodent.
In captivity, mice will live about 2 years and rats about 4, but a naked mole rat will live for about 30 years.
And they theorized that one of the reasons why they can live so long is because they have no senescent cells,
or at least, not an accumulation of them.
In naked mole rats, when their cells become senescent, they enter apoptosis and die.
So what they did was they experimentally induced cellular senescence
by irradiating some skin samples of both mice and naked mole rats with UV.
While the mice samples exhibited the expected senescent cells, the naked mole rat samples had none.
Yet analysis of the naked mole rat cultures revealed lots of dead cells,
the remains of senescent cells that had died rather than becoming senescent.
How are the senescent cells in naked mole rats different from the senescent cells in mice?
Well, they differ in a couple of ways.
First, the naked mole rats cells had a stronger expression of genes related to oxidative stress.
Second, when mice cells enter senescence, they undergo a large shift in their metabolic profile.
But this metabolic shift is much less in naked mole rats.
In the senescent cells of naked mole rats,
the stronger expression of genes related to oxidative stress suggests
that an increase in Reactive Oxygen Species, or ROS
might be causing the senescent naked mole rat cells to die.
In mice, that large metabolic shift deactivates many of the pathways that produce ROS,
making them less susceptible to oxidative stress.
But in naked mole rats, perhaps because of the smaller shift,
they found that 2 of these ROS-producing pathways were still very active.
Now, naked mole rats may have evolved a really poor defense against ROS
because oxygen levels are very low in their underground burrows.
They have no ventilation and oxygen levels can drop to only 6 or 7%.
While this makes the senescent cells of naked mole rats vulnerable to ROS,
it’s useful in clearing them out and helping the rats to avoid their harmful effects.
This discovery of senescent cell death in naked mole rats
lends a lot of strength to the argument for the use of senolytic drugs to clear out excess senescent cells,
which will hopefully lead to an increase in lifespans and healthspans in humans.
Speaking of senolytics,
the next couple of studies are about some new senolytics that have recently been discovered,
and the first of these is from a study published on the 27th of April.
This study takes a really interesting approach.
A group of chinese researchers created a new “prodrug” to be used as a senolytic.
It’s called “Senescence-Specific Killing” compound, or SSK1 for short.
Now, a prodrug 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 a pro-survival gene that is emitted by all senescent cells,
and that enzyme is called β-galactosidase, or β-gal.
After screening an extensive list of FDA-approved drugs,
the researchers were looking for a compound with potent cytotoxicity for senescent cells as an end product.
And they chose a drug called Gemcitabine, for 3 reasons.
First, it killed both mouse and human senescent cells effectively and potently.
Second, it had a 4-amino group with a well-established site for prodrug development,
and third, because it exhibited reduced systemic toxicity due to its short circulation time in the body.
So, as I understand it, they combined Gemcitabine with an acetyl group, which effectively neutralized it,
until it came into contact with β-gal.
The resulting prodrug is then cleaved by β-gal, releasing the cytotoxic Gemcitabine,
which then induces apoptosis in the senescent cell, killing it.
Since it’s only activated by pro-survival enzymes released by cells that have entered senescence,
it completely ignores healthy cells and focuses exclusively on senescent cells.
In early testing, SSK1 proved to be one of the best senolytic 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.
The researchers compared SSK1 to other senolytic candidates such as dasatinib plus quercitin, and fisetin,
and found that although all theses drugs showed senolytic abilities,
SSK1 proved superior in the combined categories of potency, specificity and non-toxicity.
Now, there’s an interesting side note.
Macrophages are an important part of our immune system,
but an accumulation of macrophages can cause chronic inflammation
and tend to exhibit heightened levels of β-gal, just like senescent cells.
The researchers also found the SSK1 lowered the number of activated macrophages
in the livers of aged mice, and this significantly reduces chronic inflammation both locally and systemically.
So the researchers decided to run functionality tests of these mice
and found that they showed improvements in motor function, balance ability, exercise endurance,
skeletal muscle capacity, and spontaneous exploration compared to untreated mice.
The last news item for today comes from a study that was published May 15,
and it’s also about a new senolytic.
There’s a family of drugs called “SYK Inhibitors”.
SYK stands for “Spleen Tyrosine Kinase”, and it’s expressed in hematopoietic cells in bone marrow.
SYK plays a major role in the B-cell receptor signaling pathway
and SYK inhibitors are used in the treatment of B-cell malignancies and autoimmune diseases.
There are a number of different SYK inhibitors, and one of them is called R406.
According to the published study, researchers “identified a novel senolytic drug R406
that showed selective toxicity in senescent cells” and were able to confirm that
“R406 caused apoptotic cell death along with morphological changes in senescent cells.”
R406 is an orally bioavailable SYK inhibitor
and in early mouse and human studies it’s been shown to reduce immune system-mediated inflammation,
improving the function of the immune system and preventing excessive activation of immune cells.
It’s well known that immune systems become dysfunctional with aging
due in part to excessive exposure to chronic systemic inflammation known as inflammaging.
So R406 could be reducing the senescent cell burden
by enabling the immune system to be better at locating and destroying senescent cells more efficiently.
Now, SSK1 and R406 are still not ready for prime time,
but the future of senolytics is really starting to look pretty bright.
And that’s it for this installment of the news.
If you liked these news segments, leave me a comment and tune back in next month for another installment.
If you’d like more information of senescent cells and senolytics, check out this video.
Thanks for watching, catch ya next time.