MCB 135K: Discussion February 7, 2005 GSI: Laura Epstein

MCB 135K: Discussion

February 7, 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.


• WHY IMPORTANT?– AGING OF THE HUMAN POPULATION– HEALTH AND VITALITY OF AN AGING

POPULATION– QUALITY OF LIFE AND COST OF CARE


• 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.


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

• ACCUMULATION OF ENVIRONMENTAL/BEHAVIORAL INSULTS.

• REDUCED IMMUNOLOGICAL SURVEILLANCE



• 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%


• THERE IS CONSIDERABLE VARIABILITY BY REGION OF THE COUNTRY, 2000

– FLORIDA 18.1%– CALIFORNIA 10.4%– ALASKA 5.8%


• 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


• 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 21 per 100– 2030 37 per 100

Elderly Support Ratio2000-2030

2000 2030

• Italy 29 49

• Japan 27 52

• China 12 26

• India 9 15

• Guatemala 8 11


• MAJOR AGE-ASSOCIATED CAUSES OF DEATH

– CARDIOVASCULAR DISEASE

– CANCER

– CHRONIC OBSTRUCTIVE PULMONARY DISEASE

– DIABETES


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


• 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


• DEPRESSIVE SYMPTOMS

Males Females

• 65-69 12.1 18.0

• 85 + 22.5 23.0


• 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


• 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.


• CAUSES OF FALLS IN THE ELDERLY

• - DIZZINESS

• - POOR COGNITIVE FUNCTION

• - VISION PROBLEMS

• - GENERAL FRAILTY

• - ENVIRONMENTAL HAZARDS


• 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


• 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

TelomereTelomere

Repetitive DNA sequence(TTAGGG in vertebrates)

Specialized proteins

Form a 'capped' end structure

TELOMERE STRUCTURE

5’ 3’

5'

3'

Telomerict loop

Telomericproteins:

TRF1TRF2TIN2RAP1

TANKS 1,2POT1

etc

NUCLEARMATRIX

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)

Why are telomeres important?Prevent chromosome fusions by NHEJ

NHEJ

Mitosis

FUSIONBRIDGE

BREAKAGE

Fusion-bridge-breakage cycles

Genomic instability

Cell death OR neoplastic transformation

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??

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

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

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 andsenescent cells may contribute to aging

TRUE

HYPOTHESIS:Telomere shortening causes aging and

telomerase will prevent agingTRUE 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 replicativesenescence but not senescence induce by

other causes

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

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?

Documents

MCB 135K: Discussion February 7, 2005 GSI: Laura Epstein