Cell Injury and Adaptation 2

1
Cell Injury and Adaptation 2

• Basic Cell Pathology
• Robbins (7th edition), Chapter 1

2
Cell Injury and Adaptation1 2

• Causes of Cell Injury Reversible
  and Irreversible
• Mechanisms of Cell Injury Cell Injury
• General Biochem. Mechanisms. General
  Pathways.
• Ischemic and Hypoxic Injury.
  Mechanisms of Irreversible
• Ischemia/Reperfusion Injury. Injury.
• Free Radical-Induced Cell Injury.
  Morphology of Reversible Cell
• Chemical Injury. Injury and
  Cell Death Necrosis.
• Programmed Cell
  Death
• 2 Apoptosis
• Cellular Adaptation to Injury
• Atrophy.
• Hypertrophy.
• Hyperplasia.
• Metaplasia.
• Subcellular Responses to Injury.
• Intracellular Accumulations.
• Pathologic Calcification.

3
Cellular Adaptation to Injury

• Physiologic adaptation Examples
• More protein to enlarge myocytes after repetitive
  exercise.
• Breast enlargement with induction of lactation by
  pregnancy.
• Pathologic adaptation
• Ideally, changes in a stressed ell
  are to avoid or to overcome injury.
• A protective protein may be increased as
  part of adaptation.
• Chaperone proteins to fix damaged proteins or to
  shunt damaged proteins for elimination in
  lysosomes or proteasomes.
• Collagen (? fibrosis) may be increased
  extracellularly to protect.
• The cell may alter its growth and differentiation
  as a response.
• Atrophy (decrease in cell size). Metaplasia
  (change in cell type).
• Hypertrophy (increase in cell size).
• Hyperplasia (increase in cell number).
• Lesions/cellular death occur when the above ideal
  is not met.

4
Cellular Adaptation to Injury Atrophy

• Atrophy
• Cellular size decrease by loss of cellular
  substance.
• Organ size decreases.
• Atrophic cells still function, but
  perhaps less effectively.
• Causes.
• Loss of neurons in brain degen-
  eration (Alzheimers disease).
• Loss of functional load for muscle (after
  denervation, lack of use).
• Nutritional loss (starvation).
• Endocrine loss ? Distant atrophy.
• New size equilibrium is achieved in a new
  environment (new blood supply or change in
  trophic stimulation).

5
Cellular Adaptation to Injury Atrophy

• Structural components reduced
• Decreased synthesis of components.
• Increased catabolism (lysosomal
  function essentially, autophagy).
• Catabolism remains the usual medical term for
  metabolic breakdown, although the
  concept of autophagy explains the
  process more fully.
• Hormonal influence varies.
• Insulin, thyroid-stimulating hormone.
• Usually cell growth is initiated or promoted.
• Key role of protein degradation
• Less need for structural protein.
• Atrophy is often accompanied by a marked increase
  in autophagic vacuoles (residual material is
  lipofuscin).

6
Atrophy Protein Degradation

• Autophagy ? Atrophy of cell.
• Lysosomal function.
• Catabolism/autophagy Adaptive, protective.
• Nonlysosomal Proteasomes Adaptive,
  protective.
• Targeted protein degradation.
• Chaperone proteins guide specific proteins to
  lysosomes.
• Proteasomes degrade only ubiquitinated proteins.
• Result of catabolism/autophagy
• A minor physiologic change.
• A smaller more efficient cell.
• An atrophic cell surviving stress.
• Undigested material in an
  autophagolysosome is membrane-bound
  residual pigment (lipofuscin).

Peptides Amino acids
Proteasome
Receptor for chaperone complex
Ubiquitin
Wear and tear pigment
Lysosome
7
Cellular Adaptation to Injury Hypertrophy

• Cardiac hypertrophy
• Mechanical triggers (stretch).
• Trophic triggers (a-adrenergic).
• The initial response to epinephrine (adrenaline)
  may suffice without hypertrophy, but continued
  stimulation ? hypertrophy.
• Hypertrophy may not be functionally sufficient if
  the workload remains too high for the
  hypertrophic compensation.
• Continued high burden, past the limit of
  functional adaptation, leads to cardiac failure.
• Myocardial cells show fragmentation and loss of
  contractile myofibrils (actin and myosin).
• Factors limiting hypertrophy and causing
  degeneration may be vascular (myocardial cells
  may be too large for O2 to reach into them),
  mitochondria may not be able to supply enough
  ATP, or biosynthetic machinery may be inadequate
  to keep up the demand on protein synthesis.
• Myocardial (cardiac) failure due to one or more
  of these factors.

8
Cellular Adaptation to Injury Hyperplasia

• Two types of hyperplasia
• Physiologic.
• Polypeptide growth factors from parenchymal and
  nonparenchymal cells.
• Following restoration of homeostasis, growth is
  turned off.
• Important for connective tissue cellular response
  in wound healing.
• Pathologic.
• Growth factors May persist when stress persists
  .

9
Cellular Adaptation to Injury Hyperplasia

• A major difference between hyperplasia and
  neoplasia
• Cessation of hormonal or growth factor
  stimulation results in reversal of the
  hyperplasia the organ reverts to normal.
• Physiologic and benign pathologic states.
• Cancer ensues when an initial hyperplastic
  reaction is no longer controlled and cells
  proliferate unchecked.
• Lose a negative feedback loop.
• Gain a positive mitotic signal.
• Hyperplastic cells are in danger of losing
  control.

10
Cellular Adaptation to Injury Metaplasia

• Reversible change wherein one adult cell type
  (epithelial or mesenchymal) is replaced by
  another adult cell type.
• Cells sensitive to a particular stress are
  replaced by other cell types better able to
  withstand the adverse environment.
• Rugged squamous epithelial cells may survive a
  more hostile environment than fragile columnar
  cells.
• May arise by genetic reprogramming of
  stem/reserve cells.
• Example
• Squamous metaplasia in respiratory
  epithelium in cigarette smokers.
• Normal ciliated columnar epithelial
  cells of trachea and bronchi are at
  least partly replaced by
  stratified squamous epithelial
  cells.
• Vitamin A deficiency may have the same result.

11
Cellular Adaptation to Injury Metaplasia

• The upside of metaplasia
• Survival advantages for the epithelium.
• The downside of metaplasia
• Protective mechanisms are lost.
• Secretion of mucus.
• Clearance of particulate matter (bacteria, dust)
  by ciliary action.
• Persistent influences underlying metaplastic
  transformation may induce malignant
  transformation in the metaplastic epithelium.
• Metaplastic squamous epithelium (of respiratory
  epithelium) can coexist with pulmonary squamous
  cell carcinoma.
• Soft tissue (mesenchymal) metaplasia
• Not always clear that this is an adaptive
  response.
• Typically of bone or cartilage formation at a
  site of injury.
• May also occur in the brain, such as in old
  hemorrhages.

12
Subcellular Responses to Injury

• Some acute, chronic, and ultimately lethal
  injuries can be responded to by distinctive
  alterations of cellular organelles and cytosolic
  proteins.
• Some of the more common such reactions have been
  discussed
• Lysosomal catabolism.
• Membrane bound organelles containing hydrolytic
  enzymes.
• Fuse with autophagic vacuoles.
• This turns the primary lysosome into a
  secondary lysosome, or
  autophagolysosome (or
  phagolysosome).
• Heterophagy (eating other).
• Pinocytosis (drinking), endocytosis, and
  phagocytosis.
• Autophagy (eating self).
• Starvation, remodeling, aging organelles,
  damaged proteins.

13
Subcellular Responses to Injury

• Lysosomes
• May extrude undigested material, or retain
  it for decades as lipofuscin.
• Lipid peroxidation residue.
• Exogenous pigments.
• Inhaled carbon particles.
• Inoculated tattoo pigments.
• Lysosomal storage diseases.
• Enzyme deficiences leave partially
  degraded macromolecules (intermediate
  metabolites) in large intracellular
  collections that cannot be altered
  effectively and eventually the abnormal
  intermediates become lethal
  (apoptosis is signaled).

14
Subcellular Responses to Injury

• Induction (hypertrophy) of smooth endoplasmic
  reticulum (SER)
• In, for instance, adaptation to alcohol or to a
  medication.
• Commonly cited instance is the induction of
  increased volume (hypertrophy) of hepatocyte SER
  in response to a toxin.
• P-450 mixed-function oxidase system in hepatocyte
  SER alters endogenous and exogenous compounds to
  increase their solubility and thereby facilitate
  their excretion in urine.
• Steroids, alcohol, various hydrocarbons and
  insecticides.
• The activity produces more enzyme systems and
  more SER.
• This, unfortunately, does not always detoxify,
  since some compounds are rendered more toxic
  (e.g., CCl4 ? CCl3).
• Increased enzyme systems in the SER can
  secondarily act on other compounds Increased
  alcohol intake (? ? P-450) allows faster action
  to break down phenobarbital, which makes this
  antiseizure medication less effective at
  therapeutic levels.

15
Subcellular Responses to Injury

• Chaperone proteins (heat shock proteins)
• Intracellular housekeeping.
• Protein folding to attain normal, functional
  tertiary structure.
• Transport of proteins to organelles, such as to
  mitochondria and lysosomes, and to proteasome
  enzyme complexes.
• Disaggregation of protein-protein complexes.
• May be increased after cellular stress to deal
  with protein aggregation and denaturation.

16
Subcellular Responses to Injury

• Chaperone proteins (Older term Heat shock
  proteins)
• Injury responses.
• Refolding denatured protein to restore function.
• Denatured proteins accumulate, sometimes
  being so abnormal that they cannot
  enter proteasomes ? signal for
  apoptosis.
• Ubiquinated proteins ? proteasomes.
• Non-ubiquinated proteins ? lysosomes.

5
1 Functional 2 Stress/injury 3 Protein
needing repair 4a Successful repair 4b
Unsuccessful
1 Functional 2 Stress/injury 3 Protein
needing repair 4a Successful repair 4b
Unsuccessful 5 Mutated or very damaged
cannot enter proteasome
17
Subcellular Responses to Injury
Mutation

• Lack protein uptake
• ? Aggregation ? Apoptosis.
• Too damaged for entry into a proteasome steric
  hindrance.
• No effective membrane receptor on a lysosome.
• Receptor mutation or other damage.

18
IntracellularAccumulations

• General mechanisms
• Abnormal metabolism.
• Hepatic fatty change.
• Mutations.
• Alterations in protein folding and transport.
• Deficiency of a critical enzyme.
• Toxic metabolic intermediates accumulate.
• Inability to degrade phagocytosed particles.
• Inhaled carbon or silica particles.
• Inoculated tattoo pigment.

Intracellular
Exogenous
19
Intracellular Accumulations

• Types
• Fatty change (steatosis).
• Triglycerides accumulate in a parenchymal cell.
• Metabolic, reversible injury.
• Often liver also, heart, kidney.
• Toxins, mostly as alcoholic fatty liver in
  industrialized countries.
• Protein malnutrition.
• Diabetes mellitus.
• Obesity.
• Anoxia.

20
Intracellular Accumulations

• Fatty liver (mechanisms)
• Defects in any of 6 steps at right.
• Uptake (more to deal with).
• Catabolism (breakdown problem).
• Secretion (decreased).
• Free fatty acids (from food or from
• Converted into
• Cholesterol or phospholipids.
• Oxidized to ketone bodies.
• Esterified to triglycerides.
• Formed into lipoprotein by complexing with
  apoprotein.
• Secreted (or not), as one or more of these.
• Panel B Nuclei pushed aside by accumulated
  large droplets of lipid.

A. B.
21
Intracellular Accumulations

• Types
• Protein accumulation is generally not
  easily visible.
• Microscopic droplets of protein can
  accumulate in damaged kidneys.
• Albumin is normally filtered out of blood
  into renal tubules, and then into
  the tubule epithelial cells in
  trace amounts, some escaping into the
  urine (dashed arrow).
• Increased albumin leakage into tubule lumen in
  renal disease excess is reabsorbed by
  pinocytosis (small solid arrow).
• The accumulated pinocytotic vesicles fuse with
  lysosomes to form hyaline droplets in the
  cytoplasm (large arrows).
• Potentially reversible process, as long as the
  lesion causing proteinemia/proteinuria abates.
• Hyaline droplets are metabolized (catabolized)
  and disappear.

22
Intracellular Accumulations

• Types
• Protein accumulation.
• Alcoholic hyaline.
• Mallory bodies in alcoholic
  liver disease.
• Inclusions in liver cell (black arrow).
• Formed of prekeratin intermediate
  filaments.
• Fat droplets () also present.
• Neurofibrillary tangles (NFT) Aging,
  Alzheimers disease (below).
• Neuronal cytoskeleton disruption.
• Any large protein accumulation in
  a cell may
• Disrupt necessary housekeeping and
  work functions
  (neurotransmission).
• Signal apoptosis.

23
Intracellular Accumulations

• Types
• Glycogen.
• Metabolic diseases involving glucose or
  glycogen.
• Diabetes mellitus.
• Glycogen accumulation in renal tubular
  epithelial cells, myocardial
  cells, b cells of the islets of Langerhans.
• Glycogen storage diseases (glycogenoses).
• Enzyme defects (mutations).
• Synthesis of glycogen (intermediates forms
  of
• filamentous carbohydrates accumulate).
• Breakdown of glycogen.
• Lysosomal or non membrane-bound glycogen.
• Secondary cellular injury ? Cell death.

24
Intracellular Accumulations

• Types
• Pigments.
• Endogenous.
• Exogenous.
• Carbon is the most common pigment.
• Air pollutant (urban).
• Inhaled, phagocytosed by alveolar macrophages
  deep in the lungs.
• Transported by lymphatics to regional
  tracheobronchial lymph nodes.
• Grossly blackens lymph nodes and lung parenchyma
  (anthracosis).
• When the accumulation is heavy, it may lead to
  emphysema or a serious fibrotic lung disease
  (e.g., coal workers pneumoconiosis).

25
Intracellular Accumulations

• Hemosiderin
• Hemosiderosis Systemic overload of iron.
• First iron deposits in phagocytes/macrophages.
• Eventually, parenchymal cells accumulate iron.
• Generally hemosiderosis does not damage
  parenchymal cells. Found in these conditions
• Increased dietary iron.
• Impaired utilization of iron.
• Hemolytic anemias (excessive breakdown of red
  blood cells).
• Blood transfusions (the new heme iron on board is
  then a new load of exogenous pigment).
• Hemochromatosis.
• A chronic iron-overload disease (not just a
  temporary excess).
• Severe fibrosis (as a reaction to the iron think
  of it as rust in the patients organs) in liver,
  heart and pancreas, and other organs.
• Liver compromise, heart failure, diabetes
  mellitus (iron in the islets).

26
Pathologic Calcification

• Abnormal deposition of Ca2 salts
• Calcium may have an affinity for membrane
  lipids.
• Other minerals are part of the salts,
  such as iron.
• Dystrophic calcification.
• In dead or dying tissue.
• Normal serum level of Ca2.
• No Ca2 dysmetabolism.
• In most atherosclerotic plaques as
  they age.
• Can cause organ dysfunction.
• Calcification of areas of heart valves
  prevent proper opening during
  systole or closing during diastole.

27
Pathologic Calcification

• Abnormal deposition of calcium salts
• Metastatic calcification.
• Can occur in normal tissue when serum level of
  calcium is increased (hypercalcemia).
• Major causes of hypercalcemia
• Increased secretion of parathyroid hormone.
• Parathyroid tumor that secretes the hormone.
• Other malignant tumors that can secrete the
  hormone.
• Destruction of bone.
• Accelerated turnover (e.g., Paget disease).
• Immobilization Little or no movement ? Bone
  loss.
• Tumors, primary or secondary, with bone
  destruction.
• Vitamin D-related disorders.
• Excessive vitamin D intake.
• Renal failure.
• Phosphate retention ? Secondary
  hyperparathyroidism.

28
Reversible and Irreversible Cell Injury

• Persistent or excessive injury ? At some point,
  there is a threshold to an irreversible injury.
• Early injury often involves the most vulnerable
  cell systems.
• Membrane damage.
• Mitochondrial swelling (less ATP produced).
• Extracellular Ca2 enters cell, intracellular
  Ca2 released.
• Ca2-activated enzymes catabolize cellular
  contents.
• Lysosomal rupture and autolysis.

29
Reversible and Irreversible Cell Injury

• Irreversible injury (continued)
• Leaked enzymes can also mark the cell type
  damaged as reflected by the elevated serum level
  of the somewhat cell-specific isoenzymes.
• Liver function tests.
• Cardiac panel.

30
Reversible and Irreversible Cell Injury

• Mechanisms of irreversible injury
• Characteristics of irreversible injury.
• Permanent mitochondrial dysfunction, even if the
  insult ceases.
• Profound membrane disturbances.
• Major problems
• Phospholipid loss.
• Cytoskeletal changes.
• Toxic oxygen radicals.
• Lipid breakdown products.
• Membrane damage may be a central
  factor in cell death.

31
Morphology of Reversible Injury and Death

• Functional changes typically precede morphologic
  changes
• Necrosis
• Coagulative necrosis.
• Cellular swelling.
• Protein denaturation.
• Organellar breakdown.
• Result of two concurrent processes in the cell.
• Primarily protein denaturation.
• Variable enzymatic digestion of the cell.
• Liquefactive necrosis.
• Primarily enzymatic digestion.

32
Morphologic Appearance of Necrosis

• Classic patterns of necrosis
• Terms that are routinely used by clinicians and
  pathologists.
• Primarily protein denaturation Coagulative
  necrosis.
• Basic structural outline of cells and
  vessels can still be seen.
• Presumably, even the hydrolytic enzymes
  have degenerated, and cannot further
  degrade the structures by themselves.
• Until scavenger white blood cells
  infiltrate, heart (and rarely brain) will
  not be degraded further for days or weeks.
• Characteristic process of ischemic
  cell death.
• (A), Renal infarct with coagulative
  necrosis.
• (B), Renal liquefactive necrosis (fungal
  infection).

33
Morphologic Appearance of Necrosis

• Classic patterns of necrosis
• Primarily enzymatic digestion Liquefactive
  necrosis.
• Characteristic of bacterial and of some fungal
  infections.
• Brain usually undergoes liquefactive necrosis,
  perhaps due to the ability of brain to signal
  apoptotic cell death with membrane changes that
  do not invite inflammation (see later).
• Macrophages are invited in, but not acute
  inflammatory cells.
• Presumably, this protects the brain from
  overdigestion.

34
Morphologic Appearance of Necrosis

• Other classic patterns/subpatterns of necrosis
• Gangrenous necrosis.
• A term used mostly in surgical practice.
• Refers to ischemic coagulative necrosis
  (frequently of a limb).
• When an infection with tissue edema is
  superimposed in the liquefying area, the process
  is called wet gangrene.
• Caseous necrosis.
• Distinctive, usually seen in tuberculosis, but it
  is actually a combination of coagulative and
  liquefactive necrosis.
• Necrosis, not well liquefied (if at all
  significantly liquefied), but without
  cellular outlines, surrounded by
  granulomatous inflammation (lymphocytes,
  multinucleated giant cells, and large
  macrophages called epithelioid cells from
  which the giant cells arise).
• Lung with tuberculosis, showing caseous
  (cheesy-appearing) necrosis.

35
Morphologic Appearance of Necrosis

• Other classic patterns/subpatterns of necrosis
• Fat necrosis.
• Common term for any necrosis in fat, but
  not a separate type.
• Foci of necrosis in adipose tissue, or often
  in pancreas, with breakdown of fat cell
  membranes and hydrolysis of the cell
  content of triglycerides.
• Resultant fatty acids combine with calcium
  (saponification, or formation of calcium soaps)
  to produce chalky white areas visible grossly.
• Most necrotic cells and their debris disappear by
  a combination of enzymatic digestion and
  leukocyte phagocytosis some may remain and
  become calcified (dystrophic calcification)

36
Programmed Cell Death Apoptosis

• Some mechanisms of necrosis and apoptosis are
  similar
• Necrosis might be thought of as homicide
  apoptosis, as suicide
• Apoptosis
• Root word of apoptosis means a falling away
  from.
• Programmed cell destruction in embryogenesis.
• Hormone-dependent physiologic involution.
• Cell deletion in proliferating populations
  (including tumors).
• T-lymphocyte autodeletion.
• Reaction to injurious stimuli.
• Heat.
• Radiation.
• Chemotherapeutic drugs (mostly
  cancer drugs).

37
Programmed Cell Death Apoptosis

• Mechanisms
• Signaling.
• Control and integration.
• While some membrane and cytoplasmic molecules
  provide signals that promote apoptosis, other
  signals inhibit apoptosis (survival signals),
  most notably BCL-2.

• Variety of signals to promote apoptosis, mostly
  external.
• Intrinsic (as in development).
• Lack of growth factor.
• Receptor-ligand interactions.
• Tumor necrosis factor (TNF) family of
  plasma membrane receptors is a major
  initiator of death signals.
• Toxin from cytotoxic T cells.
• Radiation, heat, chemicals.

38
Programmed Cell Death Apoptosis

• Mechanisms
• c
• Control and integration.
• Specific proteins connect the original death
  signals to the final execution program.
• Result is commitment or abortion of potentially
  lethal signals.
• Two pathways.
• Adapter proteins.
• Mitochondrial permeability.
• Ca2 and free radicals can
  affect mitochondria
  (mitochondrial permeability
  transitions).

Mechanisms
39
Programmed Cell Death Apoptosis

• Mechanisms
• c
• Control and integration.

Mechanisms
BCL-2
X
40
Programmed Cell Death Apoptosis

• Mechanisms
• .
• Control and integration.
• Adapter proteins execute the message through
  caspases.
• Mitochondrial BCL-2 may inhibit and other
  proteins may promote pore formation in
  mitochondria (reduces their membrane potential).
• Promotion leads to less ATP production
  with mitochondrial swelling.
• Outer mito. membrane permeability
  releases cytochome c into cytosol.
• This signals apoptosis, through
  intermediate proteins, via
  caspases.
• Caspases, when activated, begin proteolytic
  events that kill the cell.

Cytochome c
Caspases
41
Programmed Cell Death Apoptosis

• Mechanism
• .
• .
• Execution.
• Distinctive constellation of biochemical events
  resulting from activity of catabolic enzymes in
  the cytosol.
• Protein cleavage by caspases, a result of any
  loss of control over their activity (they must be
  tightly controlled).
• Endonuclease activation fragments DNA in 180
  200 base pair fragments (by cleaving at
  nucleosomes).
• Cytoskeletal components cleaved.
• Proteins are cross- linked by
  transglut- aminase fragment with
  organelles into apoptotic bodies.

Mechanisms
42
Programmed Cell Death Apoptosis

• DNA breakdown
• At nucleosomes, giving 180 200 base pair
  fragments, by action of Ca2- and Mg2-dependent
  endonucleases.
• Ladders of DNA fragments of discrete size give
  a distinctive pattern on gels (B, Lane b).
• This laddering pattern is not specific for
  apoptosis, but necrosis usually gives a more
  random pattern of fragmentation, if any pattern
  (B, Lane c).

43
Programmed Cell Death Apoptosis

• Mechanism
• .
• .
• .
• Removal of dead cells.
• Apoptotic bodies have plasma membrane surface
  markers signaling phagocytes or even adjacent
  parencymal cells to engulf them.
• A flip of inner plasma membrane
  phosphatidylserine to the outer surface is a
  sufficient signal to attract other cells for
  phago- cytosis, without
  the harmful secondary
  effects of inflammation.

Mechanisms
This tissue space has been vacated!
44
Programmed Cell Death Apoptosis
45
Cellular Aging

• Perhaps a progressive accumulation of sublethal
  injury
• Cellular compromise, at least with diminished
  function.
• Results in a diminished capacity to respond to
  injury.
• May lead to cell death.
• Reduction of
• Oxidative phosphorylation.
• Synthetic activity.
• Structural molecules.
• Enzymes.
• Receptor proteins.
• Nutrient uptake.
• Chromosomal repair.
• Morphologic changes
• Nuclei, mitochondria, endoplasmic reticulum,
  Golgi apparatus.
• Perhaps based on sublethal injuries and
  diminished repair.

Everything important in the cell!

46
Cellular Aging

• Cellular accumulation with age
• Lipofuscin pigment (past oxidative damage,
  membrane injury).
• Abnormally folded proteins (that at some point
  could be fatal).
• Advanced glycosylation end products (cross-link
  proteins).
• Cellular senescence is multifactorial
• Extrinsic stressors (wear-and-tear theories).
• Ability to repair DNA and cytoplasmic damage.
• Free radical damage, including post-translational
  modification of proteins.
• Other post-translational modifications.
• Intrinsic cellular aging theories.
• Predetermined genetic programming.
• Telomere shortening.
• Clock genes (intrinsic molecular clock).

47
Cellular Aging

• Ability of aging cells to repair damage
• Wear-and-tear theories.
• Robust repair mechanisms (protein refolding, DNA
  repair) seem to be overcome, eventually, by
  long-term adverse exogenous factors.
• Efficient DNA repair mechanisms, yet errors may
  occur with age.
• Error rate increases with senescence (possible
  causality).
• Helicase, a DNA-unwinding protein active in
  replication and repair, is defective in Werner
  syndrome, a cause of progeria.
• Ataxia telangiectasia is another disease with
  accelerated aging and DNA repair defects.
• Free radical damage.
• Ionizing radiation (suntans, etc. life-long
  accumulation).
• Decline of antioxidant mechanisms (glutathione
  peroxidase).
• Lipofuscin may itself be toxic, and not just a
  sign of toxicity.
• Lower caloric intake ? ? Oxidative damage ? ?
  Life span.

48
Cellular Aging

• Mechanisms of restricted cellular division
• Incomplete replication of chromosomal ends
  (telomere shortening).
• As chromosomes replicate, they shorten slightly.
• This would cause genes at chromosomal ends to be
  lost.
• Telomeres are short, repeated sequences of
  nontranscribed DNA (TTAGGG) that on chromosomal
  ends, rather than real genes.
• These are the units that are lost with
  replication, protecting functional DNA (at least
  in the short run).
• Lost with replication because the end telomere
  is not replicated with each somatic cell
  division.
• Possibly, when most telomeres are gone,
  senescence is signaled.
• Germ cells and stem cells contain telomerase that
  allows faithful replication of all of the
  telomeres.
• Cancer cells contain telomerase, possibly
  immortalizing them.

Telo- meres
with each mitosis
49
Cellular Aging

• Mechanisms of restricted cellular division
• Graph shows telomere-telomerase hypothesis and
  proliferative capacity.
• Normal (somatic) cells
• No telomerase activity.
• Telomeres shorten with each division.
• Growth arrest or
• Senescence.
• Germ cells have adequate amounts of
  telomerase.
• Stem cell telomerase level is lower, and
  eventually insufficient.
• Cancer cells activate telomerase to turn off the
  telomeric clock and they become immortal.

50
Cellular Aging

• Mechanisms of restricted cellular division
• Clock genes.
• Genetic timers may control the tempo of aging.
• Supported mostly by data in worms and other
  objects of scientific study that have given us
  much information on cellular injury.
• A specfic nematode gene (clk-1), when mutated,
  leads to a decreased rate of development and to a
  shortened life span.
• Do mammals have such genes?

51
Cellular Injury,Adaptation,and Death
( . . . . to be continued for the rest of your
life.)