MCB 135K: Discussion
February 6, 2005
GSI: Laura Epstein
Topics
1. Epidemiology of Aging
2. Telomeres
EPIDEMIOLOGY OF AGING
• THE STUDY OF THE AGE-RELATED
DISTRIBUTION AND CAUSES OF
DISEASE, DISABILITY, AND
MORTALITY IN HUMAN
POPULATIONS.
EPIDEMIOLOGY OF AGING
• WHY IMPORTANT?
– AGING OF THE HUMAN POPULATION
– HEALTH AND VITALITY OF AN AGING
POPULATION
– QUALITY OF LIFE AND COST OF CARE
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?
• ACCUMULATION OF
ENVIRONMENTAL/BEHAVIORAL INSULTS.
• REDUCED IMMUNOLOGICAL
SURVEILLANCE
EPIDEMIOLOGY OF AGING
EPIDEMIOLOGY OF AGING
• AGING OF THE U.S. POPULATION,
PERCENTAGE AGED 65+ YEARS BY YEAR
1900
1940
1980
2000
2030
4.0%
8.0%
11.5%
12.6%
20.0%
EPIDEMIOLOGY OF AGING
• THERE IS CONSIDERABLE
VARIABILITY BY REGION OF THE
COUNTRY, 2000
– FLORIDA
– CALIFORNIA
– ALASKA
18.1%
10.4%
5.8%
EPIDEMIOLOGY OF AGING
• RACE, ETHNICITY, AND AGE, U.S.
2000
2050
NH white 83.5%
NH black
8.1
NH Asian/PI 2.4
Hispanic
5.6
64.2%
12.2
6.5
16.4
EPIDEMIOLOGY OF AGING
• Global Differences in the Aging of the
Population
– Number of years required to increase the
percentage of people aged 65+ from 7% to
14%.
–
–
–
–
France: 115 years (1865-1980)
Japan:
26 years (1970-1996)
Chile:
20 years (2000-2020)
Tunisia 15 years (2020-2035)
Elderly Support Ratio,
2000-2030
• Ratio = Number of people aged 65+ per 100
aged 20-64
• USA
– 2000
– 2030
21 per 100
37 per 100
Elderly Support Ratio
2000-2030
•
•
•
•
•
Italy
Japan
China
India
Guatemala
2000
29
27
12
9
8
2030
49
52
26
15
11
EPIDEMIOLOGY OF AGING
• MAJOR AGE-ASSOCIATED CAUSES OF
DEATH
– CARDIOVASCULAR DISEASE
– CANCER
– CHRONIC OBSTRUCTIVE PULMONARY
DISEASE
– DIABETES
EPIDEMIOLOGY OF AGING
AGE-SPECIFIC COLORECTAL
CANCER INCIDENCE RATES
(Per 100,000 in population)
<65
65+
WM WF
BM BF
20.4 14.7 25.3 20.4
408.0 269.3 385.8 286.1
EPIDEMIOLOGY OF AGING
• COGNITIVE FUNCTION
• Moderate/Severe Memory defined as four or fewer
words recalled (out of 20) on combined immediate
and delayed recall tests. Source: Health and
Retirement Survey.
•
• 65-69
• 85+
Male
5.3
37.3
Female
3.8
35.0
EPIDEMIOLOGY OF AGING
• DEPRESSIVE SYMPTOMS
Males
• 65-69
• 85 +
12.1
22.5
Females
18.0
23.0
EPIDEMIOLOGY OF AGING
• PERCENT OF MEN AND WOMEN
AGED 60+ REPORTING TWO OR MORE
HEALTH CONDITIONS
•
MEN
WOMEN
• 60-69
35
45
• 70-79
47
61
• 80+
53
70
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
• CAUSES OF FALLS IN THE ELDERLY
• - DIZZINESS
• - POOR COGNITIVE FUNCTION
• - VISION PROBLEMS
• - GENERAL FRAILTY
• - ENVIRONMENTAL HAZARDS
EPIDEMIOLOGY OF AGING
• Types of studies
–
–
–
–
–
Clinic/Laboratory-Based Studies
Adapted Population Studies
Established Population Studies
Special General Population Studies
Special Chronic Disease Studies
• Types of Research Designs
– Case-Control Studies
– Longitudinal or Prospective Studies
EPIDEMIOLOGY OF AGING
• STRATEGIES TO ENHANCE HEALTH
AND FUNCTIONING THROUGH
PHYSICAL ACTIVITY—it seems to be an
“elixir”
– RWJ PROGRAM IN “ACTIVE FOR LIFE”
– RWJ PROGRAM IN “ACTIVE
ENVIRONMENTS”
Questions
• Why are older people at elevated risk for disease,
disability and death?
• In the US, which age/ethnic group will increase
the most between 2000 and 2050?
• Who has a higher frequency of 2 or more health
conditions, men or women?
• Why is it important to look at the epidemiology of
falls, and why are we concerned about this?
TELOMERES
What are they?
Why are they important?
Telomere shortening and the end-replication problem
Telomerase
Telomere hypothesis of aging
Telomeres
Ends of linear chromosomes
Centromere
Telomere
Telomere
Repetitive DNA sequence
(TTAGGG in vertebrates)
Specialized proteins
Form a 'capped' end structure
TELOMERE STRUCTURE
5’
3’
Telomeric
t loop
5'
3'
NUCLEAR
MATRIX
Telomeric
proteins:
TRF1
TRF2
TIN2
RAP1
TANKS 1,2
POT1
etc
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)
Why are telomeres important?
Prevent chromosome fusions by NHEJ
NHEJ
FUSION
BRIDGE
Mitosis
BREAKAGE
Fusion-bridge-breakage cycles
Genomic instability
Cell death OR neoplastic transformation
Proliferative capacity
Telomere also provide a means for
"counting" cell division
Finite
Replicative
Life Span
"Mortal"
Infinite
Replicative
Life Span
"Immortal"
Number of cell divisions
How do cells "know" how many
divisions they have completed??
The End Replication Problem:
Telomeres shorten with each S phase
5'
3'
3'
5'
3'
5'
3'
5'
5'
DNA replication is bidirectional
Polymerases move 5' to 3'
Requires a labile primer
Ori
Each round of DNA
replication leaves
50-200 bp DNA unreplicated
at the 3' end
TELOMERASE:
Key to replicative immortality
+ TELOMERASE
Overcomes telomere shortening and the endreplication problem
Expressed by germ cells, early embryonic cells
Not expressed by most somatic cells (human)
May be expressed by some stem cells, but highly controlled
Expressed by 80-90% of cancer cells
(remaining still need to overcome the end replication problem;
do so by recombinational mechanisms -ALT (alternative lengthening of telomeres) mechanisms
HOWEVER,
CELLS THAT EXPRESS TELOMERASE
STILL UNDERGO SENESCENCE
(E.G., IN RESPONSE TO DNA
DAMAGE, ONCOGENES, ETC.)
Telomerase:
Biomedical uses
Expand cells for replacement therapies
(burns, joint replacements, etc)
Telomerase inhibitors to selectively kill cancer cells
The telomere hypothesis of aging
Telomeres shorten with each cell division
and therefore with age
TRUE
Short telomeres cause cell senescence and
senescent cells may contribute to aging
TRUE
HYPOTHESIS:
Telomere shortening causes aging and
telomerase will prevent aging
TRUE OR FALSE?
The telomere hypothesis of aging
Telomere length is not related to life span
(mice vs human; M musculus vs M spretus)
Telomeres contribute to aging ONLY if
senescent cells contribute to aging
Telomerase protects against replicative
senescence but not senescence induce by
other causes
SUMMARY
Telomeres are essential for chromosome stability
Telomere shortening occurs owing to the biochemistry of
DNA replication
Short telomeres cause replicative senescence
(other senescence causes are telomere-independent)
Telomerase prevents telomere shortening and
replicative senescence
The telomere hypothesis of aging depends on the
cellular senescence hypothesis of aging
Questions
•
•
•
•
What are telomeres?
Why are telomeres important?
What is telomerase?
True or false: Telomeres protect cells from
ALL types of senescence.
• What is the telomere hypothesis of aging?