1. Midterm – II March 30, 2005 Jason Lowry
MCB 135K Review
Midterm – II
March 30, 2005
Jason Lowry

2. Outline 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

3. Aging of the Nervous System
Structural Changes
Changes in Brain Weight
Neurons vs. Glial Cells
Denudation
Neuropathological Markers
Biochemical Changes
Neurotransmitters
CNS Synapses
Neurotransmitter Imbalance and Brain Disorders
Brain Plasticity
CNS Regenerative Potential

4. Changes in Brain Weight

5. Neurons vs. Glial Cells Neurons Glial Cells Cell Body Axons Dendrites
Synapses
Glial Cells
Astrocytes
Oligodendrocytes
Microglial

6. Denudation Normal Aging Degenerative Disease 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

7. Neuropathologies Lipofuscin Lewy Bodies Neurofibrillary Tangles
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

8. 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

9. 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

10. Common ectodermic derivation of neurons and neuroglia
Neural Cells
Common ectodermic derivation of neurons and neuroglia
Astrocytes:
Star shaped cells
Support neurons metabolically
Assist in neuronal transmission
Oligodendrocytes: myelinate neurons
Neural Epithelium
Neuroblast Spongioblast
Neuron Migratory Spongioblast Astrocyte Ependyma
Oligodendrocyte Astrocyte

11. Tsonis, P. A. , Stem Cells from Differentiated Cells, Mol. Interven
From newt amputated limb, terminally differentiated cells de-differentiate by losing their original characteristics. This de-differentiation 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,

12. Brain Disorders Parkinson’s Disease Alzheimer’s Disease Pathologies
Symptoms
Treatment Strategies
Alzheimer’s Disease
Symptoms and Signs
Disease Progression
Pathophysiology
Treatment / Management

13. Parkinson’s Disease
Loss of neuromelanin containing neurons in brain stem and presence of Lewy bodies in degenerating dopaminergic cells

14. Parkinson’s Disease Symptoms Treatment Strategies
Loss of motor function
Loss of balance
Speech and Gait abnormalities
Tremor
Rigidity
Treatment Strategies
Pharmacological
Ldopa
Neuroprotective
Surgical
Cell Therapies

15. 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

16. 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

17. Imaging of the Brain Types of Neuroimaging
Neuronal Recruitment and Reaction Time

18. Aging of the Visual System

19. 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

20. 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

21. Aging of the Visual System
Recommendation to Accommodate Problems:
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

22. Aging of Cardiovascular System
Atherosclerosis
Characteristics
Disease Results
Arterial Changes
Atherogenesis
Contributing Factors
Age Changes in Vascular Endothelium

23. Atherosclerosis Characteristics Universal Progressive Deleterious
Irreversible …but (?)

24. Atherosclerosis Disease Manifestation Myocardial Infarct Stroke
Aneurysm
Gangrene

25. 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

26. 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

27. 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

28. 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

29. Aging of Cardiovascular System
Atherosclerosis
Theories
Coronary Heart Disease
Risk Factors
Risk Assessment
Treatment

30. Lipids and Apolipoproteins
Major Categories
Risk Factors in Atherosclerosis
Lipoprotein Synthesis
Apolipoproteins
Lipolytic Enzymes
Receptors

31. Lipids and Apolipoproteins
Categories
Chylomicrons and VLDL
High triglycerides
IDL and LDL
High cholesterol
HDL
High proteins
High phospholipids

33. Lipids and Apolipoproteins
Risk Factors for Heart Disease
Total cholesterol to HDL ratio above 4.0
Family history
Elevated LDL; Low HDL
Diabetes Mellitus
Age
Hypertension
Obesity
Smoking

34. Lipoprotein Synthesis
Intestine CM
Nascent HDL
Liver
VLDL
IDL
LDL

35. Apolipoproteins Definition: Roles in Metabolism
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

36. 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

37. Enzymes Lipoprotein Lipase Hepatic Triglyceride LCAT
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)

38. Receptors LDL Macrophage Scavenger (SR-A1) SR-B1
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

39. Exercise and Aging Cardiovascular Fitness Metabolic Fitness
Muscular Strength
Anti-oxidant defenses
Freedom from Injury
Sense of Well Being

40. Exercise and Aging Cardiovascular Fitness Maximal oxygen consumption
VO2 Max increased by regular exercise
Declines with aging
Decreases morbidity
Decreases mortality

41. Exercise and Aging Metabolic Fitness
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)

42. 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

43. Aging of Muscles Etiology of Sarcopenia Decrease in mitochondrial mass
Reduced protein synthesis
PNS and CNS changes
Hormonal changes
State of inactivity (most prominent)

44. 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

45. MYOPLASTICITY -muscles enlarge with resistance type of exercise
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)

46. 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

47. The Aging Heart Heart ages well in absence of disease
Age associated changes
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 “220-age”
Blood pressure increases due to increased peripheral vascular resistance

48. Physiological Changes with Age
Parameter
20 years
60 years
VO2 Max (mL x kg x min) 39 29
Maximum Heart Rate
194
162
Resting Heart Rate 63 62
Max. Cardiac Output (L x min) 22 16
EJECTION FRACTION
70-80%
50-55%
Resting BP
120/80
130/80
Total Lung Capacity (L)
6.7
6.5
Vital Capacity (L)
5.1
4.4
Residual Lung Volume (L)
1.5
2.0
Body Fat %
20.1
22.3

49. 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

50. Prevalence of heart failure:
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

51. Contributory Causes to Heart Failure in the Elderly
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

52. 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)

53. 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

54. Cell Types 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

55. Lymphocytes (cont.) 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)

56. Neutrophils- found throughout body, in blood
-phagocytosis of Ab-Ag CX
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

57. Macrophage
Bacteria
Bacterial Infection

58. Viral Infection

60. 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

61. 5 Classes of Ig IgD: Low level in blood, surface receptor on B- cell
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.

62. 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

63. 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)

64. 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

65. 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.

66. 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

67. 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

68. 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

69. 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