Neurobiology of Disease,
Journal Year:
2020,
Volume and Issue:
143, P. 105008 - 105008
Published: July 3, 2020
Aging
is
the
strongest
risk
factor
for
metabolic,
vascular
and
neurodegenerative
diseases.
alone
associated
with
a
gradual
decline
of
cognitive
motor
functions.
Considering
an
increasing
elderly
population
in
last
century,
understanding
cellular
molecular
mechanisms
contributing
to
brain
aging
vital
importance.
Recent
genetic
transcriptomic
findings
strongly
suggest
that
glia
are
first
cells
changing
aging.
Glial
constitute
around
50%
total
play
key
roles
regulating
homeostasis
health
disease.
Their
essential
functions
include
providing
nutritional
support
neurons,
activation
immune
responses,
regulation
synaptic
transmission
plasticity.
In
this
review
we
discuss
how
altered
whether
these
alterations
protective
or
contribute
age-related
pathological
cascade.
We
focus
on
major
morphological,
transcriptional
functional
changes
affecting
range
systems,
including
human,
non-human
primates,
rodents.
also
highlight
future
directions
investigating
Frontiers in Immunology,
Journal Year:
2020,
Volume and Issue:
11
Published: March 31, 2020
Neuroinflammation
commences
decades
before
Alzheimer's
disease
(AD)
clinical
onset
and
represents
one
of
the
earliest
pathomechanistic
alterations
throughout
AD
its
continuum.
Large-scale
genome-wide
association
studies
point
out
several
genetic
variants
-
TREM2,
CD33,
PILRA,
CR1,
MS4A,
CLU,
ABCA7,
EPHA1,
HLA-DRB5-HLA-DRB1
potentially
linked
to
neuroinflammation.
Most
these
genes
are
involved
in
proinflammatory
intracellular
signaling,
cytokines/interleukins
cell
turn-over,
synaptic
activity,
lipid
metabolism,
vesicle
trafficking.
Proteomic
indicate
that
a
plethora
interconnected
aberrant
molecular
pathways,
set
off
perpetuated
by
TNF-α,
TGF-β,
IL-1β,
receptor
protein
Microglia
astrocytes
key
cellular
drivers
regulators
Under
physiological
conditions,
they
important
for
neurotransmission
homeostasis.
In
AD,
there
is
turning
pathophysiological
evolution
where
glial
cells
sustain
an
overexpressed
inflammatory
response
synergizes
with
amyloid-β
tau
accumulation,
drives
synaptotoxicity
neurodegeneration
self-reinforcing
manner.
Despite
strong
therapeutic
rationale,
previous
trials
investigating
compounds
anti-inflammatory
properties,
including
non-steroidal
drugs
(NSAIDs)
did
not
achieve
primary
efficacy
endpoints.
It
conceivable
study
design
issues,
lack
diagnostic
accuracy
biomarkers
target
population
identification
proof-of-mechanism
may
partially
explain
negative
outcomes.
However,
recent
meta-analysis
indicates
potential
biological
effect
NSAIDs.
this
regard,
candidate
fluid
neuroinflammation
under
analytical/clinical
validation,
i.e.
MCP-1,
IL-6,
TNF-α
complexes,
YKL-40.
PET
radio-ligands
investigated
accomplish
in-vivo
longitudinal
regional
exploration
Biomarkers
tracking
different
pathways
(body
matrixes)
along
brain
neuroinflammatory
endophenotypes
(neuroimaging
markers),
can
untangle
temporal-spatial
dynamics
between
other
mechanisms.
Robust
biomarker-drug
co-development
pipelines
expected
enrich
large-scale
testing
new-generation
active,
directly
or
indirectly,
on
targets
displaying
putative
disease-modifying
effects:
novel
NSAIDs,
AL002
(anti-TREM2
antibody),
anti-Aβ
protofibrils
(BAN2401),
AL003
(anti-CD33
antibody).
As
next
step,
taking
advantage
breakthrough
multimodal
techniques
coupled
systems
biology
approach
path
pursue
developing
individualized
strategies
targeting
framework
precision
medicine.
Frontiers in Aging Neuroscience,
Journal Year:
2021,
Volume and Issue:
13
Published: Feb. 25, 2021
Aging
of
the
brain
can
manifest
itself
as
a
memory
and
cognitive
decline,
which
has
been
shown
to
frequently
coincide
with
changes
in
structural
plasticity
dendritic
spines.
Decreased
number
maturity
spines
aged
animals
humans,
together
synaptic
transmission,
may
reflect
aberrant
neuronal
directly
associated
impaired
functions.
In
extreme,
neurodegenerative
disease,
completely
devastates
basic
functions
brain,
develop.
While
cellular
senescence
peripheral
tissues
recently
linked
aging
aging-related
disorders,
its
involvement
is
just
beginning
be
explored.
However,
accumulated
evidence
suggests
that
cell
play
role
it
documented
other
organs.
Senescent
cells
stop
dividing
shift
their
activity
strengthen
secretory
function,
leads
acquisition
so
called
senescence-associated
phenotype
(SASP).
have
also
characteristics,
such
altered
morphology
proteostasis,
decreased
propensity
undergo
apoptosis,
autophagy
impairment,
accumulation
lipid
droplets,
increased
senescence-associated-β-galactosidase
(SA-β-gal),
epigenetic
alterations,
including
DNA
methylation,
chromatin
remodeling,
histone
post-translational
modifications
that,
consequence,
result
gene
expression.
Proliferation-competent
glial
both
vitro
vivo
,
they
likely
participate
neuroinflammation,
characteristic
for
brain.
apart
from
proliferation-competent
cells,
consists
post-mitotic
neurons.
Interestingly,
emerged
recently,
non-proliferating
present
or
cultivated
some
hallmarks,
SASP,
typical
senescent
ceased
divide.
It
senolytics,
by
definition,
eliminate
improve
ability
mice
models.
this
review,
we
ask
questions
about
impairments
how
senolytics
them.
We
will
discuss
whether
plasticity,
defined
morphological
functional
at
level
neurons
spines,
hallmark
susceptible
effects
senolytics.
Journal of Neurochemistry,
Journal Year:
2019,
Volume and Issue:
151(6), P. 676 - 688
Published: Sept. 3, 2019
The
single
largest
risk
factor
for
etiology
of
neurodegenerative
diseases
like
Alzheimer's
disease
is
increased
age.
Therefore,
understanding
the
changes
that
occur
as
a
result
aging
central
to
any
possible
prevention
or
cure
such
conditions.
Microglia,
resident
brain
glial
population
most
associated
with
both
protection
neurons
in
health
and
their
destruction
disease,
could
be
significant
player
age
related
changes.
Microglia
can
adopt
an
aberrant
phenotype
sometimes
referred
either
dystrophic
senescent.
While
aged
microglia
have
been
frequently
identified
there
no
conclusive
evidence
proves
causal
role.
This
has
hampered
by
lack
models
microglia.
We
recently
generated
model
senescent
based
on
observation
all
show
iron
overload.
Iron-overloading
cultured
causes
them
take
cause
neurodegeneration
similar
those
observed
patients.
review
considers
how
this
used
determine
role
diseases.
Journal of Neuroinflammation,
Journal Year:
2021,
Volume and Issue:
18(1)
Published: Jan. 22, 2021
Age-related
macular
degeneration
(AMD),
a
degenerative
disease
in
the
central
macula
area
of
neuroretina
and
supporting
retinal
pigment
epithelium,
is
most
common
cause
vision
loss
elderly.
Although
advances
have
been
made,
treatment
to
prevent
progressive
lacking.
Besides
association
innate
immune
pathway
genes
with
AMD
susceptibility,
environmental
stress-
cellular
senescence-induced
alterations
pathways
such
as
metabolic
functions
inflammatory
responses
are
also
implicated
pathophysiology
AMD.
Cellular
senescence
an
adaptive
cell
process
response
noxious
stimuli
both
mitotic
postmitotic
cells,
activated
by
tumor
suppressor
proteins
prosecuted
via
secretome.
In
addition
physiological
roles
embryogenesis
tissue
regeneration,
augmented
age
contributes
variety
age-related
chronic
conditions.
Accumulation
senescent
cells
accompanied
impairment
immune-mediated
elimination
mechanisms
results
increased
frequency
termed
"chronic"
senescence.
Age-associated
exhibit
abnormal
metabolism,
generation
reactive
oxygen
species,
heightened
senescence-associated
secretory
phenotype
that
nurture
proinflammatory
milieu
detrimental
neighboring
cells.
Senescent
changes
various
choroidal
including
microglia,
neurons,
endothelial
contemporaneous
systemic
aging
emerged
important
contributors
onset
development
The
repertoire
senotherapeutic
strategies
senolytics,
senomorphics,
cycle
regulation,
restoring
homeostasis
targeted
at
levels
expanding
potential
treat
spectrum
diseases,
Aging Cell,
Journal Year:
2021,
Volume and Issue:
21(1)
Published: Dec. 10, 2021
The
increase
in
senescent
cells
tissues,
including
the
brain,
is
a
general
feature
of
normal
aging
and
age-related
pathologies.
Senescent
exhibit
specific
phenotype,
which
includes
an
altered
nuclear
morphology
transcriptomic
changes.
Astrocytes
undergo
senescence
vitro
age-associated
neurodegenerative
diseases,
but
little
known
about
whether
this
process
also
occurs
physiological
aging,
as
well
its
functional
implication.
Here,
we
investigated
astrocyte
vitro,
old
mouse
brains,
post-mortem
human
brain
tissue
elderly.
We
identified
significant
loss
lamin-B1,
major
component
lamina,
hallmark
astrocytes.
showed
severe
reduction
lamin-B1
dentate
gyrus
aged
mice,
hippocampal
astrocytes,
granular
cell
layer
hippocampus
from
non-demented
was
associated
with
deformations,
represented
by
increased
incidence
invaginated
nuclei
circularity
astrocytes
hippocampus.
found
differences
levels
between
polymorphic
elderly
hippocampus,
suggesting
intra-regional-dependent
response
Moreover,
described
senescence-associated
impaired
neuritogenic
synaptogenic
capacity
Our
findings
show
that
conserved
shed
light
on
defects
lamina
structure
may
contribute
to
dysfunctions
during
aging.
International Journal of Molecular Sciences,
Journal Year:
2023,
Volume and Issue:
24(3), P. 1869 - 1869
Published: Jan. 18, 2023
Aging
is
the
most
prominent
risk
factor
for
late-onset
Alzheimer’s
disease.
associates
with
a
chronic
inflammatory
state
both
in
periphery
and
central
nervous
system,
evidence
thereof
mechanisms
leading
to
neuroinflammation
being
discussed.
Nonetheless,
significantly
enhanced
by
accumulation
of
amyloid
beta
accelerates
progression
disease
through
various
pathways
discussed
present
review.
Decades
clinical
trials
targeting
2
abnormal
proteins
disease,
tau,
led
many
failures.
As
such,
via
different
strategies
could
prove
valuable
therapeutic
strategy,
although
much
research
still
needed
identify
appropriate
time
window.
Active
focusing
on
identifying
early
biomarkers
help
translating
these
novel
from
bench
bedside.
Life,
Journal Year:
2022,
Volume and Issue:
12(9), P. 1332 - 1332
Published: Aug. 28, 2022
Aging
is
a
biological
feature
that
characterized
by
gradual
degeneration
of
function
in
cells,
tissues,
organs,
or
an
intact
organism
due
to
the
accumulation
environmental
factors
and
stresses
with
time.
Several
have
been
attributed
aging
such
as
oxidative
stress
augmented
production
exposure
reactive
oxygen
species,
inflammatory
cytokines
production,
telomere
shortening,
DNA
damage,
and,
importantly,
deposit
senescent
cells.
These
are
irreversibly
mitotically
inactive,
yet
metabolically
active
The
reason
underlying
their
senescence
lies
within
extrinsic
intrinsic
arms.
arm
mainly
expression
secretory
profile
known
senescence-associated
phenotype
(SASP).
results
from
impact
several
genes
meant
regulate
cell
cycle,
tumor
suppressor
genes.
P16
Life Medicine,
Journal Year:
2022,
Volume and Issue:
1(2), P. 103 - 119
Published: Aug. 9, 2022
Abstract
Aging
is
a
natural
but
relentless
process
of
physiological
decline,
leading
to
physical
frailty,
reduced
ability
respond
stresses
(resilience)
and,
ultimately,
organismal
death.
Cellular
senescence,
self-defensive
mechanism
activated
in
response
intrinsic
stimuli
and/or
exogenous
stress,
one
the
central
hallmarks
aging.
Senescent
cells
cease
proliferate,
while
remaining
metabolically
active
and
secreting
numerous
extracellular
factors,
feature
known
as
senescence-associated
secretory
phenotype.
Senescence
physiologically
important
for
embryonic
development,
tissue
repair,
wound
healing,
prevents
carcinogenesis.
However,
chronic
accumulation
persisting
senescent
contributes
host
pathologies
including
age-related
morbidities.
By
paracrine
endocrine
mechanisms,
can
induce
inflammation
locally
systemically,
thereby
causing
dysfunction,
organ
degeneration.
Agents
those
targeting
damaging
components
phenotype
or
inducing
apoptosis
exhibit
remarkable
benefits
both
preclinical
models
early
clinical
trials
geriatric
conditions.
Here
we
summarize
features
outline
strategies
holding
potential
be
developed
interventions.
In
long
run,
there
an
increasing
demand
safe,
effective,
clinically
translatable
senotherapeutics
address
healthcare
needs
current
settings
global