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 unknown. in vivo In vitro function remains , 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 4.0% 8.0% 1980 11.5% 2000 12.6% 2030 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)

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

20

Germ Cells

(Telomerase Positive) 10

Normal Somatic Cells

(Telomerase Negative)

+ Telomerase 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.