Midterm I exam review

February 12, 2007

Lectures 1-13

Ryan Klimczak, Office Hours TuTh 10-11am at Pat Brown’s Cafe

Questions emailed 24hrs before the exam will be answered, I can’t guarantee anything after that (RRK135@gmail.com)

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• Neuroglia (astrocytes, oligodentrocytes) and microglia

(immune cells) with the ability to perpetually self renew and produce the three types of neural cells

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Rat Hippocampal Cells in Culture

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

Death Rates in 1986 among Persons 25- 64 Years Old in Selected Education and Income Groups According to Race and Sex.________________________________________________________

Group White BlackMen Women Men Women

deaths per 1000

Education- yr CompletedSchool0-11 7.6 3.4 13.4 6.212 4.3 2.5 8.0 3.9College1-3 4.3 2.1 5.0 3.24 2.8 1.8 6.0 2.2

Income-$<9,000 16.0 6.5 19.5 7.6 9,000-14,999 10.2 3.4 10.8 4.5 15,000-18,999 5.7 3.3 9.8 3.7 19,000-24,999 4.6 3.0 4.7 2.8>25,000 2.4 1.6 3.6 2.3 ______________________________________________________________________________________

Pappas, G., Queen, S., Hadden, W., and Fisher, G. The increasing disparity in mortality between socioeconomic groups in the United States, 1960 and 1986. N. Engl. J Med. 329, 103-109, 1993.

Anatomical Correlates of Educational Protective Effects*Educational Level Increasing levels from <12 to >12

grades

Anatomical Correlate total dendritic length

mean dendritic length

dendritic segment count

Location Pyramidal cells in layer 2,3 of Wernicke’s area

Variable Studied GenderHemisphereEducationPersonal history

Hormonal Correlate Thyroid Hormones dendritic number and length Glucocorticoids reactive synaptogenesis ______________* From Jacobs et al., J Comp. Nuerol., 327, 97, 1993

Mechanisms of Education EffectsMechanisms of Education Effects

Better access to recreational activity

Better nutrition

Higher income

Responsibility to health behaviors

No alcohol intake

No smoking

Increased brain reserve capacity?More dendritic branching, cortical synapses?;Better cerebral blood flow?;Better neural cell efficiency, adaptability, redundancy, survival and growth

Better access to medical care

Common ectodermic derivation of neurons and neuroglia

Astrocytes:Star shaped cellsSupport neurons metabolicallyAssist in neuronal transmission

Oligodendrocytes: myelinate neurons

Neural Epithelium

Neuroblast Spongioblast

Neuron Migratory Spongioblast Astrocyte Ependyma

Oligodendrocyte Astrocyte

Neural Cells

Assays of enzymatic activity (e.g. glutamine synthetase--a marker of astrocytes)

show decreased activity suggesting a loss of astrocytic specificity

From:

• Proliferation

•Maturation

To:

• Proliferation

•De-differentiation

“virgin” cell

daughter1

1st

Generation(cell cycle)

dead cell(lysis)

nth

daughtern

• Sterility• increased size• wrinkles• bud scars• increased generation time

AGING

Lifespan = n (20-40)

Adapted from Jazwinski, et al Exp Geront 24:423-48 (1989)

The Cell Spiral Model of Yeast Aging

How does the population remain immortal?

• In every daughter cell, the lifespan “clock” is reset to zero

• Each division produces a cell that can divide many more times

• “Old” cells are very rare in a large, exponentially growing population (1/2a+1)

What limits yeast lifespan?

• A clue: exceptions to the rule of the resetting clock• Occasionally, daughters of old mothers are born

prematurely aged!• Their lifespan equals the mother’s remaining lifespan

• The asymmetry has broken down -- accompanied by loss of size asymmetry (“symmetric buds”)• The daughters of symmetric buds have normal lifespan

• Suggests these symmetric buds have inherited a “senescence factor”…

The Yeast Senescence Factor Model (1989)

• Preferentially segregated to mother cell each division• Accumulates to high concentrations in old mothers• Eventually inhibits cell division and/or causes other aging

phenotypes• Is occasionally inherited by symmetric buds

What is the yeast senescence factor?

or, as it turns out:What are the yeast senescence factors?

1) extrachromosomal rDNA circles (ERCs)

2) dysfunctional mitochondria

3) oxidatively damaged proteins

How does Yeast Aging relate to Cellular Senescence in Humans?

• Telomere-independent

• Asymmetrically dividing cells

• For what cell type is this a model?

Stem cells:• Express

telomerase• Divide

asymmetrically• Undergo

senescence• No ERCs!

Genetic instability in aging yeast cells

• After about 25 divisions, aging mother cells begin to produce daughters that are genetically unstable

• High rates of mitotic recombination at multiple chromosomes

• What is the senescence factor responsible for this aging phenotype?

• Altering ERC levels alters lifespan, but does not accelerate or delay onset of genetic instability (still 25 generations)

• CR completely prevents genetic instability

Conclusions

• Budding yeast cells are uniquely tractable for aging research

• Yeast replicative aging involves longevity regulation as well as senescence phenotypes unlinked from longevity

• The search continues for the senescence factors responsible for yeast aging phenotypes

• May be a good model for stem cell aging

Assessment of Physiological Age in Humans

Physiological age depends on

Physiologic competence: good to optimal function of all body systems

&

Health status: absence of disease

Physiological age may or may not coincide with chronological age

Secrets to Long Life

Geriatric AssessmentInvolves a multi-dimensional diagnostic process designed to

qualify an elderly individual in terms of:

• Functional capabilities• Disabilities

• Medical & Psychological characteristics

A list of typical assessments is summarized in Table 3.3

For our discussion, we will consider particularly: • Activities of Daily Living (ADL)

• Instrumental Activities of Daily Living (IADL) **See Table 3.4**

Assessment Programs include tests that are grouped into three

categories:1. Tests examining general physical health

2. Tests measuring ability to perform basic self care (ADLs)

3. Tests measuring ability to perform more complex activities (IADLs), reflecting the ability to live independently in the community

Methods to Study Physiology of Aging

1. Study in humans a. Cross-sectional methods

• Compare characteristics among different individuals of the same age at one time.

• Rapidity but relative accuracy b. Longitudinal studies

• Examine the same individuals at regular time intervals throughout life (or portion of life).

• Each person is his/her own control.• Accuracy but difficulty of repeatedly reaching

the same people.c. Activities of Daily Living (ADL) / Instrumental Activities of Daily Living (IADL)a. Clinical Studies

Table 3-4 Categories of Physical Health Index MeasuringPhysical Competence

ACTIVTIES INSTRUMENTAL ACTIVITIESOF DAILY LIVING OF DAILY LIVING

Feeding CookingBathing CleaningTo ileting Using telephoneDressing WritingAmbulation ReadingTransfer from toilet LaundryVisual acuity Driving a carOthers Others

Why do women have more disability?

Women have more chronic disabling diseases than men but less life

threateningExamples of conditioning limiting ADL (%

indicate number of people affected in a given population):

• Arthritis (10.6%)

• Heart disease (4.0%)

• Stroke (2.6%)

• Respiratory (2.5%)

• Diabetes (1.5%)

• Age Related Terminology– Aging– Geriatrics– Gerontology– Senescence– Biomarkers– Life-Span– Average Life Span– Life Expectancy– Active Life Expectancy– Longevity– Maximum Life Span

1. Increased length of lifespan & increased number of the elderly in the human population

2. Increased proportion of persons aged 65+ in the population as compared to those aged 14-19

3. This change in the human population is acknowledged by the industries and professions

4. Need to better educate the population in healthy habits

5. Need to support research in biomedicine

6. Points 4 and 5 must take into consideration the entire life cycle as our health today depends on our health yesterday and will influence our health tomorrow

Life expectancy and infant mortality throughout human history

Life expectancy Infant mortality rate

at birth (years) (per 1000 live births)

Prehistoric 20-35 200-300

Sweden, 1750s 37 210

India, 1880s 25 230

U. S., 1900 48 133

France, 1950 66 52

Japan, 1996 80 4

Divisions of the Lifespan

Prenatal LifeOvum: Fertilization

- end 1st week

Embryo: 2nd-8th week

Fetus: 3rd-10 lunar month

Neonatal Period

Newborn: end of 2nd week

Infancy: 3rd week-1st year

Childhood: 2-15 years

Adolescence: 6 yrs after puberty

Postnatal LifeAdulthood

Prime & transition (20-65 yrs)

Old age & senescence (65 yrs+)

Table 3-1 Physiologic Correlates with Longevity

INDEX STUDIED CORRELATION

Body weight Direct

Brain/ body weight Direct

Basal metabolic rate Inverse

Stress Inverse

Reproductive function/Fe cundity Inverse

Length of growth period DirectEvolution Uncertain

Among invertebrates, the most used models have been the fly (Drosophila melanogaster) and the nematode (C. elegans)

Suppression of the receptor for insulin/IGF hormone will produce a mutant nematode that will live 6x longer than corresponding controls and be more resistant to all stress.

C. Elegans 2 week lifespanhermaphrodite19,000 genes

959 cells

Transcriptional Profile of Aging Related Genes in the Human Brain

Rodwell et al. 2004

Disease may be viewed as a process that is :

• Selective (i.e., varies with the species, tissue, organ, cell and molecule)

• Intrinsic and extrinsic (I.e., may depend on environmental and genetic factors)

• Discontinuous (may progress, regress, or be arrested)• Occasionally deleterious (damage is often variable, reversible)• Often treatable (with known etiopathology, cure may be available)

Probable causes for longevity in favor of women:

• Genetic (XX vs. XY) or Environmental (geography, country, income)

• Other causes: Lesser life stress in females

Less smokingProtective action of estrogens?

Lesser accumulation of mDNA deletions/mutations with better protection against oxidative damage

Others?Implication for prevention and treatment

Older women whose parents survived past age 90 are generally healthier than women whose parents did not survive as long. These women

…• overall death rates• die of cardiovascular disease • report a diagnosis of diabetes• mental and mobility limitaions• risk of hip fracture and non-spine fractures*

• have higher self-rated quality of life• have faster walking speed and better measures of grip strength

*reduced fracture risk seen for maternal, but not paternal survival past age 90

Data from the Study of Osteoporotic Fractures (SOF), Peggy Cawthon

Recent approaches challenge the inevitability of

function pathology by grouping the aging processes into three categories:

1. Aging with disease and disability2. Usual aging, with absence of overt

pathology but presence of some declines in function

3. Successful or healthy aging, with no pathology and little or no functional loss

Mitochondria from old rats compared to those from young rats:

1) Lower Cardiolipin

2) Lower Membrane Potential

3) Lower Oxygen Utilization

4) Increased Oxidant Leakage

L-Carnitine/Acetyl-L-Carnitine (ALCAR)

• Mediates the ratio of acetyl-CoA/CoA• Decreases with age in plasma and in brain• Improves cognitive function in rats

• Transports long-chain fatty acids into mitochondria• Removes short- and medium-chain fatty acids that accumulate

R--Lipoic Acid (LA) in mitochondria

• LA reduced to dihydrolipoic acid, a potent antioxidant, & chelator of Fe & Cu• Coenzyme of pyruvate and -ketoglutarate dehydrogenases, involved in the citric

acid cycle• Involved with carbohydrate utilization for ATP production, shown to increase the

cellular uptake of glucose in vitro by recruiting a glucose transporter to the cellular membrane

15

Effects of ALCAR and LA supplements•ALCAR increases Cardiolipin levels, increases mitochondrial membrane potential

•ALCAR/LA reduce the amount of mitochondrial DNA adduct levels in old rats

-increases ambulatory activity of old rats

-enhances immune function

-improves spatial memory/ mental acuity

•Clinical trials in humans suggest LA can improve neuropathic symptoms and deficits in diabetic patients

MolecularCodon restriction

Somatic mutation

Error catastrophe

Gene regulation.

Dysdifferentiation

Classification and brief description of main theories of aging

CellularWear-and-tear

Free radical accumulation

Apoptosis

SystemRate-of-living

Neuroendocrine

Immunologic

Evolutionary

Disposable Soma

Antagonistic Pleiotropy

Mutation Accumulation

0

20

40

60

80

100

120

0 4 812 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96

100

Evolution in the Laboratory

young flies selected

Normal

% S

urv

ivin

g

Age in Days

- Early adult fecundity increased *antagonistic pleiotropy

Offspring of “young” flies are selected

- Reproductive period extended- Stress resistant, -super flies- Early adult fecundity reduced *antagonistic pleiotropy

Offspring of “old” flies are selected

Cellular Senescence

What is it?

Response of normal cells to potentially cancer-causing events

First description: the Hayflick limit

Pro

lifer

ativ

e ca

paci

ty

Number of cell divisions

FiniteReplicativeLife Span"Mortal"

InfiniteReplicativeLife Span"Immortal"

EXCEPTIONSGerm line

Early embryonic cells (stem cells)Many tumor cells

What happens when cells exhaust their replicative life span

Inducers of cellular senescence

Cell proliferation(short telomeres)

DNA damage

Oncogenes

Strong mitogens

PotentiallyCancerCausing

Normal cells(mortal)

Immortal cells(precancerous)Inducers

of senescence

Cell senescence Transformation Apoptosis

Tumor suppressor mechanisms

Cellular SenescenceAn important tumor suppressor mechanism

•Induced by potentially oncogenic events

•Most tumor cells are immortal

•Many oncogenes act by allowing cells to bypassthe senescence response

•Senescence is controlled by the two most importanttumor suppressor genes -- p53 and pRB

•Mice with cells that do not senesce die youngof cancer

Aging before cell phones ……

100%

Su

rviv

ors

AGE

Natural environment: predators, infections, external hazards, etcMost of

humanevolution

Modern, protectedenvironment

(very VERY recent)

Antagonistic pleiotropy:Some traits selected to optimize fitness in young

organisms can have unselected deleteriouseffects in old organisms

(what's good for you when you're young may be bad for you when you're old)

EPITHELIUMBasement Membrane

STROMA

Senescent Epithelial Cell

Senescent Fibroblast

EPITHELIUMBasement Membrane

STROMA

YOUNG TISSUE

OLD TISSUE

Degradative enzymes, Inflammatory cytokines, etc.

AGING ?

EpithelialCells

Fibroblasts

EPITHELIUMBasement Membrane

STROMA

Senescent Epithelial Cell

Senescent Fibroblast

OLD TISSUE

Degradative & inflammatory molecules, growth factors, etc

AGING ?

EPITHELIUMBasement Membrane

STROMA

YOUNG TISSUE "Initiated" Cell

Neoplastic Growth

Senescent cells can strongly alter tissue microenvironments.May contribute to age-related declines in tissue structure and function, andage related disease

Why are telomeres important?

Telomeres allow cells to distinguish chromosomesends from broken DNA

Stop cell cycle!Repair or die!! Homologous recombination

(error free, but need nearby homologue)

Non-homologous end joining(any time, but error-prone)

The importance of telomeres (con’t)

•Prevent chromosome fusion by non-homologous end joining

•Provide a means for counting cell division

•They resolve the end replication problem

Ori

DNA replication is bidirectional

Polymerases move 5' to 3'

Requires a labile primer

3'

5'3'

5'5'

5' 3'3' 5'

Each round of DNAreplication leaves

50-200 bp DNA unreplicatedat the 3' end

Replicatively immortal cells bypass the restrictions telomeres impose by using the enzyme telomerase

Enzyme (reverse transcriptase) with

RNA and protein components

Adds telomeric repeat DNA directly to 3' overhang (uses its own RNA as a template)

Vertebrate repeat DNA on 3' end:TTAGGG

Telomerase RNA template:AAUCCC

HOWEVER,

CELLS THAT EXPRESS TELOMERASE

STILL UNDERGO SENESCENCE

(E.G., IN RESPONSE TO DNA DAMAGE, ONCOGENES, ETC.)

Inducers of cellular senescenceCell proliferation(short telomeres)

DNA damage OncogenesStrong mitogens/

stress

Potential Cancer Causing Events

Diseases of Aging

Disease may be viewed as a process that is :

• Selective (i.e., varies with the species, tissue, organ, cell and molecule)

• Intrinsic and extrinsic (I.e., may depend on environmental and genetic factors)

• Discontinuous (may progress, regress, or be arrested)• Occasionally deleterious (damage is often variable, reversible)• Often treatable (with known etiopathology, cure may be available)

Diseases as a tool for studying aging:

Syndromes in humans: having multiple characteristics of premature (early onset) of aging, or

accelerated (rapid progression) of aging

Infantile Progeria: Hutchinson-Gilford SyndromeAdult onset progeria: Werner’s syndrome

Down syndrome

Hutchinson-Gilford Progeria Syndrome:

-Hutchinson-Gilford Progeria syndrome is an extremely rare genetic condition which causes physical changes that resemble greatly accelerated aging in sufferers.

-Affects between 1 in 4 million (estimated actual) and 1 in 8 million (reported) newborns. Currently, there are approximately 40-45 known cases in the world.

-Most people with progeria die around 13 years of age

Werner Syndrome

-The gene responsible for Werner syndrome (WRN) was identified (and found to be a member of the RecQ family of helicases. -The Werner protein is thought to perform several tasks in the cell, including the maintenance and repair of DNA. It also assists in making copies of DNA in preparation for cell division. Mutations in the WRN gene often lead to the production of an abnormally short Werner protein. -Some research suggests that this shortened protein is not sent to the nucleus, where it normally interacts with DNA. Evidence also suggests that the altered protein is broken down quickly in the cell, leading to a loss of Werner protein function.-Research into the biological role of the WRN protein is ongoing, but current evidence strongly suggests a role for WRN in the resolution of Holliday junctions. Roles in non-homologous end joining (NHEJ) and the restoration of stalled replication forks have also been suggested.

-Individuals with this syndrome typically grow and develop normally until they reach puberty. Following puberty, they age rapidly, so that by the time they reach age 40 they often appear as though they are several decades older.

-Overall, people affected by Werner syndrome have thin arms and legs and a thick trunk. Affected individuals typically have a characteristic facial appearance described as "bird-like" by the time they reach their thirties. Patients with Werner sydrome also exhibit genomic instability and various age-associated disorders; these include cancer, heart disease, atherosclerosis, diabetes mellitus, and cataracts. However, not all characteristics of old-age are present in Werner patients; for instance, senility is not seen in individuals with Werner syndrome. People affected by Werner syndrome usually do not live past their late forties or early fifties, succumbing to death, often resulting from cancer or heart disease.

EPIDEMIOLOGY OF AGING

• CHRONOLOGICAL AGE IS ASSOCIATED WITH INCIDENCE AND PREVALENCE OF MOST HEALTH OUTCOMES.

• DESPITE THIS AGE ASSOCIATION, THERE IS CONSIDERABLE VARIATION IN HEALTH OUTCOMES WITHIN AGE CATEGORIES.

EPIDEMIOLOGY OF AGING

• WHY ARE OLDER PEOPLE AT ELEVATED RISK FOR DISEASE, DISABILITY, AND DEATH?

EPIDEMIOLOGY OF AGING

• ACCUMULATION OF ENVIRONMENTAL/BEHAVIORAL INSULTS.

• REDUCED IMMUNOLOGICAL SURVEILLANCE

EPIDEMIOLOGY OF AGING

• Improvements in life expectancy are not constant. Not a “force of nature.”

• Life expectancy is quite fragile.

Decline in Life Expectancy in Russia, 1990-94

• Life expectancy declined from 63.8 years to 57.7 years for men.• Life expectancy declined from 74.4 years to 71.2 years for

women.• 75% of the decline in life expectancy was due to increased

mortality rates for ages 25-64 years.• Causes of death included cvd, injuries, influenza, chronic liver

disease, cirrhosis and other alcohol-related diseases.

EPIDEMIOLOGY OF AGING

• MAJOR AGE-ASSOCIATED CAUSES OF DEATH

– CARDIOVASCULAR DISEASE– CANCER– CHRONIC OBSTRUCTIVE PULMONARY DISEASE– DIABETES

EPIDEMIOLOGY OF AGING

• FALLS

• 30% OF PEOPLE AGED 65+ FALL EACH YEAR.

• 10-15% OF THOSE FALLS ARE CONSIDERED “SERIOUS/NON-FATAL”

• FALLS REPRESENT THE LEADING CAUSE OF ACCIDENTAL DEATH IN PEOPLE AGED 65 AND OLDER.

• FEAR OF FALLING IS A LEADING REASON FOR NOT ENGAGING IN PHYSICAL ACTIVITY.

EPIDEMIOLOGY OF AGING

• NIA STRATEGIC PLAN – PHYSICAL ACTIVITY

Delay the onset of disabilities and disease

Reduce the risk of falls and fractures

Improve mood and depressionIncrease life span

A Few Definitions• GENOME: THE COMPLETE SET OF GENES OF AN ORGANISM

• GENOTYPE: THE GENETIC CONSTITUTION OF A CELL OR AN ORGANISM

• PHENOTYPE: THE OBSERVABLE PROPERTIES OF AN ORGANISM THAT HAVE DEVELOPED UNDER THE COMBINED INFLUENCES OF

ｷｷ The genetic constitution of the organism, and ｷｷ The effects of environment6al factors

• PHENOME: GENOME + ENVIRONMENT THE CONSTITUTION OF AN ORGANSIM COMBINING GENETIC AND ENVIRONMENTAL FACTORS

Correlation between Aging and Genetic Epidemiology

• Genetic variation interacts with the environment

to modify the risk of disease e.g. cancercoronary heart diseaseneurologic, psychiatric diseases, etc.

• Monogentic (one gene only) or multigenetic (several genes) may or the risk of developing a certain trait

In examining the role of genes in the etiology of

complex disease

we must distinguish:

1. causal genes: single gene mutation leads to

diseasee.g.Huntington disease

2.susceptibility genes: associated with the

disease butthemselves not sufficient to

cause the disease

1. Determination of familial aggregation

2. Determination of evidence of familial aggregation discrimination between

environmental/cultural and genetic factors that may contribute to the mutation clustering

3. Determination of genetic factors and their identification

Determination of genetic participation to disease

Complex disease genes express traits:

(a) that show no clear Mendelian inheritance (one gene/ one phenotype);

(b) but have moderate to high evidence of genetic inheritance;

(c) exhibit familial aggregation cases

(d) are either polygenic, that is, involve multiple genes or

(e) are multifactorial, that is, involve multiple genes interacting with the environment.

Ways in which genetic susceptibility may influence a disease:

(a) by itself,

(b) by making the carrier more susceptible to the disease, or

(c) by exacerbating the expression of a risk factor or the risk factor may exacerbate the genetic effects

Questions:

What is the reason for the increase in average life span from ~1880 - 1960? From 1960 - present?

1880-1960 - advent of germ theory, improvements in public health, public hygiene, agricultural technology, reduction in infant mortality, therapies for combatting infection/disease I.e. vaccines and antibiotics

1960-present - improvements in physiotechnology, more sophisticated medical treatments for common diseases in the eldery (I.e. improved treatment for cardiovascular disease)

Why doesn’t the degree of pathophysiology correlate directly with age?

Heterogeneity in aged populations; increases over time

What physiological characteristics are generally observed in individuals who live past the age of 100?

Generally good health

Escapers, late onset of disease or overcoming a disease earlier on

Greater ambulatory activity/ mental function

Possible role of IGF-1 receptor

Children have a greater chance of becoming centenarians

What is aging vs. usual aging vs. successful aging?

1. Aging with disease and disability2. Usual aging, with absence of overt pathology but

presence of some declines in function3. Successful or healthy aging, with no pathology and little or

no functional loss

Discuss the idea that women have more disability than men.

Women live longer than men, but generally have more disability, suffering from non-life threatening conditions such as arthritis, osteoporosis, cataracts, etc… whereas men tend to suffer more from conditions that are life-threatening, and not necessarily as disabling, heart disease, cancer, etc…

Describe the general changes that may underlie the short lived and long-lived phenotypes in the evolutionary fly studies.

Change in reproductive period - early and late onset fecundity

Greater stress resistance, expression of antioxidant enzymes

Selection for or against antagonistic pleiotropic related genes

Free radical accumulationOxidative metabolism produces free radicals which are highly reactive (containing unpaired electrons) and thus damages DNA and/or proteins and thus degrades the system structure and function. This damage accumulates over time

Older individuals have reduced stress mechanistic response to free radicals/ROS. Generate free radicals more rapidly due to compromised mitochondria.

Explain the free radical theory of aging.

What causes cellular senescence, what are the inducers and what do they have in common?

Cell proliferation (replicative senescence)= TELOMERE SHORTENINGDNA damageOncogene expressionSupermitogenic signals

All potential cancer causing events; each inducer triggers tumor suppressors (I.e. p53, pRB) to induce senescence

What are the two most common causes of death in individuals over the age of 50? What reasons underlie this trend?

Cardiovascular Disease and Cancer

Cardiovascular system becomes increasingly compromised and fragile over time, the accumulation of arterial plaques, calcification - blockage

Increase mutational accumulation over time; compromised tissue structure and function from senescent tissue environments

How do the symptoms of Hutchinson-Gilford Progeria Syndrome and Werner Syndrome mimic the characteristics of ‘normal’ aging? How are they different?

HG Progeria causes wrinkled skin, atherosclorosis, and other cardiovascular problems - no mental dysfunction or propensity to develop cancer

Werner’s - old/bird-like facial appearance, thin, fragile, increased incidence of cancer, heart disease, diabetes, cataracts - no mental dysfunction

What are the characteristics of yeast “symmetric” cells derived from old mothers?

Prematurely aged

Inherited greater amount of “senescence factors” from old mother (more ERCs, damaged proteins/mitochondria)

Greater genomic instability

Larger in initial size than their “asymmetrically-divided” sisters

Have daughters which are normal

What is the correlation between aging, cellular senescence, and telomere length?

Body tissue contains more senescent cells over time, telomeres are shorter… this isn’t causation, but a correlation

What are ADL, IADL?

1. Activities of Daily Living [feeding, bathing, walking] …Tests measuring ability to perform basic self care (ADLs)

2. Instrumental activities of daily living [cooking, driving, reading, balancing check book]…Tests measuring ability to perform more complex activities (IADLs), reflecting the ability to live independently in the community

In terms of genetic epidemiology, how are diseases such as Huntingtons and Alzheimers different?

Huntingtons disease has Mendelian inheritance, monogenic

Alzheimers is a complex disease, not linked to a single, specific genetic mutation - although exhibits familial aggregation - certain mutations are risk factors, multifactorial - occurs from the confluence of environmental and genetic factors