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The Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

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Page 1: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

The Cellular Basis of Disease Cell Injury 3

Apoptosis and Necrosis

Cellular Aging

Christine Hulette MD

hulet001
Approved
Page 2: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Objectives

• Discriminate cell adaptation, reversible cell injury and irreversible cell injury (cell death) based on etiology, pathogenesis and histological and ultrastructural appearance.

• Compare and contrast pathologic features and the clinical settings in which necrotic and apoptotic cell death occurs.

• List in temporal order the genetic and biochemical steps in apoptosis.

• Contrast and compare physiologic and pathologic apoptosis.

• Describe the mechanisms and implications of cellular aging.

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This lecture is pretty straightforward. You should be able to address these objectives by the end.
Page 3: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Necrosis

• Morphologic expression of cell death

• Progressive disintegration of cell structure

• Initiated by overwhelming stress

• Usually elicits an acute inflammatory cell

response (neutrophils may be present).

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Just because Dr. H mentioned it, inflammatory response doesn't occur in immunocompromised patients.
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Immunosuppressive therapy, which is needed for organ transplantation and treatment of immune mediated disease, impairs the immune response in many different ways. Refer to Dr. Gunn for details.
Page 4: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Apoptosis

• Pathway of cell death induced by a tightly regulated suicide program.

• Controlled by specific genes.

• Fragmentation of DNA.

• Fragmentation of nucleus.

• Blebs form and apoptotic bodies are released.

• Apoptotic bodies are phagocytized.

• No neutrophils.

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No inflammation in apoptosis.
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In a regular pattern.
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Page 5: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

• Necrosis or

Apoptosis?

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Necrosis. Why? Lots of Leukocytes. Does Apoptosis involve an inflammatory response? No!
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Page 6: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Consequences of Cell Death

Necrosis

Loss of functional tissue

Impaired organ function, transient or permanent

Apoptosis

Removal of damaged or unnecessary cells

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Page 7: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Re vers ible injury

NORMAL CELL

Recovery

Bf9akdown 01 plasma membr""" organolills and . ....:IIIUS ; hla kage of contents

NECROSIS 1 Amofpnous densities ., m~ochoodria

Capyrighl c>"",o ~ s-.. ""-"--

I NORMAL J CELL

~~3 __ Condeosation 01 chroma tin

:--"" Membrane blobs

Cllliula r fragmentation

I A POPTOSIS 1

_ ... of apoptotic calls and fragments

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Necrosis
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Apoptosis
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Page 8: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Causes of Apoptosis

• Physiologic

• Pathologic

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This slide is incredibly hi-yield.
Page 9: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

• Embryogenesis and fetal development.

• Hormone dependent involution.

Prostate glandular epithelium after castration

Regression of lactating breast after weaning

• Cell loss in proliferating cell populations.

• Immature lymphocytes

• Epithelial cells in the GI tract

• Elimination of self-reactive lymphocytes.

• Death of cells that have served their function.

• Neutrophils, Lymphocytes

Physiologic Apoptosis

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Think development of hands and feet.
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Lymphocytes that act against host. If not eliminated, you get autoimmune diseases.
Page 10: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Apoptosis in Pathologic

Conditions

• DNA damage due to radiation, chemotherapy.

• Accumulation of misfolded proteins leads to ER stress which ends with apoptosis.

• Cell death in viral infections that induce apoptosis such as HIV and Adenovirus or by the host immune response such as hepatitis.

• Organ atrophy after duct obstruction.

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Page 11: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

General Characteristics

NECROSIS

Usually affects large areas

of contiguous cells

Control of intracellular

environment is lost

early

Cells swell and

organelles swell

APOPTOSIS

Usually affects scattered

individual cells

Control of intracellular

environment maintained

in early stages

Cells contract

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Compare and contrast Necrosis and Apoptosis.. Look at the chart.
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Page 12: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

General Characteristics

NECROSIS

Nuclear chromatin

marginates early,

while injury is still

reversible

When DNA is cleaved,

which is usually a late

event, fragments are

random in size

(smear pattern in gels)

APOPTOSIS

Nuclear chromatin

marginates and

chromatin condenses,

becoming very compact

Chromatin condensation

and DNA fragmentation

occur together; DNA

cleaved into multiples of

200 base pair units

(ladder pattern in gels)

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We will see this soon.
Page 13: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

General Characteristics

NECROSIS

Cell membrane ruptures as

terminal event and cell

contents are released,

which are chemotactic

Chemotactic factors lead to

neutrophil infiltration to

degrade dead cells

APOPTOSIS

Blebs form and apoptotic

bodies containing

nuclear fragments

are shed

Phagocytosis of intact

apoptotic bodies, no

chemotactic factors

are generated

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Page 14: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Apoptosis

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Section of skin with immunologic mediated disease
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Regular margination and break up of DNA
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Page 15: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

e ElioM'r 2005

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Normal cell
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Apoptotic cell with ladder pattern, reflecting cleavage at 200bp intervals.
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Necrosis. DNA in all different lengths, smear pattern.
Page 16: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

A - early apoptosis; chromatin

margination & condensation

B - later in apoptosis; nucleus

is fragmented

C - phagocytosis of apoptotic

cellular remnants by

adjacent cell

D - swollen, necrotic cell for

comparison

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disruption and dissolution of cytoplasmic components
Page 17: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Apoptosis

A. Refers to the process of cellular disintegration

A. Caused by ischemia and inflammation.

B. Responsible for changing cell type in response to

stress

C. Beneficial process to eliminate damaged cells

D. Reduces the size of an organ

E. Induced by retinoic acid

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What do you think?
Page 18: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Apoptosis

A. Refers to the process of cellular disintegration

A. Caused by ischemia and inflammation.

B. Responsible for changing cell type in response to

stress

C. Beneficial process to eliminate damaged cells

D. Reduces the size of an organ

E. Induced by retinoic acid

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Necrosis
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Metaplasia
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Atrophy
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Patterning during embryogenesis
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Page 19: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Mechanisms of Apoptosis

• Death receptor (Extrinsic) pathway

• Mitochrondrial (Intrinsic) pathway

• Execution Phase

• Removal of dead cells

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This slide indicates that there are 2 pathways (Intrinsic/Extrinsic) that lead to the execution phase and removal of cells.
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Page 20: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

MITOCHONDRIAL (INTRINSIC) PATHWAY

Cell injury Mitocr.on<!na o Growth lacto,

-Mthdrawal oONA damage

(by radiation. toUls, froo radtcals)

o P'oI~~~::~~ ,

Cytoc hrome c and olh&r

JIIO-apoptoltc proIains

" Inilialo< caspaS<lS

DEATH RECEPTOR (EXTRINSIC) PATHWAY

Receptor-li gand interactions o Fas o TNF '908ptOf

\ caspas ... ,_ ..... .J caspases

_ _ _ A,--~'.

~ndoo\ldOOS<l Br8akdown 01 activation cytosk8letoo

lig ands 10, phagocytic c81 ' 9C8p1orS

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I think this slide is pretty self explanatory. Any important points are brought up again.
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Page 21: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Mechanisms of Apoptosis

• Cells contain intrinsic death and survival

signals that are genetically regulated.

• Genes are highly conserved across

species and are homologous to ced (cell

death abnormal) genes in nematodes that

initiate or inhibit apoptosis.

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Page 22: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Intrinsic -Mitochrondrial pathway

• Increased mitochondrial permeability with release of pro-apoptotic molecules into the cytoplasm (cytochrome c).

• Synthesis of anti-apoptotic molecules (Bcl-2) promoted by Growth factors.

• When cells are deprived of growth factors or subjected to stress anti-apoptotic molecules (Bcl-2) are lost.

• Bcl-2 is over expressed in most follicular B-cell lymphomas – allowing abnormal cells to proliferate.

• Mitochondrial membrane becomes permeable and proteins that activate caspase leak out.

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Clinical significance.
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For more detailed information, check out the Molecule and Cells Apoptosis lecture.
Page 23: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

• Intrinsic

(Mitochondrial)

Pathway of

Apoptosis

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Normal Cell
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Don't memorize details unless you plan on getting a PhD.
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Hi MSTPs!!
Page 24: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Essence of intrinsic

(mitochondrial) pathway

• Pro-apoptotic and protective molecules that

regulate mitochondrial permeability and the

release of death molecules sequestered in

the mitochrondria are maintained in balance

normally.

• Imbalance initiates the death pathway.

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Page 25: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Extrinsic (Death receptor

initiated) pathway

• Death receptors are members of the tumor

necrosis factor receptor family and a

related protein called Fas (CD95).

• These molecules contain a death domain.

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Page 26: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

• Extrinsic (Death

Receptor-initiated)

Pathway of

Apoptosis

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Fas Expressed on cell surface linked to Death domain. If activated, apoptosis is initiated.
Page 27: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Execution Phase

• The intrinsic and extrinsic pathways converge to a caspase activation cascade.

• Caspases (cysteine-aspartic-acid-proteases) are conserved across species.

• Synthesized as inactive precursors; activated by proteolytic cleavage.

• Family of at least 12 proteases, a few of which are involved in inflammation, and many of which are involved in apoptosis

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Page 28: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

How Caspases Disassemble a Cell

• Cleave structural proteins leading

to nuclear breakdown.

• Converts cytoplasmic DNase to

active form.

• DNase causes characteristic

internucleosomal cleavage of DNA.

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Page 29: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Removal of Dead Cells

• Dying cells secrete factors the recruit

phagocytes.

• This facilitates prompt clearance before

they undergo secondary necrosis.

• Dead cells disappear without a trace and

do not produce inflammation.

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Page 30: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Which of the following features is

seen in apoptosis but not in

necrosis?

A. Internucleosome cleavage of DNA

B. Inflammation

C. Pyknosis

D. Cytoplasmic hypereosinoplilia

E. Karyolysis

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Thoughts?
Page 31: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Which of the following features is

seen in apoptosis but not in

necrosis?

A. Internucleosome cleavage of DNA

B. Inflammation

C. Pyknosis

D. Cytoplasmic hypereosinoplilia

E. Karyolysis

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Features of Necrosis
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Reflection of cell injury and not death.
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Page 32: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Examples of Apoptosis Lack of growth factor or hormone

• Hormone sensitive cells deprived of hormone.

• Lymphocytes that are not stimulated.

• Neurons deprived of growth factor.

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Remember Brain and Behavior?
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Page 33: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Examples of Apoptosis Specific activation of death receptors

• DNA damage - Tumor suppressor gene p53 accumulates in

damaged cells and arrests the cell cycle. p53 is mutated or absent in some cancers and can not initiate apoptosis in malignant cells.

• Protein misfolding – unfolded protein response and ER stress – Alzheimer, Parkinson and Huntington diseases.

• TNF Receptor family.

• Cytotoxic T lymphocyte

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Page 34: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Apoptosis in Pathologic

Conditions

• Ionizing radiation

• Cytotoxic chemotherapeutic drugs

• Mild thermal injury

• Cell injury in some viral diseases

• Pathologic atrophy after duct obstruction

• Cell death in tumors

• Glucocorticoids induce apoptosis in lymphocytes

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Page 35: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Apotosis Summary

“Programmed cell death” can be activated by moderate stress which has damaged the cell beyond its ability to recover fully or by viral infection.

This has the desirable effect of removing damaged or infected cells.

Selective manipulation of apoptotic pathways may be an important approach for treating cancer in the future.

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Page 36: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

We recognize that cell death has occurred

by morphologic manifestations which are

often influenced by the environment.

Is the distinction between necrosis and

apoptosis absolute?

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NO!!!
Page 37: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Cellular Aging

• Structural and Biochemical Changes with Aging

• Decreased cellular replication

• Telomere shortening causes cell cycle arrest

• Accumulation of Metabolic and Genetic Damage

• Calorie restriction delays aging

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We're done with Apoptosis now. Here are the main points to focus on for cellular aging:
Page 38: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Telomere shortening

Roplicativo senescence

Environmental insults

t-......LJ DNA repair

defeels t....,,;,;,

Free ____ • • radialis damage DNA

Damago to protoins and organelles

l Accumulation of mutat:ons

CELLULAR AGING

Aelivation of Sirtuins

I Caloric rcctrielion

?

Abnormal growth flllctor si;:!nllliing

(e.g .. insulinl1GF)

I Mechanism?

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Well understood
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Not well understood
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Unfortunately "?" is not a sufficient explanation in science.
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Also unfortunately, relatively common in the clinical practice of medicine.
Page 39: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Structural and Biochemical Changes

with Aging

• Oxidative phosphorylation is reduced

• Synthesis of nucleic acids, structural proteins,

enzymes, cell receptors and transcription factors

are reduced

• Decreased capacity for nutrient uptake and repair

of DNA damage

• Cytologic changes

• Accumulation of abnormally folded proteins

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Page 40: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Replicative Senescence

• Cells have a limited capacity for replication.

• Cultured human fibroblasts have limited division

potential.

• Werner’s syndrome is a rare disease characterized

by premature senescence.

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Werner's syndome patients often die as early as age 20, but may look 100.
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Page 41: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

20 ,---------------------------------,

.n 15 o

x -IT

Newborn

W Werner m 10 :;; syndrome => z ---' ---' w U 5

o -t--,------,r-----r- :?---r-----' ;r-----r~ '>-,------1 o 10 20 30 40 50 60 70 80

POPULATION DOUBLING LEVEL

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Oh hey, Robbins.
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Fibroblasts from individuals, # of times they can reproduce.
Page 42: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Replicative Senescence

• With each cell division there is incomplete replication of telomeres.

• Broken telomeres signal cell cycle arrest.

• As cells age, the telomere becomes shorter.

• Telomerase normally adds nucleotides.

• Telomerase is active in germ cells and stem cells but absent in somatic tissue.

• Telomerase may be reactivated in cancers

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Page 43: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD
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Telomerase
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Telomerase activated
Page 44: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Parental strand

Newly synthesized (lagging) strand

5' iii iii i I I i I I i I I i II' 3' TT AGGG TT AGGG TT AG · . · .... . . . . . . AAtccc

3' .. I ! I I I I 5' ! Binding of telomerase

5'-r, T"'-'-' T"'""1'rT' T"'-'-' T"'-"rT' T' ...... 3' TT AGGG TT AGGG TT AG · . . ...... AATCCC AU CCC AAU C

Telomerase Extension of 3' end

by telomerase

5' ~!"' 'I' , '"'T' !' "'!':-:'rT' " "'!':T' !' , ':-:',,' 'I' "'!':T' 'I' ,':-T' !' ...... 3~'~ T TAG~GTT AGGG T T~~~YTT~Y / AAtccc

3' .. I I I I I I 5'

Telomerase A

(D&o_.-... .... .... _ .......... c.o. _____ . lfIItt.l

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Telomerase enzyme
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Page 45: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Genes that influence Aging

• Insulin growth factor receptor.

• Decreased signaling of IGF -1 receptor is the result of

decreased caloric intake or mutations and results in

longer lifespan in C. elegans.

• Evidence suggests that aging is genetically determined.

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Active area of research.
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Some families have more individuals that seem to live longer.
Page 46: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Accumulation of Metabolic and

Genetic Damage

• Reactive oxygen species (lipofuscin).

• Over expression of SOD extends life span in

Drosophila.

• Werner’s syndrome – defective helicase.

• Ataxia telangiectasia – ineffective repair of dsDNA

breaks.

• Damaged organelles accumulate.

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Occurs with aging.
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In older person, more likely to have lipofuscin in cytoplasm
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Page 47: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Which of the following cells has the highest

telomerase activity?

A. Endothelial cells

B. Germ cells

C. Neurons

D. Neutrophils

E. Erythrocytes

Page 48: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Which of the following cells has the highest

telomerase activity?

A. Endothelial cells

B. Germ cells

C. Neurons

D. Neutrophils

E. Erythrocytes

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Don't replicate, remember?
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Don't even have chromatin!
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Page 49: The Cellular Basis of Disease - Duke University · PDF fileThe Cellular Basis of Disease Cell Injury 3 Apoptosis and Necrosis Cellular Aging Christine Hulette MD

Summary

• Necrosis and Apoptosis

• Molecular mechanisms

• Role in health and disease

• Cellular aging

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Don't memorize molecular mechanisms.