Senescent Cell Transcript 11-30-11

2015-01-13

azim58 - Senescent Cell Transcript 11-30-11

I'm going to talk about a paper that was fairly exciting that was just
published this month November 2011. And it was published by several
departments of the Mayo clinic in Rochester Minnesota as well as between
a collaboration with Groningen University in the Netherlands. I might
have pronounced Groningen wrong. Yeah and just a little bit about the
Mayo clinic. .they're quite a good clinic and hospital. They have several
different facilities. Their headquarters are in Rochester Minnesota, but
they also have a clinic in the Phoenix Scottsdale Arizona area and also
in Jacksonville Florida. And the Mayo clinic has been rated one of the
best healthcare places in the world and they also do a lot of combination
between treating patients but then also core research too. They try to
put 40% of their effort about into research. So in this paper. . it's
about the aging effects of senescent cells, and they were able to remove
the senescent cells from mice and show that this reduced age related
phenotypes. The mice were much healthier. Before I go too much further I
just ant to talk about one sentence they have here in the abstract. They
say cellular senescence which halts the proliferation of damaged or
disfunctional cells is an important mechanism to constrain the malignant
progression of tumor cells. So I mean yeah they claim as well as many
people claim the purpose of senescent cells is to prevent cancer. I'm
sure many of you know cells will become senescent after it's telomeres
get too short. So cells can keep on dividing and every time they divide
their telomeres get shorter and shorter and once the telomeres reach a
critically short length those cells will either no longer divide and
become senescent or it could escape this stopping of division and they
can become senescent (*supposed to be "cancerous"). So but I just wanted
to say that I don't know if this necessarily has to be the case. Another
theory that some people have proposed about the purpose of senescence is
that maybe it's not so much to stop cancer. . another possibility could
be that cells just become senescent because there was never really any
reason in the past for evolution to uh design an organism like ourselves
that had cells that didn't become senescent. So the organism just had to
live long enough to reproduce in it's environment and if it reached that
goal then there's no really pressure to escape this senescence mechanism.
So rather than having a purpose to stop cancer, it may have just been. .
the avoidance of senescence may have just been left out because there
wasn't evolutionary pressure for it. Anyway, enough of that. I'll go on
and start talking about the paper a little bit more here. The mice they
were working with were a BubR1 progeroid mouse background. And um some of
you may know about the disease progeria. There's some humans with
progeria as well and when they have progeria they age extremely quickly.
So when they're teenagers or in their early twenties, they look much much
older and they die at a young age. And uh so in this particular mouse
they have something similar and they have a mutation which causes the
chromosomes to not separate during cell division. And uh some of the cell
types that are most affected by this process are the adipose tissue and
skeletal muscle and eye tissue. But some of the things that won't be
affected by this process of reaching senescence are things like heart
cells which divide very rarely if at all so that's something to keep in
mind as they go into some of the results later in the paper. So right now
I'll just show you the schematic of this construct they put into these
progeria mice. This is the Ink attack construct. So they genetically
engineered the mice so that when they administered the drug it they could
kill just the senescent cells. So kind of the way it worked here is they
had uh they had this p16 promoter. . so p16 is a biomarker in some
senescent cells. . so it's a gene in some senescent cells. So this gene
would normally turn on and produce p16 but they also added these other
genes that would be transcribed or created with it. So one of the genes
is caspase, and then the other one was green fluorescent protein this
EGFP. So the green fluorescent protein would allow them to detect which
cells had this genetically engineered construct. And then uh with the
caspase what that's all about is uh actually caspase is turned on when a
cell undergoes apoptosis and kind of kills itself. In fact when a T cell
of the immune system finds a cell that it needs to kill what it will do
is actually activate some pathways that will activate caspase and then
caspase will tell the cell to undergo apoptosis and kill itself. So here
with the way this system works that they created the caspase will be
created and then it won't have any effect until they add this drug
AP20187 so this AP drug. Once this AP drug binds it turns this inactive
caspase into an active caspase and the cell will undergo apoptosis. So
all of these other figures here I'm not going to spend time talking
about. All they're doing is that they're showing that their construct
does work the way they expect it to work. And uh yeah here's a sentence
summarizing all of these figures. Taken together these results indicate
that INK attack which is that genetic construct is selectively expressed
in p16 positive senescent cells. So senescent cells will produce that
p16. Okay so so now let's get to the results with the mice and see what
happens there. So um first here they show that uh when they do add the
drug it does truly kill the cells that have been genetically engineered
to respond to this AP drug. So this drug rosglitazone. What it will do is
it will cause cells to become senescent and it will cause cells to
produce senescent cell biomarkers such as p16. And then here in this
figure they do not add the minus AP. And here, this is a little bit of a
fuzzy image but uh here they do add the AP and you can see there's much
fewer cells here. So it is true that the AP does kill the cells. Now now
for these mice they different groups of mice which received the AP drug
during their lifetime so the senescent cells were being killed and
removed and some didn't. And the ones that received the drug fared
better. So here what they have on this curve is they have the percent of
the mice which have lordokyphosis which is just like a curvature of the
spine associated more with old age and uh damaged skeletal muscle tissue.
And uh with these dotted lines, you can see that um they had a much lower
incidence of lordokyphosis. And the dotted lines up here are the ones
that received the AP drug. So plus AP and plus AP. You'll see that this
is ATTAC-3 and this is ATTAC-5 um that's there just two different cell
lines that both have this genetically engineered construct. And this
minus AP hre are those dark lines and this didn't even have the
genetically engineered construct and you can see these lines here. . they
have a much higher rate of lordokyphosis. They also measured cataract . .
yeah cataract incidence. And the same thing here there was a lower
incidence of cataract with the mice that had the senescence cells killed
by the administration of the AP. Here's actually a screenshot comparing
the two mice. So here's the one's that received the drug and the
senescent cells were killed. You can see they look alm kind of chunkier
but their posture looks better they don't have that curvature of their
spine. They look kind of healthy whereas the uh and these are 9 month old
mice. . these particular progeria mice if I recall they live just a
little over a year. . not too much longer than that. And then um these
mice did not receive the drug and died sooner. So they also show the
muscle fiber diameters are thicker. Here the light blue and the orange
have thicker muscle fibers in both the muscle associated with the stomach
area. . or the gastrointestinal area and also the abdominal muscle. .and
uh they also compare treadmill exercise. So in this graph both there's
the 3 and the 5 like lines of mice and this is the percent improvement
over the untreated mice. So these mice could run on a treadmill for a
longer period of time for a longer distance and they performed more work
also. Like work as you would calculate in physics. So it's quite
impressive. They also measured the cell diameter of uh fat cells and the
thickness and the fat cells and thickness were higher were larger greater
in the mice that received the drug and had the senescent cells killed.
This here they just have a table of numbers kind of showing the same
thing. And uh the mass of these cells was measured with a technique
called DEXA. I'm not very familiar with that but DEXA is. . well here I
made a note down here. DEXA is dual energy x-ray absorptiometry. Yeah so
that's kind of interesting uh this figure over here I won't spend much
time on that, but I do want to talk about the next figure because
everything I talked about before they were treating the mice from a young
age they kept giving them that AP drug, but they also wanted to see what
kind of effect they could observe if they started a late treatment. So
the mice were already kind of old and they started administering the
drug. And basically what they found. . maybe I won't even go into too
many of the details of the figure. I'll just summarize what they did find
here. And they measured many of the same things they measured before for
example muscle fiber diameter, how far and how well they could run on a
treadmill, all those different things, as well as the relative expression
of different genes associated with senescence. Yeah so the treatment
reflected attenuated progression of age related decline rather than a
reversal of aging. So oh right so basically they weren't able to reverse
the aging as well. . on these figures they show 10 month old mice and
they also show just compare that with the 5 month old mice the black bar.
The black bar always has the best values. So the 5 month old mice always
have the best values. So when they started the treatment at 10 months
they weren't able to reverse the treatment back to the condition of a 5
month old mice, but it was better than the mice that received no
treatment at all. So basically what they were able to achieve is
attenuation of these age related phenotypes rather than reversal. So um
let me think if there's anything else I want to point out here. Uh oh
yeah importantly they didn't notice any overt side effects so that's very
positive. And um yeah so I'd just like to spend a little bit of time
talking about what we would need to do in order to transfer this
treatment to humans. So basically in order to apply this treatment to
humans you wouldn't be able to copy exactly what they did in this paper
obviously because we haven't been genetically engineered to respond to
this AP drug and have our cells be killed when that drug is administered.
However, what scientists could try to do is uh identify specific
biomarkers unique to senescent cells. For example even these two papers
go into which I haven't read yet myself, but they go into uh more details
about specific components that senescent cells secrete or possess. And
you can make um try develop drugs or specific therapies that will target
and kill cells that have those things. So I mean it would take quite a
bit of work to figure out how to do that, but then you would also be able
to delay age-related phenotypes in humans. So we could be much healthier
in old age. And uh another question about these mice that many people
would ask is whether or not they actually lived longer, and the answer
was no. So these mice that received the AP drug and had the senescent
cells killed did not live longer. And the reason was that these mice
appeared to die of cardiac failure or heart failure. So all of the
problems that you would have with a normal heart or in the control mice
you also saw in those mice because those were tissues and cells that were
not affected as much by this senescence process because there's not a lot
of cell division in the heart anyway so they still had the hardening of
the arteries and everything. So if you did want to treat a human and
prolong the life you would also need to develop treatments that can help
these tissues that don't have a lot of dividing cells such as the heart.
I believe also the brain does not have a lot of cell division. Um there's
one last comment I'd like to make and that's about a company named TA
Sciences in New York. And uh TA Sciences (TA is for Telomerase
Activation) this telomerase activation science company . . they're kind
of a branch off from the Geron corporation which is a big biotech company
and uh what they did is they just screened many different compounds from
different areas of nature and they identified this one compound that came
from a Chinese tree that was capable of activating telomerase. And so
this telomerase enzyme, once it's activated in your cells it will
lengthen telomeres and prevent those cells from reaching senescence. So
this company is actually selling this compound today. I think it's kind
of expensive, but they are selling it to people today and there's people
taking the drug. And the company has also had 3rd parties publish
academic papers testing their compound, and from what I've seen I think
it looks legitamite. You can never be completely sure. I mean there's a
lot of there can be a lot of fraud in the world and everything. But uh
yeah after this paper that was about removing the senescent cells was
publish TA Sciences also sent out an e-mail just describing how it's
great that removing the senescent cells did show such benefits. However,
their treatment is focused on making sure that the cells never reached
senescence in the first place. And so that may, and they seem to have
tested and shown, that that has a lot of great benefits as well. So
possibly in a human if you could do both. If you could make sure that
fewer cells even reach senescence and also that you could remove the
cells that do become senescent, then that may be a pretty good treatment
and increase the healthspan of people.

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