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
Rat Hippocampal Cells in Culture
Qu ick Time ™ an d a
TIFF (U nc o mp re ss e d) d ec o mp re ss o r
a re n ee d e d to se e th is p ictu re .
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
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
Men
Black
Women
Men
Women
deaths per 1000
Education- yr
Completed
School
0-11
12
College
1-3
4
7.6
4.3
3.4
2.5
4.3
2.8
2.1
1.8
5.0
6.0
3.2
2.2
Income-$
<9,000
9,000-14,999
15,000-18,999
19,000-24,999
>25,000
16.0
10.2
5.7
4.6
2.4
6.5
3.4
3.3
3.0
1.6
19.5
10.8
9.8
4.7
3.6
7.6
4.5
3.7
2.8
2.3
13.4
8.0
6.2
3.9
______________________________________________________________________________________
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
Anatomical Correlate
Increasing levels from <12 to >12
grades
total dendritic length
mean dendritic length
dendritic segment count
Location
Pyramidal cells in layer 2,3 of
Wernicke’s area
Variable Studied
Gender
Hemisphere
Education
Personal history
Hormonal Correlate
Thyroid Hormones
Glucocorticoids
______________
* From Jacobs et al., J Comp. Nuerol., 327, 97, 1993
dendritic number and length
reactive synaptogenesis
Mechanisms of Education Effects
Better access to medical care
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
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
From:
•
Proliferation
•Maturation
To:
•
Proliferation
•De-differentiation
Assays of enzymatic activity
(e.g. glutamine synthetase--a marker of astrocytes)
show decreased activity
suggesting a loss of astrocytic specificity
The Cell Spiral Model of Yeast Aging
“virgin” cell
Generation
(cell cycle)
AGING
1st
daughter1
nth
daughtern
dead cell
(lysis)
• Sterility
• increased size
• wrinkles
• bud scars
• increased generation time
Lifespan = n (20-40)
Adapted from Jazwinski, et al Exp Geront 24:423-48 (1989)
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?
• Telomereindependent
• 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 Assessment
Involves 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
Cate gories of Physical Health Index Measuring
Physical Compete nce
ACTIVTIES
OF DAILY LIVING
INSTRUMENTAL ACTIVITIES
OF DAILY LIVING
Feeding
Bat hing
Toilet ing
Dressing
Ambulat ion
Transfer fro m t oilet
Visual acuit y
Ot hers
Cooking
Cleaning
Using t elephone
Writ ing
Reading
Laundry
Driving a car
Ot hers
Why do women have more disability?
Women have more chronic disabling
diseases than men but less life
threatening
Examples 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.
2.
3.
4.
5.
6.
Increased length of lifespan &
increased number of the elderly in the
human population
Increased proportion of persons aged
65+ in the population as compared to
those aged 14-19
This change in the human population is
acknowledged by the industries and
professions
Need to better educate the population
in healthy habits
Need to support research in
biomedicine
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
Sweden, 1750s
India, 1880s
U. S., 1900
France, 1950
Japan, 1996
20-35
37
25
48
66
80
200-300
210
230
133
52
4
Divisions of the Lifespan
Prenatal Life
Ovum: Fertilization
end 1st
week
Embryo: 2nd-8th
week
Fetus: 3rd-10
lunar
month
Postnatal Life
Neonatal Period
Adulthood
Newborn: end of 2nd week
Prime & transition
(20-65 yrs)
Infancy: 3rd week-1st
year
Childhood: 2-15 years
Adolescence: 6 yrs after
puberty
Old age &
senescence (65 yrs+)
Table 3 -1
Physiologic Correlat es with Longevity
INDEX STUDIED
CORRELATIO N
Body w eight
Direct
Brain/ body w eight
Direct
Basal me ta bolic rate
Inverse
Stre ss
Inverse
Reproduc t ive f unct ion/Fe cun dit y
Inverse
Length of growt h p eriod
Evo lut ion
Direct
Uncert ain
C. Elegans
2 week lifespan
hermaphrodite
19,000 genes
959 cells
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.
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 smoking
Protective 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 disability
2. 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)
•
•
Transports long-chain fatty acids into mitochondria
Removes short- and medium-chain fatty acids that accumulate
•
•
•
Mediates the ratio of acetyl-CoA/CoA
Decreases with age in plasma and in brain
Improves cognitive function in rats
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
Classification and brief description
of main theories of aging
Molecular
Cellular
Codon restriction
Wear-and-tear
Somatic mutation
Free radical accumulation
Error catastrophe
Apoptosis
Gene regulation.
Dysdifferentiation
Evolutionary
Disposable Soma
Antagonistic Pleiotropy
Mutation Accumulation
System
Rate-of-living
Neuroendocrine
Immunologic
Evolution in the Laboratory
Offspring of “young” flies are selected
- Early adult fecundity increased
*antagonistic pleiotropy
% Surviving
Offspring of “old” flies are selected
- Reproductive period extended
- Stress resistant, -super flies
- Early adult fecundity reduced
*antagonistic pleiotropy
Normal
young flies
selected
Age in Days
Cellular Senescence
What is it?
Response of normal cells to
potentially cancer-causing events
Proliferative capacity
First description: the Hayflick limit
Finite
Replicative
Life Span
"Mortal"
Infinite
Replicative
Life Span
"Immortal"
Number of cell divisions
EXCEPTIONS
Germ line
Early embryonic cells (stem cells)
Many tumor cells
What happens when cells exhaust their replicative life span
Inducers of cellular senescence
Cell proliferation
Potentially
Cancer
Causing
(short telomeres)
DNA damage
Oncogenes
Strong mitogens
Normal cells
(mortal)
Cell senescence
Inducers
of
senescence
Immortal cells
(precancerous)
Transformation
Apoptosis
Tumor suppressor mechanisms
Cellular Senescence
An important tumor suppressor mechanism
•Induced by potentially oncogenic events
•Most tumor cells are immortal
•Many oncogenes act by allowing cells to bypass
the senescence response
•Senescence is controlled by the two most important
tumor suppressor genes -- p53 and pRB
•Mice with cells that do not senesce die young
of cancer
Aging before cell phones ……
Modern, protected
environment
(very VERY recent)
Survivors
100%
Most of
human
evolution
Natural environment: predators,
infections, external hazards, etc
AGE
Antagonistic pleiotropy:
Some traits selected to optimize fitness in young
organisms can have unselected deleterious
effects in old organisms
(what's good for you when you're young may be
bad for you when you're old)
Senescent cells can strongly alter tissue microenvironments.May
contribute to age-related declines in tissue structure and function, and
age related disease
YOUNG TISSUE
YOUNG TISSUE
"Initiated" Cell
EPITHELIUM
EPITHELIUM
Epithelial
Cells
Basement Membrane
STROMA
Fibroblasts
Basement Membrane
STROMA
AGING ?
AGING ?
Senescent
Epithelial Cell
Senescent
Epithelial Cell
OLD TISSUE
OLD TISSUE
EPITHELIUM
EPITHELIUM
Basement Membrane
Basement Membrane
STROMA
STROMA
Degradative enzymes,
Inflammatory cytokines, etc.
Neoplastic
Growth
Senescent Fibroblast
Degradative & inflammatory
molecules, growth factors, etc
Senescent Fibroblast
Why are telomeres important?
Telomeres allow cells to distinguish chromosomes
ends 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
5'
3'
3'
5'
5'
3 5'
'
DNA replication
is
5' 3
'
O
ri
bidirectional
Each round of DNA
replication leaves
Polymerases move 5' to
3'
50-200 bp DNA unreplicated
at the 3' end
Requires a labile primer
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 senescence
Cell proliferation
(short telomeres)
DNA damage
Oncogenes
Strong 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 Syndrome
Adult 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 nonhomologous 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 depression
Increase 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
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. cancer
coronary heart disease
neurologic, 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 disease
e.g.Huntington disease
2.susceptibility genes:
associated with the disease
but
themselves not sufficient to
cause the disease
Determination of genetic participation to 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
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.
2.
3.
Aging with disease and disability
Usual aging, with absence of overt pathology but
presence of some declines in function
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
Explain the free radical theory of aging.
Free radical accumulation
Oxidative 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.
What causes cellular senescence, what are the inducers
and what do they have in common?
Cell proliferation (replicative senescence)
= TELOMERE SHORTENING
DNA damage
Oncogene expression
Supermitogenic 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