MCB 135K Review

Midterm – II

March 30, 2005

Jason Lowry

Outline

1. Aging of the Nervous System

2. Brain Disorders

3. Imaging of the Brain

4. Aging of the Visual System

5. Aging of the Cardiovascular System

6. Exercise and Aging

7. Aging of Muscles

8. Immune System

Aging of the Nervous System

• Structural Changes1. Changes in Brain

Weight

2. Neurons vs. Glial Cells

3. Denudation

4. Neuropathological Markers

• Biochemical Changes

1. Neurotransmitters2. CNS Synapses3. Neurotransmitter

Imbalance and Brain Disorders

• Brain Plasticity1. CNS Regenerative

Potential

Changes in Brain Weight

S tructural brain changes with agingchanges in brain volume

young old

FRONTAL

OTHER BRAIN REGIONS

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

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

Neural Cells

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 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, 1331-1334. 2004

Brain Disorders

• Parkinson’s Disease1. Pathologies

2. Symptoms

3. Treatment Strategies

• Alzheimer’s Disease1. Symptoms and Signs

2. Disease Progression

3. Pathophysiology

4. 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

Y O U N G E L D E R L YU N D E R

R E C R U IT M E N TO V E R

R E C R U IT M E N T

Y O U N G

O L D

N O N -S E L E C T IV E R E C R U IT M E N T

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:– 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– 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– 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

• 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– 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– 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

– 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

Physiological Changes with AgeParameter 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

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

• 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)

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

Evidence for Decline in Immune Function with Aging

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 CellsEnhance T killer or B cell activity

-Supressor CellsReduce/suppress immune activityMay help prevent auto immune disease

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)

Lymphocytes (cont.)

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

Bacterial Infection

Macrophage

Bacteria

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, milkvariable 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 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.

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. ColiStreptococcus pneumoniaMycobacterium tuberculosisPseudomonas aeruginosaHerpes virusGastroenteritis, bronchitis, and

influenza

Reappearance of latent viral infection

Autoimmune diseases and inflammatory reactions:ArthritisDiabetesOsteoporosis

Dementia

Table 15-9 Hallmarks of ImmunosenescenceAtrophy 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