mcb 135k: discussion
DESCRIPTION
MCB 135K: Discussion. February 7, 2005 GSI: Laura Epstein. Topics. Epidemiology of Aging 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? - PowerPoint PPT PresentationTRANSCRIPT
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MCB 135K: Discussion
February 7, 2005
GSI: Laura Epstein
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Topics
1. Epidemiology of Aging
2. Telomeres
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EPIDEMIOLOGY OF AGING
• THE STUDY OF THE AGE-RELATED DISTRIBUTION AND CAUSES OF DISEASE, DISABILITY, AND MORTALITY IN HUMAN POPULATIONS.
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EPIDEMIOLOGY OF AGING
• WHY IMPORTANT?– AGING OF THE HUMAN POPULATION– HEALTH AND VITALITY OF AN AGING
POPULATION– QUALITY OF LIFE AND COST OF CARE
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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.
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EPIDEMIOLOGY OF AGING
• WHY ARE OLDER PEOPLE AT ELEVATED RISK FOR DISEASE, DISABILITY, AND DEATH?
• ACCUMULATION OF ENVIRONMENTAL/BEHAVIORAL INSULTS.
• REDUCED IMMUNOLOGICAL SURVEILLANCE
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EPIDEMIOLOGY OF AGING
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EPIDEMIOLOGY OF AGING
• AGING OF THE U.S. POPULATION, PERCENTAGE AGED 65+ YEARS BY YEAR
1900 4.0%1940 8.0%1980 11.5%
2000 12.6% 2030 20.0%
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EPIDEMIOLOGY OF AGING
• THERE IS CONSIDERABLE VARIABILITY BY REGION OF THE COUNTRY, 2000
– FLORIDA 18.1%– CALIFORNIA 10.4%– ALASKA 5.8%
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EPIDEMIOLOGY OF AGING
• RACE, ETHNICITY, AND AGE, U.S.
2000 2050
NH white 83.5% 64.2%
NH black 8.1 12.2
NH Asian/PI 2.4 6.5
Hispanic 5.6 16.4
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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)
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Elderly Support Ratio,2000-2030
• Ratio = Number of people aged 65+ per 100 aged 20-64
• USA – 2000 21 per 100– 2030 37 per 100
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Elderly Support Ratio2000-2030
2000 2030
• Italy 29 49
• Japan 27 52
• China 12 26
• India 9 15
• Guatemala 8 11
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EPIDEMIOLOGY OF AGING
• MAJOR AGE-ASSOCIATED CAUSES OF DEATH
– CARDIOVASCULAR DISEASE
– CANCER
– CHRONIC OBSTRUCTIVE PULMONARY DISEASE
– DIABETES
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EPIDEMIOLOGY OF AGING
AGE-SPECIFIC COLORECTAL CANCER INCIDENCE RATES
(Per 100,000 in population)
WM WF BM BF
<65 20.4 14.7 25.3 20.4
65+ 408.0 269.3 385.8 286.1
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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.
• Male Female• 65-69 5.3 3.8• 85+ 37.3 35.0
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EPIDEMIOLOGY OF AGING
• DEPRESSIVE SYMPTOMS
Males Females
• 65-69 12.1 18.0
• 85 + 22.5 23.0
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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
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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.
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EPIDEMIOLOGY OF AGING
• CAUSES OF FALLS IN THE ELDERLY
• - DIZZINESS
• - POOR COGNITIVE FUNCTION
• - VISION PROBLEMS
• - GENERAL FRAILTY
• - ENVIRONMENTAL HAZARDS
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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
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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”
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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?
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TELOMERES
What are they?
Why are they important?
Telomere shortening and the end-replication problem
Telomerase
Telomere hypothesis of aging
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Telomeres
Ends of linear chromosomes
Centromere
TelomereTelomere
Repetitive DNA sequence(TTAGGG in vertebrates)
Specialized proteins
Form a 'capped' end structure
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TELOMERE STRUCTURE
5’ 3’
5'
3'
Telomerict loop
Telomericproteins:
TRF1TRF2TIN2RAP1
TANKS 1,2POT1
etc
NUCLEARMATRIX
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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)
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Why are telomeres important?Prevent chromosome fusions by NHEJ
NHEJ
Mitosis
FUSIONBRIDGE
BREAKAGE
Fusion-bridge-breakage cycles
Genomic instability
Cell death OR neoplastic transformation
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Telomere also provide a means for "counting" cell division
Pro
lifer
ativ
e ca
paci
ty
Number of cell divisions
FiniteReplicativeLife Span"Mortal"
InfiniteReplicativeLife Span"Immortal"
How do cells "know" how many divisions they have completed??
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The End Replication Problem:Telomeres shorten with each S phase
OriDNA 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
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TELOMERASE:Key to replicative immortality
+ TELOMERASE
Overcomes telomere shortening and the end-replication 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
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HOWEVER,
CELLS THAT EXPRESS TELOMERASE
STILL UNDERGO SENESCENCE
(E.G., IN RESPONSE TO DNA DAMAGE, ONCOGENES, ETC.)
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Telomerase:Biomedical uses
Expand cells for replacement therapies(burns, joint replacements, etc)
Telomerase inhibitors to selectively kill cancer cells
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The telomere hypothesis of aging
Telomeres shorten with each cell division and therefore with age
TRUE
Short telomeres cause cell senescence andsenescent cells may contribute to aging
TRUE
HYPOTHESIS:Telomere shortening causes aging and
telomerase will prevent agingTRUE OR FALSE?
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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 replicativesenescence but not senescence induce by
other causes
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SUMMARY
Telomeres are essential for chromosome stability
Telomere shortening occurs owing to the biochemistry ofDNA replication
Short telomeres cause replicative senescence (other senescence causes are telomere-independent)
Telomerase prevents telomere shortening andreplicative senescence
The telomere hypothesis of aging depends on the cellular senescence hypothesis of aging
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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?