MCB 135K: Discussion

MCB 135K: Discussion

February 9, 2005

GSI: Jason Lowry

Topics

1. Epidemiology of Aging

2. Telomeres

3. Evolution and Aging

Werner’s Syndrome

• The gene responsible for Werner syndrome was identified by a team led by Shellenberg and Martin in 1996. The WRN gene encodes a DNA helicase of the RecQ family [HQ] - however its in vivo function remains unknown. In vitro, WRN protein unwinds double-stranded DNA and has a high affinity for qudruplex "G-DNA", a structure that may form at telomeres, ribosomal DNA [HQ] (rDNA) and other GC-rich sequences

EPIDEMIOLOGY OF AGING

• THE STUDY OF THE AGE-RELATED DISTRIBUTION AND CAUSES OF DISEASE, DISABILITY, AND MORTALITY IN HUMAN POPULATIONS.


• 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%


• MAJOR AGE-ASSOCIATED CAUSES OF DEATH

– CARDIOVASCULAR DISEASE

– CANCER

– CHRONIC OBSTRUCTIVE PULMONARY DISEASE

– DIABETES


• FUNCTIONAL LIMITATIONS – DIFFICULITIES IN THE PERFORMANCE OF GENERIC TASKS, E.G., THOSE RELATED TO UPPER- AND LOWER-BODY STRENGTH, BALANCE, AND FINE DEXTERITY.


• DISABILITY – DIFFICULTY OR INABILITY IN THE PERFORMANCE OF A SOCIAL ROLE CAUSED BY A PHYSICAL OR COGNITIVE PROBLEM.


• 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.


• FEMALES AGED 55-64 ARE MORE LIKELY THAN MEN OF THE SAME AGE TO LIMIT OR AVOID LTPA BECAUSE OF THE ABSENCE OF AN EXERCISE COMPANION.

• NEARLY 1/3 OF WOMEN AGED 75+ REPORT THE ABSENCE OF AN EXERCISE COMPANION AS A LEADING REASON.

• AMONG MARRIED COUPLES, THE LTPA OF THE SPOUSE WAS THE BEST PREDICTOR OF THE SUBJECT’S LTPA.

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)

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??

TELOMERASE:Key to replicative immortality

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

Telo

mere

Len

gth

(h

um

an

s)

Number of Doublings

20

10

Cellular (Replicative) Senescence

Normal Somatic Cells

(Telomerase Negative)

Germ Cells (Telomerase Positive)

+ Telomerase

Telomere Length and Cell Division Potential

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?

Telomere 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

StressGenome Stress

DNA damageOxidative Stress

p53ApoptosisSenescenceGrowth Inhibition

The p53 Tumor Suppressor

- Loss of p53 function results in an increased incidence of cancer

- p53 is mutated in ~80% of all human tumors

Evolution Basics

Natural Selection -The process by which the individual with the greatest fitness is selected from a population of genetically variable individuals of one species.

Fitness = reproductive success

Individuals with the best reproductive success have more offspring.And so on, and so on, until the adaptation (gene) that led to greater reproductive success is present throughout the species.

Evolution (natural selection) will only act on genes (traits) that lead to greater reproductive success.

Evolutionary Theories of Aging

Disposable Soma - Somatic cells are maintained only to ensure

continued reproductive success, following reproduction

the soma is disposable. (life span theory)

Antagonistic Pleiotropy - Genes that are beneficial at younger

ages are deleterious at older ages.

Mutation Accumulation - Mutations that affect health at older

ages are not selected against (no strong evidence).

Life Span versus Aging

Aging - can not be selected for, results from an absenceof natural selection.

Life Span - results from a balance between two majorselective forces.

Environmental Selection - predators, natural hazards

Social Selection - parental investment, sexual behavior

Main Ideas

1. Life span results from selective pressure.

2. Life span is inversely proportional to extrinsic mortality.

3. Aging results from a lack of natural selection with age.

Documents

MCB 135K: Discussion