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Aging is the prime risk factor for the broad-based development of diseases. Frailty is a phenotypical hallmark of aging and is often used to assess whether the predicted benefits of a therapy outweigh the risks for older patients. Senescent cells form as a consequence of unresolved molecular damage and persistently secrete molecules that can impair tissue function. Recent evidence shows senescent cells can chronically interfere with stem cell function and drive aging of the musculoskeletal system. In addition, targeted apoptosis of senescent cells can restore tissue homeostasis in aged animals. Thus, targeting cellular senescence provides new therapeutic opportunities for the intervention of frailty-associated pathologies and could have pleiotropic health benefits.
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Musculoskeletal
senescence:
a
moving
target
ready
to
be
eliminated
Marjolein
P
Baar
1,2
,
Eusebio
Perdiguero
3
,
Pura
Mun
˜oz-Ca
´noves
3,4
and
Peter
LJ
de
Keizer
1
Aging
is
the
prime
risk
factor
for
the
broad-based
development
of
diseases.
Frailty
is
a
phenotypical
hallmark
of
aging
and
is
often
used
to
assess
whether
the
predicted
benefits
of
a
therapy
outweigh
the
risks
for
older
patients.
Senescent
cells
form
as
a
consequence
of
unresolved
molecular
damage
and
persistently
secrete
molecules
that
can
impair
tissue
function.
Recent
evidence
shows
senescent
cells
can
chronically
interfere
with
stem
cell
function
and
drive
aging
of
the
musculoskeletal
system.
In
addition,
targeted
apoptosis
of
senescent
cells
can
restore
tissue
homeostasis
in
aged
animals.
Thus,
targeting
cellular
senescence
provides
new
therapeutic
opportunities
for
the
intervention
of
frailty-associated
pathologies
and
could
have
pleiotropic
health
benefits.
Addresses
1
Department
of
Molecular
Cancer
Research,
Center
for
Molecular
Medicine,
Division
of
Biomedical
Genetics,
University
Medical
Center
Utrecht,
Utrecht
University,
Universiteitsweg
100,
3584CG
Utrecht,
The
Netherlands
2
Department
of
Molecular
Genetics,
Erasmus
University
Medical
Center,
Rotterdam,
The
Netherlands
3
Department
of
Experimental
and
Health
Sciences,
Pompeu
Fabra
University
(UPF),
CIBERNED,
Barcelona,
Spain
4
ICREA
and
Spanish
National
Center
on
Cardiovascular
Research
(CNIC),
Madrid,
Spain
Corresponding
author:
de
Keizer,
Peter
LJ
(p.l.j.dekeizer@umcutrecht.nl)
Current
Opinion
in
Pharmacology
2018,
40:147–155
This
review
comes
from
a
themed
issue
on
Musculoskeletal
Edited
by
S
Jeffrey
Dixon
and
Peter
Chidiac
https://doi.org/10.1016/j.coph.2018.05.007
1471-4892/ã
2018
The
Authors.
Published
by
Elsevier
Ltd.
This
is
an
open
access
article
under
the
CC
BY
license
(http://creativecommons.
org/licenses/by/4.0/).
Loss
of
cell-intrinsic
and
cell-extrinsic
integrity
perturbs
musculoskeletal
rejuvenation
during
aging
Aged
individuals
can
deteriorate
exceptionally
fast
after
the
onset
of
complications
affecting
the
musculoskeletal
system.
Tissue
erosion
due
to
life-long
mechanical
and
biological
stress
can
ultimately
result
in
pathologies
such
as
osteoporosis,
sarcopenia,
and
osteoarthritis,
and
contribute
to
frailty
[1].
While
not
all
elderly
people
develop
the
same
age-related
diseases,
virtually
everyone
will
experience
musculoskeletal
complications
sooner
or
later.
To
extend,
and
possibly
even
restore,
healthy
life
expectancy
in
old
age,
it
is
essential
to
understand
the
cellular
changes
underlying
musculoskeletal
decline.
Tis-
sue
regeneration
by
stem-cell
differentiation
is
critical
in
overcoming
the
relentless
day-by-day
damage
to
the
musculoskeletal
system.
In
young
tissues,
differentiation
proceeds
without
much
hindrance
unless
one
exercises
excessively
or
suffers
undue
levels
of
stress.
However,
during
aging,
the
number
and
function
of
adult
stem
cells
declines
[2,3].
For
example,
Pax7-expressing
satellite
stem
cells,
can
replace
damaged
muscle
fibers
[4].
Removing
Pax7-positive
cells
from
mice
impairs
muscle
regeneration
after
injury
[5],
whereas
increased
availabil-
ity
of
these
cells
enhances
muscle
repair
[6].
In
addition
to
cell-intrinsic
regulation,
muscle
stem
cell
regenerative
capacity
also
depends
intimately
on
the
microenvironment.
During
aging,
the
levels
of
inflamma-
tion
chronically
increase,
an
affect
known
as
inflamma-
ging
[7].
Evidence
for
this
is
provided
by
studies
showing
that
muscle
stem
cells
(satellite
cells)
from
aged
mice
become
more
fibrogenic,
a
conversion
mediated
by
fac-
tors
from
the
aged
systemic
environment
[8].
In
contrast,
frailty
is
reduced
by
the
JAK/STAT
inhibitor
Ruxolitinib,
which
reduces
inflammation
in
naturally
aged
mice
[9].
Stem-cell
impairing
cues
do
not
necessarily
have
to
come
from
local
sources
but
can
travel
over
a
distance.
Hetero-
chronic
parabiosis
experiments
showed
that
transfusion
of
old
blood
impairs
stem
cell
function
in
young
recipient
mice
[10],
while
the
transfer
of
young
blood
factors
restoring
muscle
regeneration
and
muscle
stem-cell
acti-
vation
in
aged
animals
[11].
Therefore,
there
is
a
great
interest
in
developing
methods
to
interfere
with
the
age-
associated
pro-inflammatory
signaling
profile.
The
ques-
tion
is
how?
To
address
this
question,
cellular
senescence
has
recently
gained
attention
as
a
potential
candidate
for
intervention.
Signaling
noise
by
senescent
cells
impedes
tissue
homeostasis
during
aging
As
we
age,
each
cell
in
our
body
accumulates
damage.
Earlier
in
life,
this
damage
is
usually
faithfully
repaired
[12],
but
over
time
more
and
more
damage
gets
left
behind.
This
can
trigger
a
molecular
chain
of
events,
resulting
in
chromatin
remodeling
and
the
entry
of
cells
Available
online
at
www.sciencedirect.com
ScienceDirect
www.sciencedirect.com
Current
Opinion
in
Pharmacology
2018,
40:147–155
into
a
permanent
state
of
growth-factor
insensitive
cell-
cycle
arrest,
called
cellular
senescence.
Senescence
can
be
invoked
in
healthy
cells
that
experience
a
chronic
damage
response,
either
involving
direct
DNA
damage
or
events
that
mimic
the
molecular
response,
such
as
telo-
mere
shortening
or
oncogenic
mutations
[13
].
As
a
con-
sequence,
these
cells
undergo
an
irreversible
cell
cycle
arrest,
effectively
limiting
the
damage.
So
far,
so
good,
except
that
senescent
cells
secrete
a
broad
range
of
growth
factors,
pro-inflammatory
proteins,
and
matrix
proteinases
that
alter
the
microenvironment:
The
Senes-
cence-Associated
Secretory
Phenotype
(SASP)
[14].
Senescent
cells
persist
for
prolonged
periods
of
time
and
eventually
accumulate
during
aging
[15].
This
also
means
there
is
a
gradual
and,
importantly,
ever-present
build-up
of
deleterious
molecules.
Thus,
senescence
can
have
continuous
detrimental
effects
on
tissue
homeostasis
during
aging.
That
senescent
cells
are
a
direct
cause
of
aging
was
proven
beyond
a
doubt
in
studies
in
which
senescent
cells
were
genetically
or
pharmacologically
removed.
In
these
studies,
both
rapidly
and
naturally
aged
mice
maintained
healthspan
for
much
longer,
or
even
showed
signs
of
aging
reversal
[16,17
,18,19
].
Fac-
tors
secreted
by
senescent
cells
can
induce
pluripotency
in
vivo
[20
].
As
such,
these
can
impair
normal
stem
cell
function
by
forcing
a
constant
state
of
reprogramming,
something
we
dubbed
a
‘senescence
stem
lock’
[13
].
This
is
supported
by
observations
that
factors
secreted
by
senescent
cells
induce
pluripotency
in
vivo
[20
].
Age-
associated
inflammation
may
thus
deregulate
normal
stem
cell
function
at
different
levels,
for
instance
by
preventing
stem
cells
from
producing
differentiated
daughter
cells.
Due
to
the
constant
secretion
of
SASP
factors,
senescent
cells
could
thus
impair
local
and
distant
stem
cell
function
and
differentiation
in
times
of
need.
Here,
we
will
highlight
the
interplay
between
senes-
cence,
the
SASP
and
stemness
in
the
individual
muscu-
loskeletal
compartments:
muscle,
bone
and
cartilage.
Skeletal
muscle:
an
intrinsic
interplay
between
senescence
and
stemness
Several
reports
link
senescence
to
muscle
aging
and
muscle
stem
cell
dysfunction.
For
example,
expression
of
the
major
senescence
marker
p16
INK4A
prevents
tissue
regeneration
by
satellite
cells
after
damage
[21

].
Fast-
aging
BubR1
H/H
mice
develop
sarcopenia,
and
after
genetic
removal
of
senescent
cells,
they
showed
a
reduc-
tion
in
kyphosis
and
an
increase
in
muscle
fiber
diameter,
findings
suggestive
of
reduced
sarcopenia
[16].
Likewise,
senescence
of
muscle
stem
cells
occurs
in
muscles
of
mice
with
distinct
dystrophinopathies,
such
as
Duchenne
mus-
cular
dystrophy
or
Steinert’s
diseases
[22–25].
The
skeletal
muscle
stem
cell
niche
is
a
candidate
through
which
senescent
cells
may
exert
their
deleterious
effects.
Interleukin
6
(IL-6)
is
a
pleiotropic
cytokine
that
can
be
released
by
inflammatory
cells
and
by
muscle
fibers
(acting
as
a
myokine).
IL6
is
also
a
major
component
of
the
SASP
[14],
and
has
been
shown
to
regulate
the
transition
of
satellite
cells
from
a
quiescent
to
an
activated
state
[26].
This
is
beneficial
upon
acute
tissue
stress,
where
IL-6
is
transiently
released
by
growing
myofibers
to
activate
satel-
lite
cells
and
thereby
stimulate
myogenesis
[26].
However,
the
chronic
IL-6
signaling
caused
by
senescence
during
aging
would
have
very
detrimental
effects
on
muscle
function.
Indeed,
muscle
atrophy
is
linked
to
high
IL-6
levels
in
patients
with
inflammatory
diseases
such
as
cancer
[27].
In
addition,
persistent
IL-6
expression
was
shown
to
increase
muscle
degradation
in
combination
with
other
circulating
factors
in
mice
[28,29].
Interestingly,
when
IL-6
receptors
were
blocked
in
mice
with
ectopic
IL-6
expression,
atrophy
could
be
attenuated,
indicating
a
direct
regulation
of
muscle
wasting
by
IL-6
[30].
Chronic
IL-6
signaling
causes
protein
degradation
in
muscle,
explaining
age-related
muscle
wasting
[31].
Additionally,
IL-6
depen-
dent
muscle
degradation
may
be
linked
to
stem
cell
func-
tion.
For
example,
senescence
induction
after
muscle
injury
can promote
Pax7
positive
unipotent
cells to
undergo
reprogramming
and
regain
pluripotency
[32

].
This
pro-
cess
is
dependent
on
IL-6
secreted
by
the
senescent
cells.
Further
underscoring
the
role
between
the
senescent
niche
and
stemness
in
the
muscle
is
provided
by
elegant
work
employing
a
system
in
which
the
four
Yamanaka
stem
cell
factors,
Oct4,
Sox2,
Klf4
and
c-Myc
(OSKM)
were
tran-
siently
expressed
in
vivo.
This
resulted
in
a
marked
reduc-
tion
in
senescence,
SASP
factors
as
IL6
and
improved
recovery
in
muscle
injury
experiments
[33
].
Together,
this
supports
a
model
we
postulated
previously
that
because
senescence
increases
locally
during
aging
hotspots
are
formed
of
high
IL6
concentrations.
This
can
cause
neighboring
cells
to
become
pluripotent.
However,
due
to
the
chronic
nature
of
the
SASP,
senescent
cells
provide
a
continuous
source
of
IL6
causing
these
cells
remain
per-
manently
locked
in
a
pluripotent
state
and
rendering
them
unable
to
rejuvenate
the
tissue
after
injury
[13
]
(Figure
1).
Although
satellite
dysfunction
has
been
linked
to
sarco-
penia,
this
relationship
is
controversial.
Recent
studies
suggest
that
the
decline
in
satellite
cell
function
during
aging
is
not
the
cause
of
sarcopenia
[34,35].
When
satellite
cells
were
genetically
removed
over
a
prolonged
period,
no
difference
in
muscle
mass
was
observed
compared
with
mice
that
maintained
their
satellite
cells.
However,
there
was
a
clear
increase
in
fibrosis,
indicating
that
satellite
cells
are
indeed
crucial
for
muscle
homeostasis.
Furthermore,
several
studies
show
that
sarcopenic
muscle
has
a
reduced
ability
to
recover
after
injury,
which
is
dependent
on
satellite
cell
function
[5,21

,35,36].
Over-
all,
while
the
role
of
satellite
cells
in
sarcopenia
is
still
debated,
there
is
consensus
that
Pax7
positive
cells
are
required
for
regeneration
after
muscle
injury
and
that
reduced
function
of
these
stem
cells
leads
to
age-related
frailty.
148
Musculoskeletal
Current
Opinion
in
Pharmacology
2018,
40:147–155
www.sciencedirect.com
The
myokines
released
by
muscle
cells
not
only
signal
to
stem
cells,
but
also
attract
immune
cells
that
can
facilitate
tissue
repair
and
regulate
immune
cell
function.
IL-15
is
released
by
muscle
cells
in
response
to
exercise
and
promotes
survival
of
NK
cells
[37,38];
in
contrast,
NK
cells
are
inhibited
by
IL-6
and
TNFa
[39].
An
age-related
decrease
in
muscle
mass
could
therefore
lead
to
a
decrease
in
IL-15
and
thereby
a
decrease
in
the
number
of
NK
cells,
an
effect
aggravated
by
an
increase
in
systemic
IL-6
levels
(Reviewed
in
[40]).
Importantly,
NK
cells
are
natural
eliminators
of
senescent
cells
[41].
Muscle
atrophy
during
aging
thus
adds
to
the
build-up
of
senescence
by
reducing
the
ability
of
the
immune
system
to
clear
senescent
cells.
This,
in
turn,
further
accelerates
muscle
loss
and
age-related
frailty.
Studies
are
underway
to
determine
whether
anti-senescence
treatment
can
overcome
muscle
loss.
Aging
is
the
greatest
risk
factor
for
most
chronic
diseases,
and
mechanistic
links
between
aging
and
disease
are
starting
to
emerge.
Several
studies
show
an
involvement
of
cellular
senescence,
and
in
particular,
muscle
stem
cell
senescence,
in
distinct
types
of
muscular
dystrophies.
In
Myotonic
dystrophy
type
1
(DM1
or
Steinert’s
disease),
entry
into
senescence
of
human
satellite
cell-derived
myoblasts
correlates
with
a
lower
proliferative
rate
than
age-matched
controls
and
has
been
causally
implicated
in
the
progressive
atrophy
and
degeneration
of
DM1
muscles
[22,23].
Similarly,
cellular
senescence
traits
have
been
described
in
mdx
mice,
a
widely
used
model
of
Duchenne
muscular
dystrophy
(DMD),
correlating
with
poor
regenerative
capacity
[24,25,42].
Premature
cellular
senescence
also
underlies
myopathy
in
a
mouse
model
of
limb-girdle
muscular
dystrophy
[43].
Whether
interference
in
cellular
senes-
cence
can
provide
a
therapeutic
approach
for
these
mus-
cle
diseases
is
unknown.
Bone:
senescence
distorts
the
balance
between
resorption
and
formation
During
aging,
there
is
an
increase
in
senescence
in
the
bone.
This,
in
turn,
can
lead
to
changes
in
bone
density.
Bone
consists
of
multiple
cell
types,
including
osteoblasts
that
form
bone,
osteoclasts
that
break
down
bone
tissue,
and
osteocytes
that
make
up
the
majority
of
bone
cells
(reviewed
in
[44]).
Out
of
the
various
cell
types
that
are
affected,
the
main
SASP
producing
cells
are
senescent
osteocytes
[45].
Osteocytes
are
known
to
influence
Musculoskeletal
senescence
Baar
et
al.
149
Figure
1
Vascular
compartment
Muscle
Fiber Sarcopenic/Atrophic
Fiber
Systemic
factors
Resident inflammatory
cell Senescent
cells
Interstitial
cell
NK cell
Satellite cell
Satellite cell
(p16INK4a)
AGED/DYSTROPHICYOUNG
IL-15
Basal
lamina
IL-6
Current Opinion in Pharmacology
Aged
muscle
fibers
show
atrophy
that
is
linked
to
an
age-related
increase
in
cellular
senescence.
Satellite
cells
lose
proliferation
capacity
through
senescence
induction
or
the
chronic
presence
of
SASP
factors
such
as
IL-6.
Thus,
regeneration
of
damaged
tissue
is
prevented.
Additionally,
IL-
15
secreted
by
muscle
tissue
facilitates
NK
cell
survival
in
young
organisms,
while
IL-6
represses
these
immune
cells
during
aging
and
thereby
reduces
the
natural
ablation
of
senescent
cells,
aggravating
loss
of
muscle
mass
observed
during
aging.
www.sciencedirect.com
Current
Opinion
in
Pharmacology
2018,
40:147–155
osteoblast
and
osteoclast
function
[46],
and
SASP
factors
secreted
by
osteocytes,
such
as
IL-1
and
MMP13,
increase
osteoclast
differentiation
and
thereby
increase
bone
resorption
to
cause
the
age-related
bone
loss
associ-
ated
with
osteoporosis
[47–49].
The
conditioned
medium
of
senescent
cells
can
decrease
osteoblast
function
in
vitro
and
promote
osteoclast
activity
[50].
Furthermore,
inhi-
bition
of
senescence
induction
stimulates
osteogenesis
and
prevents
osteoporosis
[51].
These
observations
indi-
cate
a
causal
role
of
senescence
in
disrupting
the
balance
between
bone
formation
and
resorption,
leading
to
oste-
oporosis
(Figure
2).
Bone
stem
cell
function
during
aging
is
likely
influenced
by
secreted
SASP
factors.
Osteoblasts
have
a
relatively
short
lifespan
and
are
derived
from
mesenchymal
stem
cells
in
the
bone
marrow
(BMSCs),
periosteum
and
elsewhere
[52].
BMSCs
can
give
rise
to
both
osteoblasts
and
adipocytes
[53].
This
balance
is
heavily
influenced
by
the
microenvironment
[54],
and
during
osteoporosis
oxi-
dative
stress
and
inflammatory
cytokines
influence
BMSCs
to
favor
adipogenesis
over
osteogenesis
[55,56].
Therefore
adipose
tissue
accumulation
is
a
hallmark
of
osteoporosis
and
is
linked
to
senescence
in
the
microen-
vironment.
Furthermore,
BMSCs
show
a
reduced
differ-
entiation
capacity
during
aging.
For
example,
serum
from
aged
individuals
inhibits
differentiation
of
BMSCs
into
osteoblasts
[57].
Additionally,
BMSCs
can
become
senescent
during
aging,
secreting
SASP
proteins
and
promoting
osteoclast
activity
[58,59].
Overall,
these
observations
indicate
that
targeting
senescent
cells
in
bone
would
likely
improve
bone
stem
cell
function.
There
are
several
mouse
models
that
show
accelerated
aging
and
are
known
to
have
an
increased
number
of
senescent
cells,
such
as
mice
with
DNA
repair
or
telome-
rase
deficiency;
such
mice
often
show
osteoporosis
and
other
musculoskeletal
afflictions
[60,61].
They
are
there-
fore
ideal
model
organisms
for
studying
the
effect
of
senescence
in
these
disorders.
For
example,
Klotho-defi-
cient
mice
show
accelerated
senescence
and
a
wide
variety
of
age-related
diseases,
including
osteoporosis.
When
these
mice
were
crossed
with
p16
ink4a
knockout
mice,
osteoporosis
was
attenuated
[61],
indicating
that
senescent
cell
ablation
can
potentially
prevent
this
dete-
rioration.
Indeed,
osteoporosis
was
delayed
in
naturally
aged
INK-ATTAC
mice
when
senescent
cells,
which
continuously
develop,
were
ablated
twice
a
week.
More-
over,
these
mice
had
an
improved
microarchitecture
and
strength
[62

].
The
reduction
of
senescent
cells
likely
leads
to
a
lower
level
of
inflammation
in
the
bone.
This
then
reduces
the
formation
of
osteoclasts
and
prevents
bone
degradation.
Indeed,
in
INK-ATTAC
mice,
bone
resorption
was
lowered
and
bone
formation
improved.
In
conclusion,
senescent
cell
removal
prevents
age-related
bone
loss
in
mice.
Cartilage:
senescence-associated
chronic
inflammation
perturbs
cartilage
regeneration
Articular
cartilage
a
flexible
connective
tissue
that
protects
the
ends
of
bones
within
a
joint
affords
smooth
surfaces
with
low
friction
for
movement,
and
facilitates
transmission
of
loads
to
the
underlying
bone.
This
tissue
mainly
consists
of
extracellular
matrix
produced
by
chon-
drocytes,
the
cell
type
present
in
cartilage.
The
regenera-
tive
potential
of
cartilage
after
damage
is
limited,
possibly
because
the
tissue
contains
a
low
number
of
mesenchy-
mal
stem
cells
[63].
Furthermore,
like
muscle
stem
cells,
these
stem
cells
are
less
able
to
regenerate
damaged
tissue
with
age.
This
is
in
part
due
to
intrinsic
MSC
aging
and
senescence
induction
[64,65],
but
is
also
due
to
the
altered
tissue
microenvironment
and
chronic
inflam-
mation
[66].
Additionally,
chondrocytes
can
express
stem-
ness
markers
in
osteoarthritis
[67,68].
Again,
inflamma-
tory
factors
promote
a
chronic
dedifferentiated
state
and
thereby
prevent
tissue
repair
during
aging
[69].
Alto-
gether,
this
leads
to
thinning
of
cartilage
during
aging,
resulting
in
stiffness
and
pain
in
the
joints
that
are
characteristic
of
osteoarthritis
[70]
(Figure
3).
A
causal
role
of
senescence
in
osteoarthritis
was
shown
by
transplanting
senescent
cells
into
mouse
joints,
resulting
in
pain
and
morphological
changes
indicative
of
osteoar-
thritis
[71
].
150
Musculoskeletal
Figure
2
SASP
Osteocytes
Osteoblasts
Osteoclasts
AdipocytesBone marrow stem cell
Current Opinion in Pharmacology
In
aged
bone,
the
balance
between
bone
formation
by
osteoblasts
and
bone
resorption
by
osteoclasts
is
distorted.
An
accumulation
of
senescent
cells
is
observed
that
promote
an
increased
osteoclast
activation
through
the
SASP.
Bone
loss
is
also
worsened
by
the
inhibition
of
osteoblast
formation
by
pro-inflammatory
factors.
For
example,
known
SASP
factors
cause
mesenchymal
stem
cells
to
favor
adipogenesis
over
osteoblast
production.
Current
Opinion
in
Pharmacology
2018,
40:147–155
www.sciencedirect.com
Furthermore,
chondrocytes
show
an
age-related
increase
in
senescence,
and
during
osteoarthritis
pro-inflammatory
cytokines
such
as
the
prominent
SASP
factor
IL-1
induce
excess
expression
of
matrix
metalloproteinases
(MMPs),
leading
to
cartilage
loss
[72].
Increased
levels
of
circulat-
ing
SASP
factors
such
as
IL-6
are
linked
to
frailty
and
risk
of
osteoarthritis
[73].
Additionally,
in
a
mouse
model
of
osteoarthritis,
overexpression
of
SIRT6
prevents
senes-
cence
induction
and
concurrent
inflammation,
thereby
reducing
cartilage
degeneration
[74].
This
finding
indi-
cates
that
eliminating
senescent
cells
from
cartilage
would
attenuate
osteoarthritis
and
improve
joint
function,
especially
since
chondrocyte
death
does
not
seem
to
drive
cartilage
damage
in
response
to
injury
[75].
Several
stud-
ies
have
examined
the
effect
of
senescent
cell
removal
on
osteoarthritis
development.
For
example,
osteoarthritis
was
surgically
induced
in
mice
through
anterior
cruciate
ligament
transection
(ACLT)
in
the
knee
joint.
In
this
model,
genetic
removal
of
senescent
cells
delayed
the
development
of
osteoarthritis,
evidenced
by
reduced
inflammation
in
the
knee
joint
and
an
increase
in
cartilage
development,
indicating
better
joint
function
[76
].
The
mice
had
less
pain
after
the
senescent
cells
were
removed.
Furthermore,
osteoarthritis
occurs
naturally
in
aged
INK-
ATTAC
mice,
and
cartilage
degeneration
was
attenuated
after
removal
of
senescent
cells
in
this
model.
Targeting
senescence
to
counteract
age-
related
frailty
The
encouraging
results
obtained
upon
genetic
elimina-
tion
of
senescent
cells
have
important
implications
for
the
treatment
of
musculoskeletal
deterioration.
Since
senes-
cence
is
thought
to
play
a
significant
role
in
the
progres-
sion
of
age-related
frailty,
anti-senescence
drugs
can
be
predicted
to
benefit
patients
with
musculoskeletal
dis-
orders
(Table
1).
Currently,
drugs
that
target
inflammatory
cytokines
are
tested
in
patients
with
musculoskeletal
diseases.
For
example,
several
strategies
for
IL1
inhibition
in
osteoar-
thritis
have
been
explored.
These
therapies
include
IL1
receptor
antagonist
proteins
(IRAP),
monoclonal
antibo-
dies
targeting
free
IL1
or
the
IL1-receptor,
and
an
inhib-
itor
of
IL1b
production
called
Diacerein
(reviewed
in
[77]).
Most
of
these
therapies
show
a
trend
of
pain
reduction
versus
placebo.
However,
these
results
were
often
not
statistically
significant,
possibly
due
to
the
short
half-life
of
the
antagonist
proteins
or
blocking
antibodies.
Only
Diacerein
treatment
has
shown
significant
anti-
inflammatory
effects
and
pain
reduction
in
most
studies
[77].
Treatment
of
mdx
dystrophic
mice
with
the
NAD+
precursor
nicotinamide
riboside
(NR)
prevented
senes-
cence
of
muscle
stem
cells,
and
this
rejuvenated
their
regenerative
capacity
[24].
The
Notch
pathway
is
chroni-
cally
activated
in
severely
dystrophic
muscles
of
mdx
mice
double
mutant
for
dystrophin
and
utrophin,
and
blocking
this
pathway
with
the
g-Secretase
inhibitor
DAPT
reduced
stem
cell
senescence
and
the
histopath-
ological
features
of
DMD
[42].
Importantly,
abolition
of
p16
INK4a
,
which
accumulates
abnormally
in
satellite
cells
of
DM1
muscles,
partially
restores
early
growth
arrest
and
reduces
senescence
in
vitro
[22],
reinforcing
the
idea
that
Musculoskeletal
senescence
Baar
et
al.
151
Figure
3
IL-6
MMPs
IL1
Youn
gOld
Current Opinion in Pharmacology
Age-related
cartilage
degeneration
leads
to
osteoarthritis.
Senescent
chondrocytes
present
in
aged
cartilage
cannot
proliferate
to
regenerate
damaged
cartilage
and
induce
extracellular
matrix
degeneration
through
the
SASP.
Furthermore,
cartilage
regeneration
is
inhibited
during
aging
due
to
senescent
mesenchymal
stem
cells.
www.sciencedirect.com
Current
Opinion
in
Pharmacology
2018,
40:147–155
this
mechanism
might
participate
in
the
impaired
regen-
eration
of
DM1
muscles.
Notably,
the
regenerative
deficit
of
satellite
cells
from
dystrophic
muscles
resembles
that
of
geriatric
mice,
which
also
show
p16I
NK4a
-induced
senescence
and
can
be
rejuvenated
by
silencing
of
the
gene
encoding
p16
INK4a
[21

].
Overall,
these
studies
show
limited
effects,
and
the
long-term
safety
of
these
drugs
and/or
genetic
approaches
has
yet
to
be
assessed.
However,
it
is
unlikely
that
essential
molecules
and
pathways
such
as
Notch
or
p16
INK4a
can
be
targeted
systemically
without
severe
secondary
effects.
In
addi-
tion,
these
strategies
are
aimed
at
reducing
symptoms
and
do
not
treat
the
underlying
causes
of
disease
progression.
Removal
of
senescent
cells
is
expected
to
reduce
these
inflammatory
proteins
while
preserving
stem
cell
function
and
is
therefore
expected
to
be
safer
and
have
more
long-
lasting
effects.
The
results
obtained
after
genetic
removal
of
senescent
cells
prompted
a
search
for
therapeutically
applicable
anti-senescence
compounds.
A
small
number
of
these
compounds
have
been
discovered,
with
varying
degrees
of
success.
One
example
is
Navitoclax,
a
BCL2
family
inhibitor.
In
the
musculoskeletal
system,
Navitoclax
was
found
to
decrease
the
expression
of
cytokines
that
pro-
mote
osteoclast
activity
in
vitro,
such
as
IL-1a
and
MMP-
13
[58].
Furthermore,
muscle
stem
cells
isolated
from
naturally
aged,
Navitoclax-treated
mice
showed
improved
clonogenicity
[78].
A
major
challenge
when
developing
anti-senescence
therapies
is
to
avoid
toxicity
to
healthy
non-senescent
cells.
It
is
therefore
important
to
identify
the
unique
characteristics
of
senescent
cells
that
can
be
targeted
by
a
therapeutic
compound.
Senescent
cells
often
express
persistent
nuclear
damage
foci
called
DNA-SCARS
(DNA
Segments
with
Chromatin
Alterations
Reinforcing
Senescence)
that
contain
DDR
proteins
such
as
53BP1,
gH2AX
and
activated
p53
[79].
These
DNA-SCARS
play
a
role
in
maintaining
permanent
growth
arrest
and
are
critical
for
SASP
expression.
In
addition,
we
recently
showed
that
the
transcription
factor
FOXO4
resides
within
PML
bodies
fused
to
these
persistent
damage
foci
[19
].
Here,
FOXO4
binds
p53
and
prevents
p53-depen-
dent
apoptosis.
In
order
to
disrupt
this
interaction
and
to
induce
apoptosis,
we
prospectively
generated
a
D-Retro-
Inverso
peptide
mimicking
the
FOXO4
p53-binding
domain.
This
peptide,
FOXO4-DRI,
causes
the
release
of
p53
to
the
cytoplasm,
where
p53
indeed
induces
apoptosis
in
a
transcription
independent
manner.
Indeed,
in
vivo
use
of
FOXO4-DRI
shows
promising
results.
For
these
experiments
we
made
use
of
Xpd
TTD/TTD
mice
that
show
accelerated
aging
and
age-related
ailments
such
as
osteoporosis
and
are
therefore
an
ideal
model
for
muscu-
loskeletal
diseases
[60].
FOXO4-DRI
treatment
improved
overall
fitness
and
renal
function
in
these
mice,
including
an
improved
running
wheel
performance
[19
],
an
especially
promising
result
for
the
treatment
of
mus-
culoskeletal
diseases.
FOXO4-DRI
showed
around
10
fold
selectivity
for
eliminating
senescent
vs.
control
cells.
While
enough
for
experiments
in
rodents,
transla-
tion
to
the
clinic
requires
further
improvement
to
elimi-
nate
toxicity,
which
would
be
intolerable
in
this
setting.
Such
efforts
are
now
underway
in
our
laboratory.
Unanswered
questions
As
we
highlighted
here,
the
tissues
of
the
musculoskeletal
system
are
damaged
by
inflammation
during
aging.
Cel-
lular
senescence,
by
driving
a
persistent
inflammatory
response,
is
a
major
contributor
to
these
effects.
However,
it
remains
unclear
which
senescent
cell
types
are
the
main
producers
of
these
pro-inflammatory
factors.
Aging
of
the
musculoskeletal
system
is
due
to
both
local
and
systemic
factors.
For
example,
senescent
cells
transplanted
into
cartilage
can
independently
cause
osteoarthritis
[71
].
On
the
other
hand,
systemically
increased
IL-6
levels
are
linked
to
muscle
wasting,
and
the
immune
system
also
seems
to
be
crucial
in
this
process
[28,29].
This
systemic
inflammation
can
be
caused
by
many
cell
types.
For
example,
adipose
tissue
significantly
contributes
to
sys-
temic
inflammation
[80].
Fat
present
in
joints
can
produce
factors
that
promote
osteoarthritis
[81].
In
turn,
cells
of
152
Musculoskeletal
Table
1
Effects
of
senescent
cell
removal
on
the
musculoskeletal
system
Tissue
Model
system
Senescence
cleared/delayed
by:
Improvements
musculoskeletal
system
Ref.
Fast
aging
BubR1
H/H
mice
Naturally
aged
mice
Fast
aging
LAKI
(Lmna
G609G
)
INK-ATTAC
Navitoclax
Transient
OSKM
expression
Kyphosis
reduction,
increase
in
muscle
fiber
diameter
Improved
muscle
stem
cell
function
Improved
regeneration
after
muscle
injury
[16]
[78]
[33
]
Klotho
deficient
mice
Naturally
aged
mice
p16
INK4A
Knockout
INK-ATTAC
Delay
in
osteoporosis
Improved
bone
structure
and
strength,
improved
bone
formation,
reduction
in
bone
resorption
[61]
[62

]
ACLT
in
the
mouse
Knee
joint
Naturally
aged
mice
Fast
aging
Xpd
TTD/TTD
mice
p16::3MR
INK-ATTAC
FOXO4-p53
interfering
peptide
Reduced
inflammation,
pain
reduction,
increase
in
cartilage
development
Reduced
cartilage
degeneration
Improved
running
wheel
performance
[76
]
[62

]
[19
]
Current
Opinion
in
Pharmacology
2018,
40:147–155
www.sciencedirect.com
the
musculoskeletal
system
also
secrete
systemic
factors
and
influence
overall
tissue
integrity.
For
example,
mus-
cle
cells
affect
NK
cells
during
aging
and,
as
NK
cells
are
responsible
for
clearance
of
senescent
cells
[41],
these
would
also
influence
the
systemic
senescence
burden.
Since
various
anti-senescence
compounds
potentially
kill
distinct
subsets
of
senescent
cells,
it
is
vital
to
know
which
cell
type
to
target;
knowledge
about
which
senescent
cells
contribute
most
to
musculoskeletal
degeneration
will
ultimately
guide
the
development
of
effective
treatment.
Anti-senescence
therapy
may
also
be
beneficial
for
sev-
eral
incurable
muscular
dystrophies
and
for
wasting,
by
reducing
inflammaging
and
hence
boosting
the
satellite
cell
regenerative
functions.
Interestingly,
cellular
senes-
cence
has
been
shown
to
mediate
fibrotic
pulmonary
disease,
and
senescent
cell
ablation
improves
pulmonary
function
in
this
setting
[82].
Most
dystrophinopathies
also
feature
increased
muscle
fibrosis
[83],
which
aggravates
disease
progression
by
substituting
muscle
with
scar
tissue,
and
it
is
plausible
that
anti-senescence
cocktails
will
also
halt
fibrosis
and
improve
patient
health
status.
Thus,
elimination
of
senescent
cells
may
have
benefits
for
tissue
repair
by
reversing
several
detrimental
processes;
however,
it
remains
to
be
determined
whether
senes-
cence
should
be
blocked
partially
or
totally
or
eliminated
only
once
early
potential
stemness-related
functions
have
been
completed.
The
answers
to
these
questions
may
not
be
easy
to
obtain,
yet
we
are
rapidly
obtaining
tools
that
allow
manipulation
of
the
senescence
process
(for
remov-
ing
senescent
cells,
neutralizing
the
SASP,
or
both
pro-
cesses).
The
final
goal
is
to
preserve
stem
cell
benefits
while
minimizing
the
deleterious
consequences
of
senescence.
It
also
remains
unclear
how
tissues
rejuvenate
after
senes-
cent
cell
ablation
and
whether
side
effects
or
unexpected
challenges
will
occur.
For
example,
in
addition
to
its
potential
to
eliminate
senescent
cells,
tissue
engineering
is
being
explored
as
a
treatment
for
musculoskeletal
diseases.
In
this
scenario,
stem
cells
are
isolated
and
healthy
tissue
is
generated
ex
vivo
to
replace
damaged
tissues
such
as
cartilage
and
bone.
For
example,
mesen-
chymal
stem
cells
can
be
isolated
and
cultured
on
a
biodegradable
scaffold
where
they
are
stimulated
with
TGFb
to
induce
differentiation
into
chondrocytes
[84].
This
newly
formed
cartilage
could
then
be
used
for
surgical
reconstruction
of
joints.
However,
a
major
chal-
lenge
in
tissue
engineering
is
to
prevent
stem
cell
senes-
cence
[85].
It
remains
unclear
whether
similar
issues
will
arise
after
senescence
clearance.
So
far,
tissue
regenera-
tion
seems
efficient
after
these
cells
are
removed.
For
example,
although
cartilage
has
a
weak
regenerative
potential,
it
is
rejuvenated
after
senescent
cells
are
removed.
Tissue-specific
stem
cells
are
likely
key
to
this
regeneration.
It
is
possible
that
the
reduction
of
SASP
proteins
in
the
tissue
microenvironment
releases
these
cells
from
their
‘stem
cell
lock’,
resulting
in
a
restored
regenerative
potential.
In
addition,
cells
that
are
dedif-
ferentiated
due
to
senescence,
such
as
chondrocytes,
could
help
rejuvenate
musculoskeletal
tissue.
In
general,
multiple
factors
likely
contribute
to
this
rejuvenation.
Both
local
and
systemic
inflammation
are
expected
to
decline,
affecting
immune
system
functioning,
natural
senescent
cell
clearance,
stem
cell
function,
and
tissue
regeneration.
In
conclusion,
targeting
senescence
has
the
potential
to
prevent
or
reverse
multiple
age-related
diseases
and
to
reduce
frailty.
Furthermore,
it
seems
likely
that
thera-
peutically
applicable
anti-senescence
compounds
will
be
available
in
the
future.
However,
the
toxicity
of
these
drugs
remains
a
major
concern.
Periodic
treatments
will
likely
be
necessary
to
maintain
possible
beneficial
effects
and
it
is
still
largely
unknown
what
the
effect
of
multiple
treatment
rounds
will
be.
Therefore,
the
timing
and
frequency
of
these
treatments
should
be
studied,
as
well
as
the
long-term
effect
of
senescence
clearance
on
bio-
logical
processes
such
as
stem
cell
function.
Conflict
of
interest
PDK
is
co-founder,
shareholder
and
consultant
for
Cleara
Biotech
B.V.,
the
Netherlands.
Acknowledgements
The
authors
acknowledge
support
for
MB
from
Dutch
Cancer
Society
Grant
UMCU-7141
awarded
to
PdK,
and
for
EP
and
PMC
from
ERC-2016-AdG-
741966
(STEM-AGING),
SAF2015-67369-R,
MDA
and
AFM.
The
DCESX/UPF
is
recipient
of
a
‘Marı
´a
de
Maeztu’
Program
for
Units
of
Excellence
in
R&D
MDM-2014-0370
(Government
of
Spain).
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