Ageing and Apoptosis schemes

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AGING
Starts at birth
Ends at death
Age is a relative term with differences
within and between species.
Cellular
dysfunctions
Ageing
Processes
Genomic
instabilities
Accelerate
The organism
will age faster
Nutrient
sensing
Mitochondrial
function
Protein
degradation
Accumulation of
genetic changes
Telomere
shortening
Progeroid
syndromes
Epigenetic
changes in
DNA
Slow down
The
organism
will live
longer
Once the damages
reach a treshold it
results in
Some proteins
regulate
metabolic rate.
The pathway they
use is responsible
for coordinating
growth,
differentiation
and metabolism
in response to
internal and
external
environment.
For some reason
not yet known,
dietary or caloric
restriction
decreases the
activity in that
pathway,
increasing life
span. However,
this effect doesn t
work if there is a
nutrient
deprivation.
Cells have many
mitochondria.
Oxidative damage
occurs but can be
alleviated with
antioxidant
enzymes. This
repair process
declines with age,
so damaged
mitochondria
accumulate in
cells.
Damaged
mitochondria that
produce oxidative
damage are
destroyed and
recycled by
autophagy
(mitophagy)
Autophagy of
defective
mitochondria is
effective to
prevent aging
symptoms.
Occurs whenever
a protein
somehow loses its
shape by
unfolding,
becomes
modified by a
chemical reaction,
or is targeted for
degradation.
There are
mechanisms that
remove defective
proteins. The
chaperonemediated folding
fix them. Three
other
mechanisms
involving enzymes
degrade and/or
recycle damaged
proteins.
Somatic
mosaicism
Random DNA
damages by
mutation and
external sources
accumulate
because the
changes are
unrepaired when
we age, and
persist in the next
generation of
cells.
Include loss of
chromosomes,
copy number
variations in
genes, base
damage that
leads to missense
mutations and
chromosomal
translocations.
Oxidative
stress
Mitochondrias
reduce O2
partially when
producing ATP.
This creates
reactive oxygen
species that
damage protein,
lipid and DNA
nonspecifically.
Superoxide iones
(O2-)
Peroxides
(H2O2)
Hydroxyl radicals
(HO)
DNA
methylation
Telomeres
controls cell
division. During
replication DNA
polymerase
cannot replicate
the DNA at the
ends, so each
time the cell
divides the
telomeres
shortens, up to a
point in which the
cell enters
senescence.
DNA methylation
adds methyl
groups (-CH3) to
CG or CNG
sequences on one
strand of the
chromosome.
This prevents
transcription
factors from
accessing the
genes. DNA
methylation
decreases as we
age. This
increases gene
transcription of
genes that were
quiescent.
Chromatin
remodeling
Two types of
chromatin in cells:
Euchromatin
(around genes
that will be
expressed) and
Heterochromatin
(found around
repeated
sequences such as
telomeres and
centromeres)
Heterochromatin
amounts decline
with age so the
DNA relaxes and
the genome
destabilizes.
Histone
modification
Cellular
Senescence
DNA wraps
around histones.
Methylation,
phosphorylation,
acetylation of
histones
determine if
other proteins
can access the
DNA.
Theory 1:
methylation
causes aging.
Theory 2:
Acetyl groups
means that the
histone is loose so
more
recombination
occurs and
damages
increase.
Process by
which a cell
no longer
divides.
Cellular
damages
accumulate
in cells.
Senescence
prevents the
damages
from getting
out of
control
Programmed
cell death
If and when
cellular
damage
accumulates
beyond a
point of
repair,
normal cells
activate
programs to
commit
suicide.
The most
studied
programmed
cell death is
apoptosis.
Physiological condition in which
cells arrest in the non-dividing part
of the cell cycle without changing
their physiological role.
Senescent cells are cell
cycle arrested
* The cells divice for
a certain number of
generations, and
then stop dividing.
* The addition of
growth inducers has
no effect after that
point.
* Number of
replications – an
expression of aging
or senescence at the
cellular level
(Hayflick and
Moorhead – 1961)
EVIDENCE
Human fibroblasts from a
fetus will divide 60 to 80
times in culture
Human fibroblasts from
an older person divide
only 10 to 20 times in
culture
Terminal
differentiation
Cellular Senescence
They are metabolically
active:
* They produce proteins
* They generate energy
* They function in their
normal capacity
BUT
They DO NOT REPLICATE
Their DNA or DIVIDE
* metabolically distinct
* produce molecules
characteristic of arrested
cells
* altered chromatin
structure.
* They secrete more
factors
They have active tumor
suppressor molecules
RB & p53
Two key regulators
that control whether
or not a cell enters
senescence or
apoptosis (cell death)
Their activated forms
accumulate in cells
before they enter
senescence.
Some of our cells
never enter a
senescent state
STEM CELLS
Physiological
condition in which
cells also arrest in
the non-dividing part
of the cell cycle
BUT
Immature or
precursor cells
that originate
differentiated
cells.
Their
number
decreases
as we age
Because of a
physiological signal
from their
environment.
Some
remain to
repair
various
tissues
* Skin
* Intestinal lining
* Immune system
* Blood cells
Controlled pathway used by
cells to commit suicide
PROGRAMMED CELL DEATH
Different pathways
Mechanisms that destroys and
recycles defective cellular
components.
Triggered when
cell damage
accumulates
beyond a point of
repair
Proteins, lipids and nucleic acids
are digested and recycled.
TYPE I
APOPTOSIS
TYPE II
AUTOPHAGY
TYPE III
NECROPTOSIS
Steps
Genes
regulate
their
organized
steps
1- the cell membrane form
blebs (regions that balloon out)
Macroautophagy
Microautophagy
Chaperonemediated
autophagy
2- the nucleus shrinks,
condenses and divide into
smaller fragments
3- the entire cell shrinks and
divides into large condensed
fragments
(apoptic bodies)
4- other cells engulf the debris
by phagocytosis, cleaning up the
remnants
1- the cell undergoes a external
injury, oxygen starvation and/or
energy depletion
2- The osmotic balance is
perturbed
3- their proteins are denatured
and degraded.
Targets whole
organelles to
be degraded
Deal with
defective
proteins
4- The necrotic cell swells,
ruptures and dies.
5- this triggers an immune system
response; proinflammatory
substances are released.
APOPTOSIS
Evidences
Two major pathways
Studies on C.
elegans
(a small,
transparent,
easy-to-grow
worm)
4 genes
involved in the
process
Genes initiate
apoptosis in a
cascade
reaction
(the action of
one protein
activates the
next protein,
and so on)
Enzyme type:
caspase
Death receptor
pathway
Or
Extrinsic
pathway
Mitochondrial
Death pathway
Or
Intrinsic
pathway
A death protein
receptor at a cell
surface
originates the
death signal.
The receptor
transmit the
signal to its
intracellular
domain
A variety of
internal proteins
go to the
membrane
Caspases are
activated
Triggered by
intracellular
catastrophe,
such as
irreparable DNA
damage.
This activates
proteins in the
mitochondria.
The
mitochondria
releases a variety
of effector
molecules
These molecules
activate the
Caspases.
Both are often activated
simultaneously
Stage 1 - Execution phase of
apoptosis
CASPASES
One caspase activates other caspases in
a cascade of reactions
Each cascade digest different cellular
substrates such as DNA, cytoskeleton,
organelles, proteins.
Stage 2 - Corpse clearance in
apoptosis
The apoptotic bodies are removed by
phagocytosis in simple organisms.
In mammals, macrophages engulf the
apoptotic bodies and clean the area.
Also, neighboring cells can engulf the
apoptotic bodies.
Executioners
They carry out the
death sentence of
apoptosis.
Proteases that
target proteins by
recognizing four
amino acid
residues following
the aspartate aa
* many different types
* highly conserved throughout evolution
* found in mammals, flies, nematodes,
even hydra.
* in humans, there are over a dozen
types
Ways to activate them
Avoids
immune
response
When macrophages
ingest apoptotic
bodies they don t
secrete interferons
By joining
another
previously
activated
caspases
By two
caspases
that
associate
and
interact
By means
of
another
protein
(not a
caspases)
CELL DEATH
PROGRAMMED CELL DEATH
NECROPTOSIS
STEPS
Rupture of
the cellular
membrane
Cellular
contents leak
into
intracellular
area
This triggers
an immune
response
Controlled by a
cellular
mechanism
evidences
1 – there are
necrotic events
without
pathological
assaults
2 – necrosis can be
induced by some
molecules that
bind with the
membrane
receptors
3 – necrosis can be
regulated by
genetics,
epigenetics and
drugs
Metabolic
control
pathways
In Bacteria
Metabolic
enzymes
control many
aspects of
senescence and
apoptosis
senescence
apoptosis
There is no
death by
apoptosis
BUT
To protect the organism from
damaged cells.
Death is genetically encoded
Cancer cells are damaged cells
that have deleterious
mutations in the genome
An endoribunuclease degrades
mRNA if bacteria are depleted of
nutrients.
Presence of oncogenic
mutations triggers
premature cellular
senescence
Severely
damaged cells
commit suicide
via apoptosis
Some damaged cells that bypass the senescence program and block
apoptosis are called CANCER
Some bacteria commit suicide for
the good of the rest, because their
proteins, lipids and nucleic acids
provide food for surrounding
bacteria
Genetic programs for
population benefit (?)
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