[Music]
today in this country there are no
people who were born in 19th century
there are no such people already not
only in this country but probably on the
whole planet the reason for that is
obvious they’re all gone
those who died from diseases we usually
name as prematurely died that means that
those who died from aging a it died on
time so this here you see the typical
program of life which consists of two
periods while we are developing and
reaching reproductive age and then
unavoidably starts declining in all our
functions acquiring frailty and finally
dying and this is the best scenario
today so I don’t know how you but I
think it’s very depressing to have this
best-case scenario so the mystery of
aging and death from aging and
limitation of our longevity has been in
people’s mind forever and fairy tales
from the past are filled with recipes
how one can rejuvenate himself so
illustration is this famous drawing by
Lucas Cranach the elder Fountain of
Youth where you see one of these recipes
what is interesting that this picture
drawn in 16th century was drawn at the
times when vast majority of people never
reached aging because they were dying
from infectious diseases cholera plague
smallpox syphilis so nevertheless aging
was already recognized as a mystery well
what we can do today
does medicine during last hundred years
which actually found cures to numerous
diseases did something with aging as
well well clearly at Lucas Cranach
times aging and infectious diseases were
clearly separated because plague
attacked everybody with no difference
whether they were children or senior
people however after we dealt with
infectious diseases and with antibiotics
we came to the era when people start
dying from cancer from cardiovascular
disease the diseases are clearly related
to age so one would expect that a
hundred years ago when we still did not
have antibiotics and during this path
from birth to death we are losing lots
of people we lost lots of people for
these diseases hundred years later what
situation would change and it does
change we know that the ref huge
demographic differences in our society
versus society at that time so a lot
more people live to very senior age and
because of our success in treatment
first infectious and now cardiovascular
diseases and cancer so now when we
celebrate this triumph of medicine can
we also celebrate the triumph of its
defeating aging because intuitively you
think that if average life of population
today in civilized countries during the
hundred years increased more than 25
years the length of life of the whole
generation in the past that you expect
intuitively that should affect also the
maximum longevity unfortunately the
answer appeared to be quite different
because if you look what would happen
with those people who successfully
reached nineteen hundred years old today
by 120 there would be none we today
recently the oldest person in this
country died who was 114 years old and
the oldest ever recorded person on this
planet was hotter than 20
two years old so which means that
something mysterious is happening at
this last part of our life and
regardless how healthy we are coming to
this point our destiny is actually
already predetermined we will die from
increasing frailty and all achievements
of Medicine all our ability to treat
diseases at the rescue ourselves from
this did not change this at all
this actually means very important thing
that this there is a something which I
named a cliff of aging so very sharp
decline in our health which is occurring
at the times above 90 years old and
which leads to avoid about death even
the most healthy people with minimal
diseases and so they’re very strict hard
stop in our life which never could be
more than 120 years and this altogether
means that there is some mysterious
mechanism which is ticking in us which
you may name clock of life which somehow
determines our really ability to live as
long as we can and it looks like this
mechanism is species-specific
because as we all know every species
besides humans have very clear life time
which you never can cross mostly we know
it of course from our pets so is there
hope at all our common sense tells not
because during all our lifetime we
didn’t see a single example of anybody
who would avoid aging and and live twice
longer at least twice longer than what
others do we don’t see it not only in US
but also in pets we do see it in non
mammals but in mammals it looks like you
know well the hope is there and the
hopes come with these interesting
creatures so you don’t see them every
day because they live in warm countries
underground but and they are typical
rodents they are a size of a mouse or
rat and they have very similar genetics
but the Cardinal difference is that they
live up to 10 times longer than their
neighbors in their genus for example
this creature on the top leaves 10 times
longer than the mouse and dies without
frailty and also these creatures never
develop cancer so dream animals very
frequently hear remarks well if I need
to pay for longevity beings with such an
ugly appearance I’m not sure how much I
want that
well I’m usually thinking well if you
are undressed you may not be looking
that attractive to so well but what is
important about these creatures they
give us inspirational example that
technically mammals can live much longer
and live without frailty which means
that they give us the evening
inspiration to think that aging is not
law of nature which is unbreakable and
it’s not there another example of
perpetuum mobile’ a which as we all know
is impossible to build because these two
creatures they are to a certain degree
prepare to Moberly so what does science
tell us about this period of declining
of aging what do we know today about
this process and what can we do from
this knowledge so about hundred years
ago one of the first Nobel Prize winners
Elia Mexico in 1903 came up with the
idea that aging resembles poisoning I
think we all intuitively can easily
accept that because we all have
depressing examples of people who are
prematurely aging and dying who are drug
addicts or who are poisoning themselves
with alcohol so and he was thinking that
about the possible source of this
poisoning and he came up with the idea
that this poisoning is coming from the
natural microflora which with age
changes and takes some toxic
microorganism which start poisoning us
with the products of their secretion
unfortunately he was not right but
today’s science did not go that far
conceptually because today our hopes in
this poisoning theory it is with these
cells which are appear here on the
background of other cells as blue will
name them senescence cells this cells do
not exist in the body of of us and
animals when we are young but they
accumulate in large numbers in tissues
when we become older and older this
senescence cells they have a number of
differences from normal cells they
differ look differently under microscope
but most importantly they secrete a
series of bioactive factors which create
local inflammation around each of them
since aging at the physiological level
is associated with acquisition of
systemic inflammation of unknown origin
there was a idea that maybe we should
link acquisition and accumulation of
these cells with poisoning but the
factors of their secretion so this idea
was supported by a number of works and
recently became the most popular theory
of aging today and there are multiple
laboratories in the world which are
trying to make drugs which could
selectively kill only senescence cells
without touching others and through that
reach stopping the process of frailty
and rejuvenation and you know good
perspective of life well I can tell you
that there are already several papers
which came out in top visibility
journals describing the exploration of
different senility compounds and they
leave mixed impression on one hand we
clearly see that these animals which
were treated against us themselves they
have quality of life somewhat improved
however their longevity did not extend
that much not more about 20
to set not a revolution although so the
smell is that we’re on the right track
but something is not exactly right here
so and indeed the suspicion is that at
the moment we stopped treatment
senescence cells will come back and
after they come back they will continue
their bad work and you know we’re
returning us back to the tractors that’s
the gray so well what can be done if
indeed are on the right track and we
already have some good intermediate as a
potential target for a therapeutic
intervention maybe we just need to think
little deeper and when you are dealing
with for example international terrorism
what you can do you can prevent
terrorists from exploding their bells
for example but would that stop terror
is no you need to deal with the system
which creates them which train them
which recruit them which equip them so
senescence cells appear from something
and the hope is that when we find this
something which creates an essence cells
in our body that would give us knowledge
how to deal with them so and this is the
not black but blue box which till
recently was a mystery for me and now I
will share with you what we found in it
and I hope that by finding it we now can
become much closer to the resolution
because senescence cells as we learn
from our studies is probably just tip of
the iceberg just only one of the types
of cells which are damaged during our
life and which accumulate and start
poisoning us and we they better be seen
as biomarkers of aging rather than being
ultimate however targets which means
that we need to find this garbage
producing mechanism and stop it from
doing that so what do we know about this
mechanism so hope is that we find this
mechanism will decipher the source of
this
live of Aging and we’ll be able to do
something with that so we believe that
clock may be hidden in this box so how
to approach this clock well you may ask
the question what turns cell into
senescence and we know today that what
turns cell into senescence is damage to
their DNA when we know that we say aha
it’s very simple DNA is damaged by what
by ultraviolet light by gamma radiation
by smoking carcinogens by alcohol
because it creates reactive oxygen
species and so on so let’s just change
habits and we will be safe but we all
know that whatever you do with your
habits you may only increase your chance
to reach this cliff relatively healthy
but you will not be able to move it and
we have the proofs of that in mice as
well today mice in this country live in
conditions which are much more healthy
than what we live in because we are
forcing them to do that by even though
they probably would not do it themselves
and do you think they live longer not
really of course they don’t die from
infectious diseases but they still
undergo the same process which means
that by living healthy life it’s a good
thing to do but don’t think that it will
make you long living it makes you
healthier dying
so what is this source of this
mysterious clock what is the nature of
that you remember that mechnikov came up
with the idea that parasites do it
brilliant idea I would say that he was
absolutely right the problem was that at
that time he knew only one source of
parasites bacteria now gas but he didn’t
know that parasites are much more
abundant and much more intimately
involved in our structure and our life
because they are part of our own DNA we
know this for the last 50 years but only
today we start realizing what these
parasites do the the problem is that
about between 65 and hundred million
years ago the time when dinosaurs
suddenly died extinct and the era of
dinosaurs was switched to the era of
mammals of us well it was the period
when viruses appeared of certain kind
which were not recorded before which
actually represented pieces of DNA which
started invading into our DNA of our
ancestors and multiplying in it creating
numerous new copies and disrupting genes
changing their level of activity and
killing lots of lots of individuals
probably leading to massive extinctions
I wouldn’t be surprised that eventually
will prove the dinosaurs died from this
particular disease the reason we know
about that because think about that
nearly 50 percent of length of our DNA
consists of these viruses most of them
are dead most of them are without any
such a long time that they acquired
mutations which kill them until recently
we thought that our genome is a cemetery
is a graveyard of viruses which about 65
million years ago were the major source
of extinction of mammals and vertebrates
on this planet so and we have those
lucky survivors who happen to keep these
viruses in the safe place
in their genome where they luckily did
not do any bad well recently it will
appear to be wrong it will find that not
that many but few of them and if you
think about copy numbers the copy
numbers of these viruses reaches
millions millions copies in our DNA some
of them several dick several dozens are
actually alive and just deeply asleep
but they can be awake and their
probability of them waking up and start
multiplying seems to be determined by
specious specific mechanism in mice
they’re sleeping much less deeply than
in humans that’s why my sleeve two and a
half years and humans about 90 today
which means that these viruses which are
sleeping in us but in principle capable
of repeating what they have done long
ago
maybe that mysterious clock because by
multiplying our genome they put a poison
DNA they break it they create senescence
cells and other types of damage which
later on leave to this flood of events
or leading to poisoning and death
well let’s repeat what I just said about
65 million years ago there were no
diversity of mammals there were just
very few of them they were very universe
and they were not visible among tons of
dinosaurs around then this virus has
appeared God knows from where and they
start invading massively in the genomes
of these poor ancestors creating
diversity not only between those who
died and survived but also affecting
their appearance and that was the time
when the all origin of this enormous
diversity of mammals goes back to so
those who survived and this was a very
very rough turbulent period in our
evolution during which all these air Chi
types of mammals appeared and after that
you see no much happen only
microevolution so those who survived
they not only managed to stop the
mummification of these viruses but they
acquired them as a big part of the Agena
and the conditions of certain depth of
putting asleep of silencing in some of
you they’re silent completely or near
completion and this comes with the
expectation how long we they can do this
without killing us
probably forming this species-specific
clock with determine length of our life
what is very important that this process
is ongoing in every single cell in our
body so which means that ours this
mechanism is implemented in every single
cell in our body as a probability of
awakening of endogenous viruses which
can create DNA damage in somatic cell
population in our body thereby creating
that garbage which eventually will kill
us from from frailty and aging so does
this picture allow you anything to do
what does this knowledge mean to us it
looks depressing it looks scary it looks
like every cell in our body has a little
piece of uranium which is kind of a kind
of making holes in DNA and finally kills
us well either surprisingly there is
because knowing that mechanism of how
this virus is amplified we found that in
our medical history we dealt with
viruses of remotely similar kind and
some of the antiviral drugs which we
developed not very efficiently but
sufficiently well working against
mechanisms of replication of these
viruses good enough to allow us to take
some of the drugs which today being used
to treat AIDS HIV could be used by us as
a proof of principle to extend life of
mice in which this process is ongoing
today can tell you that with some of the
antiviral drugs we can stop this process
of amplification of these viruses and we
hope that it will have a dramatic
positive impact on our ability to
cardinally extend our longevity stop
acquisition frailty and so on so it’s a
targeted drug it hits what we believe
today is that mysterious cloak of life
which is the content of our DNA which we
acquired as parasite 65 – 100 million
years ago and this content is killing us
by being insufficiently well repressed
so as a result the clock can be broken
and the flood of senescence cells which
this cloak creates while it’s working
now will be drained and will dry out and
no longer poisonous and today we have it
in real hope for the first time we hope
that this road to this cliff which all
of us at different stages at we have a
chance to avoid and we can build the
bridge with the help of these drugs
which we are working on right now to
avoid this cliff and go forward to the
next disease which tell Kela stop
killing us after we deal with angel
thank
[Applause]
[Music]
today in this country there are no
people who were born in 19th century
there are no such people already not
only in this country but probably on the
whole planet the reason for that is
obvious they’re all gone
those who died from diseases we usually
name as prematurely died that means that
those who died from aging a it died on
time so this here you see the typical
program of life which consists of two
periods while we are developing and
reaching reproductive age and then
unavoidably starts declining in all our
functions acquiring frailty and finally
dying and this is the best scenario
today so I don’t know how you but I
think it’s very depressing to have this
best-case scenario so the mystery of
aging and death from aging and
limitation of our longevity has been in
people’s mind forever and fairy tales
from the past are filled with recipes
how one can rejuvenate himself so
illustration is this famous drawing by
Lucas Cranach the elder Fountain of
Youth where you see one of these recipes
what is interesting that this picture
drawn in 16th century was drawn at the
times when vast majority of people never
reached aging because they were dying
from infectious diseases cholera plague
smallpox syphilis so nevertheless aging
was already recognized as a mystery well
what we can do today
does medicine during last hundred years
which actually found cures to numerous
diseases did something with aging as
well well clearly at Lucas Cranach
times aging and infectious diseases were
clearly separated because plague
attacked everybody with no difference
whether they were children or senior
people however after we dealt with
infectious diseases and with antibiotics
we came to the era when people start
dying from cancer from cardiovascular
disease the diseases are clearly related
to age so one would expect that a
hundred years ago when we still did not
have antibiotics and during this path
from birth to death we are losing lots
of people we lost lots of people for
these diseases hundred years later what
situation would change and it does
change we know that the ref huge
demographic differences in our society
versus society at that time so a lot
more people live to very senior age and
because of our success in treatment
first infectious and now cardiovascular
diseases and cancer so now when we
celebrate this triumph of medicine can
we also celebrate the triumph of its
defeating aging because intuitively you
think that if average life of population
today in civilized countries during the
hundred years increased more than 25
years the length of life of the whole
generation in the past that you expect
intuitively that should affect also the
maximum longevity unfortunately the
answer appeared to be quite different
because if you look what would happen
with those people who successfully
reached nineteen hundred years old today
by 120 there would be none we today
recently the oldest person in this
country died who was 114 years old and
the oldest ever recorded person on this
planet was hotter than 20
two years old so which means that
something mysterious is happening at
this last part of our life and
regardless how healthy we are coming to
this point our destiny is actually
already predetermined we will die from
increasing frailty and all achievements
of Medicine all our ability to treat
diseases at the rescue ourselves from
this did not change this at all
this actually means very important thing
that this there is a something which I
named a cliff of aging so very sharp
decline in our health which is occurring
at the times above 90 years old and
which leads to avoid about death even
the most healthy people with minimal
diseases and so they’re very strict hard
stop in our life which never could be
more than 120 years and this altogether
means that there is some mysterious
mechanism which is ticking in us which
you may name clock of life which somehow
determines our really ability to live as
long as we can and it looks like this
mechanism is species-specific
because as we all know every species
besides humans have very clear life time
which you never can cross mostly we know
it of course from our pets so is there
hope at all our common sense tells not
because during all our lifetime we
didn’t see a single example of anybody
who would avoid aging and and live twice
longer at least twice longer than what
others do we don’t see it not only in US
but also in pets we do see it in non
mammals but in mammals it looks like you
know well the hope is there and the
hopes come with these interesting
creatures so you don’t see them every
day because they live in warm countries
underground but and they are typical
rodents they are a size of a mouse or
rat and they have very similar genetics
but the Cardinal difference is that they
live up to 10 times longer than their
neighbors in their genus for example
this creature on the top leaves 10 times
longer than the mouse and dies without
frailty and also these creatures never
develop cancer so dream animals very
frequently hear remarks well if I need
to pay for longevity beings with such an
ugly appearance I’m not sure how much I
want that
well I’m usually thinking well if you
are undressed you may not be looking
that attractive to so well but what is
important about these creatures they
give us inspirational example that
technically mammals can live much longer
and live without frailty which means
that they give us the evening
inspiration to think that aging is not
law of nature which is unbreakable and
it’s not there another example of
perpetuum mobile’ a which as we all know
is impossible to build because these two
creatures they are to a certain degree
prepare to Moberly so what does science
tell us about this period of declining
of aging what do we know today about
this process and what can we do from
this knowledge so about hundred years
ago one of the first Nobel Prize winners
Elia Mexico in 1903 came up with the
idea that aging resembles poisoning I
think we all intuitively can easily
accept that because we all have
depressing examples of people who are
prematurely aging and dying who are drug
addicts or who are poisoning themselves
with alcohol so and he was thinking that
about the possible source of this
poisoning and he came up with the idea
that this poisoning is coming from the
natural microflora which with age
changes and takes some toxic
microorganism which start poisoning us
with the products of their secretion
unfortunately he was not right but
today’s science did not go that far
conceptually because today our hopes in
this poisoning theory it is with these
cells which are appear here on the
background of other cells as blue will
name them senescence cells this cells do
not exist in the body of of us and
animals when we are young but they
accumulate in large numbers in tissues
when we become older and older this
senescence cells they have a number of
differences from normal cells they
differ look differently under microscope
but most importantly they secrete a
series of bioactive factors which create
local inflammation around each of them
since aging at the physiological level
is associated with acquisition of
systemic inflammation of unknown origin
there was a idea that maybe we should
link acquisition and accumulation of
these cells with poisoning but the
factors of their secretion so this idea
was supported by a number of works and
recently became the most popular theory
of aging today and there are multiple
laboratories in the world which are
trying to make drugs which could
selectively kill only senescence cells
without touching others and through that
reach stopping the process of frailty
and rejuvenation and you know good
perspective of life well I can tell you
that there are already several papers
which came out in top visibility
journals describing the exploration of
different senility compounds and they
leave mixed impression on one hand we
clearly see that these animals which
were treated against us themselves they
have quality of life somewhat improved
however their longevity did not extend
that much not more about 20
to set not a revolution although so the
smell is that we’re on the right track
but something is not exactly right here
so and indeed the suspicion is that at
the moment we stopped treatment
senescence cells will come back and
after they come back they will continue
their bad work and you know we’re
returning us back to the tractors that’s
the gray so well what can be done if
indeed are on the right track and we
already have some good intermediate as a
potential target for a therapeutic
intervention maybe we just need to think
little deeper and when you are dealing
with for example international terrorism
what you can do you can prevent
terrorists from exploding their bells
for example but would that stop terror
is no you need to deal with the system
which creates them which train them
which recruit them which equip them so
senescence cells appear from something
and the hope is that when we find this
something which creates an essence cells
in our body that would give us knowledge
how to deal with them so and this is the
not black but blue box which till
recently was a mystery for me and now I
will share with you what we found in it
and I hope that by finding it we now can
become much closer to the resolution
because senescence cells as we learn
from our studies is probably just tip of
the iceberg just only one of the types
of cells which are damaged during our
life and which accumulate and start
poisoning us and we they better be seen
as biomarkers of aging rather than being
ultimate however targets which means
that we need to find this garbage
producing mechanism and stop it from
doing that so what do we know about this
mechanism so hope is that we find this
mechanism will decipher the source of
this
live of Aging and we’ll be able to do
something with that so we believe that
clock may be hidden in this box so how
to approach this clock well you may ask
the question what turns cell into
senescence and we know today that what
turns cell into senescence is damage to
their DNA when we know that we say aha
it’s very simple DNA is damaged by what
by ultraviolet light by gamma radiation
by smoking carcinogens by alcohol
because it creates reactive oxygen
species and so on so let’s just change
habits and we will be safe but we all
know that whatever you do with your
habits you may only increase your chance
to reach this cliff relatively healthy
but you will not be able to move it and
we have the proofs of that in mice as
well today mice in this country live in
conditions which are much more healthy
than what we live in because we are
forcing them to do that by even though
they probably would not do it themselves
and do you think they live longer not
really of course they don’t die from
infectious diseases but they still
undergo the same process which means
that by living healthy life it’s a good
thing to do but don’t think that it will
make you long living it makes you
healthier dying
so what is this source of this
mysterious clock what is the nature of
that you remember that mechnikov came up
with the idea that parasites do it
brilliant idea I would say that he was
absolutely right the problem was that at
that time he knew only one source of
parasites bacteria now gas but he didn’t
know that parasites are much more
abundant and much more intimately
involved in our structure and our life
because they are part of our own DNA we
know this for the last 50 years but only
today we start realizing what these
parasites do the the problem is that
about between 65 and hundred million
years ago the time when dinosaurs
suddenly died extinct and the era of
dinosaurs was switched to the era of
mammals of us well it was the period
when viruses appeared of certain kind
which were not recorded before which
actually represented pieces of DNA which
started invading into our DNA of our
ancestors and multiplying in it creating
numerous new copies and disrupting genes
changing their level of activity and
killing lots of lots of individuals
probably leading to massive extinctions
I wouldn’t be surprised that eventually
will prove the dinosaurs died from this
particular disease the reason we know
about that because think about that
nearly 50 percent of length of our DNA
consists of these viruses most of them
are dead most of them are without any
such a long time that they acquired
mutations which kill them until recently
we thought that our genome is a cemetery
is a graveyard of viruses which about 65
million years ago were the major source
of extinction of mammals and vertebrates
on this planet so and we have those
lucky survivors who happen to keep these
viruses in the safe place
in their genome where they luckily did
not do any bad well recently it will
appear to be wrong it will find that not
that many but few of them and if you
think about copy numbers the copy
numbers of these viruses reaches
millions millions copies in our DNA some
of them several dick several dozens are
actually alive and just deeply asleep
but they can be awake and their
probability of them waking up and start
multiplying seems to be determined by
specious specific mechanism in mice
they’re sleeping much less deeply than
in humans that’s why my sleeve two and a
half years and humans about 90 today
which means that these viruses which are
sleeping in us but in principle capable
of repeating what they have done long
ago
maybe that mysterious clock because by
multiplying our genome they put a poison
DNA they break it they create senescence
cells and other types of damage which
later on leave to this flood of events
or leading to poisoning and death
well let’s repeat what I just said about
65 million years ago there were no
diversity of mammals there were just
very few of them they were very universe
and they were not visible among tons of
dinosaurs around then this virus has
appeared God knows from where and they
start invading massively in the genomes
of these poor ancestors creating
diversity not only between those who
died and survived but also affecting
their appearance and that was the time
when the all origin of this enormous
diversity of mammals goes back to so
those who survived and this was a very
very rough turbulent period in our
evolution during which all these air Chi
types of mammals appeared and after that
you see no much happen only
microevolution so those who survived
they not only managed to stop the
mummification of these viruses but they
acquired them as a big part of the Agena
and the conditions of certain depth of
putting asleep of silencing in some of
you they’re silent completely or near
completion and this comes with the
expectation how long we they can do this
without killing us
probably forming this species-specific
clock with determine length of our life
what is very important that this process
is ongoing in every single cell in our
body so which means that ours this
mechanism is implemented in every single
cell in our body as a probability of
awakening of endogenous viruses which
can create DNA damage in somatic cell
population in our body thereby creating
that garbage which eventually will kill
us from from frailty and aging so does
this picture allow you anything to do
what does this knowledge mean to us it
looks depressing it looks scary it looks
like every cell in our body has a little
piece of uranium which is kind of a kind
of making holes in DNA and finally kills
us well either surprisingly there is
because knowing that mechanism of how
this virus is amplified we found that in
our medical history we dealt with
viruses of remotely similar kind and
some of the antiviral drugs which we
developed not very efficiently but
sufficiently well working against
mechanisms of replication of these
viruses good enough to allow us to take
some of the drugs which today being used
to treat AIDS HIV could be used by us as
a proof of principle to extend life of
mice in which this process is ongoing
today can tell you that with some of the
antiviral drugs we can stop this process
of amplification of these viruses and we
hope that it will have a dramatic
positive impact on our ability to
cardinally extend our longevity stop
acquisition frailty and so on so it’s a
targeted drug it hits what we believe
today is that mysterious cloak of life
which is the content of our DNA which we
acquired as parasite 65 – 100 million
years ago and this content is killing us
by being insufficiently well repressed
so as a result the clock can be broken
and the flood of senescence cells which
this cloak creates while it’s working
now will be drained and will dry out and
no longer poisonous and today we have it
in real hope for the first time we hope
that this road to this cliff which all
of us at different stages at we have a
chance to avoid and we can build the
bridge with the help of these drugs
which we are working on right now to
avoid this cliff and go forward to the
next disease which tell Kela stop
killing us after we deal with angel
thank
[Applause]
[Music]
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