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MCB 135K Review
Midterm – II
March 30, 2005
Jason Lowry
Outline
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8.
Aging of the Nervous System
Brain Disorders
Imaging of the Brain
Aging of the Visual System
Aging of the Cardiovascular System
Exercise and Aging
Aging of Muscles
Immune System
Aging of the Nervous System
•
Structural Changes
1. Changes in Brain
Weight
2. Neurons vs. Glial
Cells
3. Denudation
4. Neuropathological
Markers
•
Biochemical
Changes
1. Neurotransmitters
2. CNS Synapses
3. Neurotransmitter
Imbalance and Brain
Disorders
•
Brain Plasticity
1. CNS Regenerative
Potential
Changes in Brain Weight
Structural brain changes with aging
changes in brain volume
OTHER
BRAIN REGIONS
FRONTAL
young
old
Neurons vs. Glial Cells
• Neurons
–
–
–
–
Cell Body
Axons
Dendrites
Synapses
• Glial Cells
– Astrocytes
– Oligodendrocytes
– Microglial
Denudation
• Normal Aging
– A, B, C
– Small amounts of
neuronal loss
– Increased dendritic
growth
• Degenerative Disease
– D,E,F,G
– Progressive loss of
dendritic spines
– Eventual Cell Death
Neuropathologies
• Lipofuscin
– By-product of cellular autophagia
– Linear increase with normal aging
– Function in disease unkown
• Lewy Bodies
– Present in normal aging (60+)
– Increased accumulation in Parkinson’s Disease
• Neurofibrillary Tangles
– Tangled masses of fibrous elements
– Present in normal aging in hippocampus
– Accumulation in cortex is sign of Alzheimer’s
• Paired Helical Filaments
– Role in Neurofibrillary tangle formation
Neurons that may proliferate into
adulthood include:
• Progenitor “precursor” neurons lining the
cerebral ventricules
• Neurons in the hippocampus
• Neurons usually “dormant” with potential for
neuron and glia proliferation
• Astrocytes and oligodentrocytes with the ability
to perpetually self renew and produce the three
types of neural cells
Regenerative potential depends on changes in
whole body and neural microenvironment
• Whole body changes:
–
–
–
–
–
–
Physical exercise
Appropriate nutrition
Good circulation
Education
Stress
others
•Neural microenvironment
changes:
–Brain metabolism (oxygen
consumption, free radicals,
circulatory changes)
–Hormonal changes
(estrogens, growth factors,
others)
–others
Neural Cells
Common ectodermic derivation of neurons and neuroglia
Neural Epithelium
Neuroblast
Neuron
Spongioblast
Migratory Spongioblast
Oligodendrocyte
Astrocyte
• Astrocytes:
– Star shaped cells
– Support neurons metabolically
– Assist in neuronal transmission
• Oligodendrocytes: myelinate neurons
Astrocyte
Ependyma
Tsonis, P.A., Stem Cells from Differentiated Cells, Mol. Interven.,4, 81-83, 2004
• From newt amputated limb,
terminally differentiated cells
de-differentiate by losing their
original characteristics. This dedifferentiation produces blastema
cells that then re-differentiate to
reconstitute the lost limb.
• After lentectomy de-differentiated
cells lose pigment and regenerate a
perfect lens.
• De-differentiated myotubes
produce mesenchymal progenitor
cells that are able to differentiate in
adipocytes and osteoblasts.
Also refer to: Brawley, C. and Matunis, E., Regeneration of male germ
line stem cells by spermatogonial de-differentiation in vivo. Science 304,
1331-1334. 2004
Brain Disorders
•
Parkinson’s Disease
1. Pathologies
2. Symptoms
3. Treatment Strategies
•
Alzheimer’s Disease
1.
2.
3.
4.
Symptoms and Signs
Disease Progression
Pathophysiology
Treatment /
Management
Parkinson’s Disease
• Loss of
neuromelanin
containing neurons
in brain stem and
presence of Lewy
bodies in
degenerating
dopaminergic cells
Parkinson’s Disease
• Symptoms
– Loss of motor function
– Loss of balance
– Speech and Gait
abnormalities
– Tremor
– Rigidity
• Treatment Strategies
– Pharmacological
• Ldopa
– Neuroprotective
– Surgical
– Cell Therapies
Alzheimer’s Disease
•
•
•
•
Onset usually after 60
Increase Risk with aging
Greater risk in women then men
There are 3 consistent neuropathological
hallmarks:
• Amyloid-rich senile plaques
• Neurofibrillary tangles
• Neuronal degeneration
– These changes eventually lead to clinical
symptoms, but they begin years before the onset of
symptoms
TREATMENT &
MANAGEMENT
• Primary goals: to enhance quality of life &
maximize functional performance by
improving cognition, mood, and behavior
• Nonpharmacologic
• Pharmacologic
– Acetylcholine esterase inhibitors
• Specific symptom management
• Resources
Imaging of the Brain
• Types of
Neuroimaging
• Neuronal Recruitment
and Reaction Time
YOUNG
UNDER
RECRUITMENT
YOUNG
OLD
ELDERLY
NON-SELECTIVE
RECRUITMENT
OVER
RECRUITMENT
Aging of the Visual System
Aging of the Visual System
• Structural Changes (See handout)
– Tear Film:
• Dry eyes or tearing
– Sclera:
• Fat deposits – yellowing
• Thinning – blueing
– Cornea
• Diameter does not change after age 1
• Shape changes
– Retina
• Photoreceptor density decreases; other layers become
disordered
• Illuminance decreases with age
– Lens
• Increased size and thickness
• Becomes more yellow
Aging of the Visual System
• Function
– Corneal and Lens
•
•
•
•
•
•
Decreased accommodation power
Increased accommodation reflex latency
Refractive error becomes more hyperopic with age
Corneal sensitivity decreases
Scatter increases
Lens fluorescence increases with age
– Retinal
•
•
•
•
•
•
•
Decreased critical flicker frequency
Visual acuity declines
Visual Field decreases
Color vision changes
Darkness adaptation is slowed
Increased glare problems
Decreased light reaches retina
Aging of the Visual System
• Recommendation to Accommodate Problems:
–
–
–
–
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–
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Wear appropriate optical correction
Increase ambient light
Make lighting even and reduce glare
Improve contrast in critical areas
Avoid rapid changes in light level
Avoid Pastel
Allow more time
Aging of Cardiovascular System
• Atherosclerosis
–
–
–
–
–
–
Characteristics
Disease Results
Arterial Changes
Atherogenesis
Contributing Factors
Age Changes in
Vascular Endothelium
Atherosclerosis
• Characteristics
–
–
–
–
Universal
Progressive
Deleterious
Irreversible …but (?)
Atherosclerosis
• Disease Manifestation
–
–
–
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Myocardial Infarct
Stroke
Aneurysm
Gangrene
Arterial Changes
• Morphological Characteristics of the Arterial Wall
– Intima – inner most layer of endothelial cells
– Media
•
•
•
•
Elastica interna – formed by elastin fibers
Smooth Muscle cells
Vasa vasorum (penetrates media)
Elastica externa
– Adventitia – outer most layer of collagen bundles
• Vasa vasorum – provide blood
• Read Pages 287-289
Atherogenesis
• Fatty Streak (Intima)
– Increased LDL and oxidized
LDL
– Accumulation of LDL in
endothelial space
– Alter and breakdown of
Elastic fiber
– Alerts immune system
– Monocytes  macrophages
– Phagocytose LDL and
elastic fibers
– Macrophages become full of
LDL and appear as foam
cells after staining
Atherogenesis
• Fibrous Plaque (Intima
and Media)
– Damaged smooth
muscle cells take up
LDL
– Increase foam cells
– Defense mechanism
create scar tissue
– Problem for metabolic
exchange later
Atherogenesis
• Atheroma
– Alteration of
endothelial cells
– Decreased number of
cell
– Platelets seal off area
where there was a loss
of cells
• Increased growth factors
• Increased RBC
• Results in thrombus
Aging of Cardiovascular System
• Atherosclerosis
– Theories
• Coronary Heart
Disease
– Risk Factors
– Risk Assessment
– Treatment
Lipids and Apolipoproteins
•
•
•
•
•
•
Major Categories
Risk Factors in Atherosclerosis
Lipoprotein Synthesis
Apolipoproteins
Lipolytic Enzymes
Receptors
Lipids and Apolipoproteins
• Categories
– Chylomicrons and VLDL
• High triglycerides
– IDL and LDL
• High cholesterol
– HDL
• High proteins
• High phospholipids
Lipids and Apolipoproteins
• Risk Factors for Heart Disease
–
–
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Total cholesterol to HDL ratio above 4.0
Family history
Elevated LDL; Low HDL
Diabetes Mellitus
Age
Hypertension
Obesity
Smoking
Lipoprotein Synthesis
• Intestine
– CM
– Nascent HDL
• Liver
–
–
–
–
VLDL
IDL
LDL
Nascent HDL
Apolipoproteins
• Definition:
– Markers on lipid cell surface that determines metabolic
fate of lipids
• Roles in Metabolism
– apoA-I
• HDL
• Reverse Cholesterol Transport
– apoB-100
•
•
•
•
VLDL, IDL, LDL
Sole protein on LDL
Necessary for assembly and secretion in liver
Ligand for LDL receptor
Apolipoproteins and RCT
• apoA-I is important in reverse cholesterol
transport (review figure 17.3)
– Process whereby lipid free apoA-I and subclasses of
HDL mediate the removal of excess cholesterol
Enzymes
• Lipoprotein Lipase
– Catabolizes CM and VLDL produces glycerol and
fatty acids
– Requires apoC-II for activation
• Hepatic Triglyceride
• LCAT
– Essential for normal maturation of HDL
– Associates with discoidal HDL and is activated by
apoA-I
– Forms hydrophobic cholesteryl ester that moves to core
and gives spheroid shape (active)
Receptors
• LDL
– Responsible for internalization of LDL
– Also known as apoB-E receptor
– Regulates cholesterol synthesis
• Macrophage Scavenger (SR-A1)
– Recognizes oxidized LDL
– Role in atherogenesis
• SR-B1
– Docking protein for HDL
– Role in selective uptake for steroid hormone production
– Role in catabolism and excretion from liver
Exercise and Aging
•
•
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•
•
•
Cardiovascular Fitness
Metabolic Fitness
Muscular Strength
Anti-oxidant defenses
Freedom from Injury
Sense of Well Being
Exercise and Aging
• Cardiovascular Fitness
– Maximal oxygen consumption
– VO2 Max increased by regular exercise
• Declines with aging
– Decreases morbidity
– Decreases mortality
Exercise and Aging
• Metabolic Fitness
–
–
–
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Control age related increases in body fat
Decrease risk of diabetes
Maintain Ideal BMI
Exercise at 45-50% of VO2 Max to facilitate fat
loss (utilize fat as energy source)
Aging of Muscles
• Sarcopenia
– Age associated loss of muscle mass
– Most significant contributing factor in the
decline of muscle strength with age
– Lean body mass decreases between 35 and
75
• 45% muscle mass  15% muscle mass
Aging of Muscles
• Etiology of Sarcopenia
–
–
–
–
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Decrease in mitochondrial mass
Reduced protein synthesis
PNS and CNS changes
Hormonal changes
State of inactivity (most prominent)
Muscle Fibers and Aging
• Type I – slow fibers
• Type II – fast fibers
– Type II decrease much more with aging than
Type I
– Explains why older people can have increased
stamina at slow pace activities (hiking)
• Bed rest results in 1.5% loss per day and 2
weeks to recover for 1 day bed rest
MYOPLASTICITY
May occur with different clinical effects,
namely:
-muscles enlarge with resistance type of exercise
-increase their contractility (and the number of
mitochondria) with endurance type of exercises
-all these changes are due to stimulations and variations in
the characteristics of the MYOSINS (protein isoforms)
CLINICAL significance of Myoplasticity:
RESISTANCE training: increases amount of contractile
proteins permitting increasing efforts.
As a consequence, muscles do ENLARGE (a decrease in Ca++
concentration is needed to elicit 50% of maximal tension).
ENDURANCE training: increases the velocity of contraction,
increases the number of mitochondria, and increases the capacity to
oxidize substrate
•Increase the Vmax (velocity of contraction) of the SO (slow) fibers
•Decreases the Vmax of the FO (fast) fibers
•Vmax = velocity of shortening of a fiber
The Aging Heart
• Heart ages well in absence of disease
• Age associated changes
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–
–
–
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Heart rate decreases
No change in stroke volume
Contractility decrease with exercise
No change in ejection fraction
Heart rate – to max rate of increase with exercise “220age”
– Blood pressure increases due to increased peripheral
vascular resistance
Physiological Changes with Age
Parameter
VO2 Max (mL x kg x min)
Maximum Heart Rate
20 years
39
194
60 years
29
162
Resting Heart Rate
Max. Cardiac Output (L x min)
EJECTION FRACTION
63
22
70-80%
62
16
50-55%
Resting BP
Total Lung Capacity (L)
120/80
6.7
130/80
6.5
Vital Capacity (L)
5.1
4.4
Residual Lung Volume (L)
1.5
2.0
Body Fat %
20.1
22.3
Heart Failure:
Cardiac Output (CO) insufficient to meet physiologic demands
In the elderly, heart failure due to:
• Mostly systemic arterial hypertension
• Coronary artery & valvular diseases (due
to impaired cardiac filling & chronic
volume overload)
• Combined right & left cardiac failure
most common, but isolated occurrence of
left or right also probable
Cardiomyopathy: Any heart muscle disorder not
caused by coronary artery disease, hypertension or
congenital valvular or pericardial diseases.
Prevalence of heart failure:
25-54 yrs: 1%
55-65 yrs: 3%
65-74 yrs: 4.5%
+75 yrs: 10%
• > 75% of patients with heart failure +60 years of age
•Primary reason is Coronary Heart Disease (CHD)
•Secondary reason is Hypertension
•Third reason is cardiomyopathy
Contributory Causes to Heart Failure in the Elderly
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•
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•
•
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•
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Hypertension (poor elasticity of arterial system)
Alcohol, but only if in excess
Viral infections
Autoimmunity
Heredity (specially for the cardiomyopathies)
Senile amyloid
Diabetes (due to the microvascular disease)
Arrhythmias and especially the TACHYCARDIAS
Evidence for Decline in Immune Function with Aging
Aged Individuals have:
1) Increased incidence of INFECTIONS:
For example: pneumonia, influenza, tuberculosis,
meningitis, urinary tract infections
2) Increased incidence of AUTOIMMUNE DISEASE:
For example: rheumatoid arthritis, lupus, hepatitis,
thyroiditis (graves-hyper/hashimotos-hypo), multiple
sclerosis
(Predisposition toward these diseases is related to Human
Leukocyte Antigens HLA genes)
Evidence for Decline in Immune Function with Aging
Aged Individuals have:
3) Increased CANCER INCIDENCE:
For Example: prostate, breast, lung, throat/neck/head,
stomach/colon/bladder, skin, leukemia, pancreatic
4) TOLERANCE to organ transplants:
Kidneys, skin, bone marrow, heart (valves), liver,
pancreas, lungs
Cell Types
1. Lymphocytes: derived in bone marrow from stem
cells 10^12
A) T cells: stored & mature in thymus-migrate
throughout the body
-Killer Cells
Perform lysis (infected cells)
Cell mediated immune response
-Helper Cells
Enhance T killer or B cell activity
-Supressor Cells
Reduce/suppress immune activity
May help prevent auto immune disease
Lymphocytes (cont.)
B) B-Cells: stored and mature in spleen
• secrete highly specific Ab to bind foreign
substance (antigen: Ag), form Ab-Ag complex
• responsible for humoral response
• perform antigen processing and presentation
• differentiate into plasma cells (large Ab
secretion)
2. Neutrophils- found throughout body, in blood
-phagocytosis of Ab-Ag CX
3. Macrophages- throughout body, blood, lymphatics
-phagocytose non-specifically (non Ab coated Ag)
-phagocytose specifically Ab-Ag CX
-have large number of lysosomes (degradative enzyme)
-perform Ag processing and presentation
-present Ag to T helper cell
-secrete lymphokines/ cytokines to stimulate T helper
cells and immune activity
4. Natural Killer Cells-in blood throughout body
-destroy cancer cells
-stimulated by interferons
Macrophage
Bacteria
Bacterial
Infection
Viral
Infection
5 classes of Ig
IgG: 150,000 m.w.
most abundant in blood, cross placental barrier,
fix complement, induce macrophage engulfment
IgA: associated with mucus and secretory glands,
respiratory tract, intestines, saliva, tears, milk
variable size
IgM: 900,000 m.w.
2nd most abundant , fix complement,
induce macrophage engulfment, primary
immune response
5 Classes of Ig
IgD: Low level in blood, surface receptor on Bcell
IgE: Binds receptor on mast cells (basophils)
secretes histamine, role in allergic
reactions
Increased histamine leads to vasodilation, which
leads to increase blood vessel permeability. This
induces lymphocyte immigration swelling and
redness.
Table 15-2: Some Aging Related
Effects on B-Cells
• Decreased number of circulating and peripheral
blood B cells
• Alteration in B-cell repertoire (diversity)
• Decreased generation of primary and secondary
memory B cells
• General decline in lymphoproliferative capacity
Table 15-14: Some Aging-Related Effects on T-cells
•General decline in cell mediated immunological function
•T-cell population is hyporesponsive
•Decrease responsiveness in T-cell repertoire (i.e. diversity of
CD8+ T-cells)
•Decline in new T-cell production
•Increase in proportion of memory and activated T-cells while
naïve T-cells decrease
•Diminished functional capacity of naïve T-cells (decreased
proliferation, survival, and IL-2 production)
•Senescent T-cells accumulate due to defects in apoptosis
•Increased proportion of thymocytes with immature
phenotype
•Shift in lymphocyte population from T-cells to NK/T cells
(cell expressing both T-cell receptor and NK cell receptors)
Table 15-13 Aging-Related Shifts in Antibodies
General decrease in humoral responsiveness:
Decline in high affinity protective antibody
production
Increased auto-antibodies:
Organ specific and non-organ specific
antibodies directed to self
Increased serum levels of IgG (i.e. IgG1 and IgG3) and IgA;
IgM levels remain unchanged
Table 15-16 Influence of Aging on Macrophages
and Granulocytes
General functional impairment of macrophages and granulocytes
GM-CSF is unable to activate granulocytes from elderly subjects
(e.g.: superoxide production and cytotoxic abilities)
Polymorphonuclear neutrophils appear to possess higher levels of
surface markers CD15 and CD11b and lesser vesicles containing
CD69 which lead to the impairment observed to destroy a bacteria
In elderly subjects the monocyte phenotype shifts (i.e. expansion of
CD14dim and CD16 bright subpopulations which have features in
common with mature tissue macrophages)
Macrophages of aged mice may produce less IFN-, less nitric
oxide synthetase, and hydrogen peroxide.
Table 15-15 Aging-Related Changes in Natural Killer (NK)
Cells
General decline in cell function
Good correlation between mortality risk and NK cell
number
Increased in proportion of cells with high NK activity
(i.e. CD16+, CD57-)
Progressive increase in percentage of NK cells
Impairment of cytotoxic capacity per NK cell
Increase in NK cells having surface molecule CD56
dim subset
Table 15-10 Some Aging-Related Shifts in Cytokines
•Increased proinflammatory cytokines IL-1, IL-6,
TNF-
•Increased cytokine production imbalance
•Decreased IL-2 production
•Increased production of IL-8, which can recruit
macrophages and may lead to pulmonary
inflammation
•Increase in dysfunctional IL-8
•Decreased secretion of IFN- (interferon)
•Altered cytokine responsiveness of NK cells, which
have decreased functional abilities
•Increased levels of IL-10 and IL-12 upregulated by
Antigen Processing Cells
Table 15-17 Major Diseases Associated with Aging
in Immune Function
Increased tumor incidence and cancer
Increased incidence of infectious diseases caused by:
E. Coli
Streptococcus pneumonia
Mycobacterium tuberculosis
Pseudomonas aeruginosa
Herpes virus
Gastroenteritis, bronchitis, and influenza
Reappearance of latent viral infection
Autoimmune diseases and inflammatory reactions:
Arthritis
Diabetes
Osteoporosis
Dementia
Table 15-9 Hallmarks of Immunosenescence
Atrophy of the thymus:
decreased size
decreased cellularity (fewer thymocytes and epithelial cells)
morphologic disorganization
Decline in the production of new cells from the bone marrow
Decline in the number of cells exported by the thymus gland
Decline in responsiveness to vaccines
Reduction in formation and reactivity of germinal center nodules in
lymph nodes where B-cells proliferate
Decreased immune surveillance by T lymphocytes and NK cells