The
senescence
phenotype
is
heterogeneous,
as
observed
by
the
context-dependent
differential
expression
of
markers.
Here,
we
provide
evidence
to
demonstrate
an
inverse
relationship
in
pattern
two
murine
variants
p21
(p21v1,
and
p21v2)
aging
hemorrhagic
shock.
While
upregulation
p21v1
was
following
shock
injury,
p21v2
upregulated
aged
mouse.
We
further
show
that
response
is,
at
least,
partially
independent
p53.
Toxicology,
Год журнала:
2024,
Номер
504, С. 153804 - 153804
Опубликована: Апрель 12, 2024
Fifty
percent
of
all
acute
liver
failure
(ALF)
cases
in
the
United
States
are
due
to
acetaminophen
(APAP)
overdose.
Assessment
canonical
features
injury,
such
as
plasma
alanine
aminotransferase
activities
poor
predictors
(ALF),
suggesting
involvement
additional
mechanisms
independent
hepatocyte
death.
Previous
work
demonstrated
a
severe
overdose
APAP
results
impaired
regeneration,
induction
senescence
by
p21,
and
increased
mortality.
We
hypothesized
that
discrete
population
p21+
hepatocytes
acquired
secretory
phenotype
directly
impedes
recovery
after
Leveraging
in-house
human
explant
publicly
available
single-nuclei
RNAseq
data,
we
identified
subpopulation
enriched
unique
secretome
factors,
CXCL14.
Spatial
transcriptomics
mouse
model
confirmed
presence
surrounded
necrotic
areas.
In
both
male
female
mice,
found
dose-dependent
p21
persistent
circulating
levels
p21-specific
constituent,
CXCL14,
parallel
experiments,
targeted
either
putative
senescent
with
senolytic
drugs,
dasatinib
quercetin,
or
CXCL14
neutralizing
antibody.
targeting
greatly
enhanced
APAP-induced
while
had
no
effect.
These
data
support
conclusion
sustained
secretion
critical
mechanistic
events
leading
ALF
mice
patients.
Journal of Clinical Investigation,
Год журнала:
2024,
Номер
134(12)
Опубликована: Май 16, 2024
Cells
expressing
features
of
senescence,
including
upregulation
p21
and
p16,
appear
transiently
following
tissue
injury,
yet
the
properties
these
cells
or
how
they
contrast
with
age-induced
senescent
remains
unclear.
Here,
we
used
skeletal
injury
as
a
model
identified
rapid
appearance
fracture
p21+
senescence
markers,
mainly
osteochondroprogenitors
(OCHs)
neutrophils.
Targeted
genetic
clearance
suppressed
senescence-associated
signatures
within
callus
accelerated
healing.
By
contrast,
cell
did
not
alter
bone
loss
due
to
aging;
conversely,
p16+
clearance,
known
alleviate
aging,
affect
Following
fracture,
neutrophils
were
enriched
in
signaling
pathways
induce
paracrine
stromal
while
OCHs
highly
secretory
phenotype
factors
impair
formation.
Further
analysis
revealed
an
injury-specific
stem
cell-like
OCH
subset
that
was
inflammatory,
similar
inflammatory
mesenchymal
population
(fibro-adipogenic
progenitors)
evident
muscle
injury.
Thus,
intercommunicating
senescent-like
progenitor
key
regulators
repair
potentially
across
tissues.
Moreover,
our
findings
established
contextual
roles
vs
senescent/senescent-like
may
be
leveraged
for
therapeutic
opportunities.
Biomedicine & Pharmacotherapy,
Год журнала:
2024,
Номер
179, С. 117288 - 117288
Опубликована: Авг. 14, 2024
Irreversible
cardiotoxicity
limits
the
clinical
application
of
doxorubicin
(DOX).
DOX-induced
has
been
associated
with
induction
senescence
and
activation
p38
MAPK
pathway.
Losmapimod
(LOSM),
an
orally
active
inhibitor,
is
anti-inflammatory
agent
cardioprotective
effects.
Nevertheless,
effect
LOSM
against
not
reported.
In
this
study,
we
determined
effects
on
chronic
in
C57BL/6
N
mice.
Five-week-old
mice
were
fed
diet
containing
(estimated
daily
intake
12
mg/kg/day)
or
a
control
for
four
days.
Thereafter,
randomized
to
receive
six
weekly
intraperitoneal
injections
either
DOX
(4
mg/kg)
saline.
Three
days
after
last
injection,
cardiac
function
was
assessed
by
trans-thoracic
echocardiography.
Activation
p38,
JNK,
ERK1/2
MAPKs
immunoblotting
heart
liver.
Gene
expressions
senescence,
inflammatory,
oxidative
stress,
mitochondrial
markers
quantified
using
real-time
PCR
serum
inflammatory
Luminex.
Our
results
demonstrated
that
attenuated
activation,
ameliorated
dysfunction,
abrogated
expression
marker
p21
Abstract
Cellular
senescence
is
an
established
cause
of
cell
and
tissue
aging.
Senescent
cells
have
been
shown
to
increase
in
multiple
organs
during
aging,
including
the
skin.
Here
we
hypothesized
that
senescent
residing
skin
can
spread
distant
organs,
thereby
accelerating
systemic
aging
processes.
To
explore
this
hypothesis,
initially
observed
several
markers
mice.
Subsequently,
conducted
experiments
wherein
fibroblasts
were
transplanted
into
dermis
young
mice
assessed
various
age‐associated
parameters.
Our
findings
reveal
presence
dermal
layer
leads
increased
both
proximal
distal
host
tissues,
alongside
frailty,
impaired
musculoskeletal
function.
Additionally,
there
was
a
significant
decline
cognitive
function,
concomitant
with
expression
senescence‐associated
within
hippocampus
brain
area.
These
results
support
concept
accumulation
exert
remote
effects
on
other
brain,
potentially
explaining
links
between
disorders
diseases
and,
contributing
physical
associated
Ageing
is
defined
as
the
progressive
loss
of
tissue
function
and
regenerative
capacity
caused
by
both
intrinsic
factors
i.e.
natural
accumulation
damage,
extrinsic
damage
from
environmental
stressors.
Cellular
senescence,
in
brief,
an
irreversible
exit
cell
cycle
that
occurs
primarily
response
to
excessive
cellular
such
ultraviolet
(UV)
exposure
oxidative
stress,
it
has
been
comprehensively
demonstrated
contribute
organismal
ageing.
In
this
review,
we
will
focus
on
skin,
organ
which
acts
essential
protective
barrier
against
injury,
insults,
infection.
We
explore
evidence
for
existence
contribution
senescence
skin
discuss
known
molecular
mechanisms
driving
with
a
dysregulation
master
growth
regulator,
mechanistic
Target
Rapamycin
Complex
1
(mTORC1).
interplay
dysregulated
mTORC1
lysosomes
how
they
phenotypes.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Фев. 7, 2024
ABSTRACT
Cells
expressing
features
of
senescence,
including
upregulation
p21
and
p16,
appear
transiently
following
tissue
injury,
yet
the
properties
these
cells
or
how
they
contrast
with
age-induced
senescent
remains
unclear.
Here,
we
used
skeletal
injury
as
a
model
identified
rapid
appearance
fracture
p21+
senescence
markers,
mainly
osteochondroprogenitors
(OCHs)
neutrophils.
Targeted
genetic
clearance
suppressed
senescence-associated
signatures
within
callus
accelerated
healing.
By
contrast,
cell
did
not
alter
bone
loss
due
to
aging;
conversely,
p16+
clearance,
known
alleviate
aging,
affect
Following
fracture,
neutrophils
were
enriched
in
signaling
pathways
induce
paracrine
stromal
while
OCHs
highly
secretory
phenotype
factors
impair
formation.
Further
analysis
revealed
an
injury-specific
stem
cell-like
OCH
subset
that
was
inflammatory,
similar
inflammatory
mesenchymal
population
(fibro-adipogenic
progenitors)
evident
muscle
injury.
Thus,
intercommunicating
senescent-like
progenitor
are
key
regulators
repair
potentially
across
tissues.
Moreover,
our
findings
establish
contextual
roles
vs
senescent/senescent-like
may
be
leveraged
for
therapeutic
opportunities.
