Transcript 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.
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
• 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
• MAJOR AGE-ASSOCIATED CAUSES OF
DEATH
– CARDIOVASCULAR DISEASE
– CANCER
– CHRONIC OBSTRUCTIVE PULMONARY
DISEASE
– DIABETES
EPIDEMIOLOGY OF AGING
• FUNCTIONAL LIMITATIONS –
DIFFICULITIES IN THE
PERFORMANCE OF GENERIC TASKS,
E.G., THOSE RELATED TO UPPER- AND
LOWER-BODY STRENGTH, BALANCE,
AND FINE DEXTERITY.
EPIDEMIOLOGY OF AGING
• DISABILITY – DIFFICULTY OR
INABILITY IN THE PERFORMANCE OF
A SOCIAL ROLE CAUSED BY A
PHYSICAL OR COGNITIVE PROBLEM.
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
• 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 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)
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??
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
Telomere Length and Cell Division Potential
Telomere Length (humans)
20
10
Germ Cells (Telomerase Positive)
Normal
Somatic
Cells
+ Telomerase
(Telomerase
Negative)
Cellular (Replicative) Senescence
Number of Doublings
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?
Telomere 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
The p53 Tumor Suppressor
Stress
Genome Stress
DNA damage
Oxidative Stress
p53
Apoptosis
Senescence
Growth Inhibition
- 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 absence
of natural selection.
Life Span - results from a balance between two major
selective 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.