Why we age Osher 106962

Why we ageOsher 106962

• Instructors: Matt Kaeberlein & Lara Shamieh• Meets Tuesdays 1/26, 2/2, 2/9, and 2/16, 10

AM – 11:50 AM, FSH 102 • Course web page:

http://www.sageweb.org/content/osher• Emails: [email protected] (Matt);

[email protected] (Lara); [email protected] (class)

http://www.sageweb.org/content/osher

mailto:[email protected]



Course topics

• Jan 26. Course introduction. Why we age and what causes aging.

• Feb 2. Calorie restriction. Does eating less help you live longer?

• Feb 9. Are there anti-aging drugs on the horizon? The red wine effect

• Feb 16. The importance of healthy aging. The relationship between aging-related diseases and healthy aging.

Today’s topics

• Introductions and ice breakers• Intro to aging-related research• Overview of human and cellular physiology• Possible molecular causes of aging

Introductions and ice breakers

• Why do you think aging happens?• What are the symptoms and diseases of

aging?• What kind of things have you heard about

that might influence how you age?• Would you want to live to be 150 years old?

Why or why not?

An (incorrect) definition of aging: The gradual changes in the structure and function of humans and animals that occur with the passage of time, that do not result from disease or other gross accidents, and that eventually lead to the increased probability of death as the person or animal grows older. It does not apply to microorganisms.

http://www.biology-online.org/dictionary/Aging

Bob Hope (1903-2003)

Introduction to aging-related research

An better definition of aging: The gradual changes in the structure and function of humans and most other organisms that occur with the passage of time, that do not result from gross accidents, and that eventually lead to the increased probability of death as the person or organism grows older.

http://www.biology-online.org/dictionary/Aging

Bob Hope (1903-2003)

Introduction to aging-related research

Oeppen and Vaupel. Science 296:1029 2006.

Average life span has increased recently

Man Profession Year of Birth (B.C.) Age at DeathPittacos King of Mytilenus c.650 ~ 80

Xenophanes Philosopher (Pre-Socratic) c.570 ~ 92

Pythagorus Mathematician c.570 ~ 80

Aristides Statesmen (Military General) c.540 ~ 72

Sophocles Playwrite (wrote Electra at the age of 82) c.495 ~ 90

Euripides Playwrite (Tragedy) c.485 ~ 76

Gorgias Philosopher (Sophist) c.483 105 or 109

Hippocrates Physician ("Father" of Modern Medicine) 460 90 or 100

Democrites Philosopher (Atomic Theory) c.460 90 or 100

Antisthenes Philosopher (Founder of Cynics School) c.445 ~ 80

Isocrates Logician (Rhetoric) 436 98

Plato Philosopher (The Republic) 429 81

Diogenes Philosopher (carried lantern) c.410 77 or 91

Xenocrates Philosopher (Platonist) c.400 ~ 86

Antipatros King of Macedonia c.397 ~ 78

Antigone 1st Successor to Alexander the Great 382 81

Theophrastes Philosopher (Aristotelian) 371 84

Ptolemy 1st Appointed Ruler of Egypt 367 84

Pyrrhon Philosopher (Founder of Skeptics) 365 90

Philemon Playwrite (Comedy) c.363 +/- 99

Seleucos 1st King of Syria c.358 +/- 78

Cleanthe Philosopher (Stoic) 331 99

Timon Disciple of Pyrrhon 320 90

“Maximum” life span has probably not changed

Extracting information from survival curves

Much greater increase in median life span than maximum life span suggests that healthspan has improved but rate of aging has not slowed.

Different people age differently

vs.

vs.

11/26/1939 12/18/1943


vs.

11/26/1939 12/18/1943

Aging is influenced by both genetic and environmental components


Hutchinson Gilford Progeria

• Hutchison Gilford Progeria (Mutations in nuclear structure gene)

• Werner Syndomes (Mutations in a DNA repair gene)

Progeroid diseases – aging quickly?

Jeanne Calment – aging slowly?

http://en.wikipedia.org/wiki/Jeanne_Calment

• Longest confirmed life span• 122 years, 164 days

• Born Feb 21, 1875 in Arles, France

• Took up fencing at 85; riding a bicycle at 100

• Quit smoking at 117• Ascribed her longevity to olive

oil, port wine, and chocolate

Goals of aging-related research

• Understand the molecular processes that cause aging

• Identify genetic and environmental interventions that slow aging

• Develop therapies to delay the onset of age-related diseases and improve healthspan

• Increase both median and maximum life span

AGINGStroke

Arthritis

Wrinkles

Frailty

Heart Disease

Type IIDiabetes

Cancer

Neurodegeneration

Slowing aging should slow progression of multiple age-associated diseases

What if aging could be slowed?

Increase in life expectancyfor a 50 year old woman

Cure cancer ~ 3 years

Cure cancer, heart disease, stroke, and kidney-related disease

~8-10 years

Slow aging 50% (starting at age 50) ~15-25 years

What if aging could be slowed?

Increase in life expectancyfor a 50 year old woman

Cure cancer ~ 3 years

Cure cancer, heart disease, stroke, and kidney-related disease

~8-10 years

Slow aging 50% (starting at age 50) ~15-25 years

Many different ways to do this have been discovered in lab animals!

Dietary restriction slows aging

Weindruch and Sohal, 1997

Dietary restriction slows aging in yeast, worms, flies, mice, rats, spiders, fish, and rhesus monkeys (note the change in both median and maximum survival)

Delays onset of most (all?) age-associated disease Does it work in humans?

Ad libDR

Rapamycin increases mouse life span

Rapamycin NIA Interventions Testing Program Rapamycin encapsulated in food Increase life span when started at 600

days of age (60 year old person) Already clinically approved for use in

people

Nature July 16, 2009

http://www.nia.nih.gov/ResearchInformation/ScientificResources/InterventionsTestingProgram.htm

Disconnect between funding and payoff

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Aging Cancer Heart Disease

Spending in billions

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150

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Aging Cancer HeartDisease

Pentagon

Spending in billions

???

Aging is shared across species

Even bacteria and yeast age In general, bigger organisms

live longer Some interesting exceptions

(e.g. naked mole rat)

http://www.senescence.info/comparative.html

Why do organisms age?

• Idea #1: Aging is programmed– Necessary to prevent older generations from

competing for resources• Idea #2: Aging occurs because there’s no

evolutionary advantage to not aging– Once you produce sufficient offspring you’re

expendable.

Programmed aging can’t explain this

If there were a “death program” in our genetic code, life expectancy couldn’t increase so dramatically over so few generations.

Natural selection won’t stop aging

Natural selection strongest early in life Favors growth and fecundity

Effects of aging strongest late in life Primarily post-reproductive

What would it cost NOT to age? repair and maintenance = reproduction

Growth, fecundity, Aging

RepairLongevity

Key ideas so far

Aging is a biological process that is under both genetic and environmental control

Aging is likely the result of an absence of evolutionary pressure to prevent it. There is no aging “program”.

Average human life span has increased dramatically recently, but maximum life span hasn’t = we haven’t really influenced the rate of aging very much (if at all)

Many interventions are known to slow aging in laboratory animals (e.g. dietary restriction)

If this can be extended to humans, the impact is much greater than curing any single disease

A brief review of human and cell physiology

Pathologies of Aging

AGINGStroke

Arthritis

Wrinkles

Frailty

Heart Disease

Type IIDiabetes

Cancer

Neurodegeneration

Systems of the Human Body Decline With Age

Is there an underlying coordinated decline across systems of the body?

skeletal

muscular

cardiovascular

nervous

Age-Related Decline in Individual Organs is Also Observed

Organelles of the Human Cell

Close-Up Schematic of the Human Nucleus

Hutchinson-Gilford progeria is caused by a defect in nuclear structure

What Causes Aging?

Possible molecular causes of aging

Telomere Shortening

Cellular Senescence

Advanced Glycation Endproducts

DNA Damage

Free Radicals / Reactive Oxygen Species

Mitochondrial Damage

How do telomeres contribute to aging?

Telomeres are TTAGGG nucleotide repeats on the end of chromosomes

Telomeres protect the DNA, by functioning as “caps” Each time the DNA is copied, the telomere gets slightly shorter

Telomeres and Aging

Two studies show a direct correlation between telomere length and life expectancyBoth are controversial studies

One study showed an inverse correlation between telomere length and stress

What Causes Aging?

Telomere Shortening

Cellular Senescence


DNA Damage



Cellular Senescence

What Causes Aging?

Telomere Shortening

Cellular Senescence


DNA Damage



Advanced Glycation Endproducts (AGEs)

AGEs are the result of inappropriate reactions between sugars, proteins, and oxoaldehydes

AGEs attack normal long-lived proteins such as collagen and other structural proteinsAGEs make bones, tendons, skin, arteries and veins more stiff and less elastic

•Inflammatory Disease

•Diabetes

•Athlosclerosis and Heart Disease

•Macular Degeneration

•Osteoarthritis

•Alzheimer’s Disease

•Poor Bone Healing

Role of AGEs in Diabetes

Role of AGEs in Diabetes

What Causes Aging?

Telomere Shortening

Cellular Senescence


DNA Damage



DNA Damage and Aging

When damage is not repaired, it results in an increase in mutations that may lead to aging and cancer

Premature Human Aging Diseases and DNA DamageWerner’s Syndrome is caused by mutations in WRN1, a DNA helicase protein

Patients have shorter than normal telomeres

Cockayne Syndrome is caused by a defect in DNA repair proteins

Xeroderma Pigmentosum is caused by a defect in DNA repair proteinsLeads to a marked increase in skin cancers at a young age

Little boy with Cockayne Syndrome – aged 9

What Causes Aging?

Telomere Shortening

Cellular Senescence


DNA Damage



Free Radicals and Reactive Oxygen Species (ROS)

Mitochondria – The Powerhouse of the Cell

Free Radicals: A By-Product of the Electron Chain

What Causes Aging?

Telomere Shortening

Cellular Senescence


DNA Damage



Mitochondrial Damage and AgingFree radicals produced by mitochondria can come back to damage proteins in the mitochondria

This leads to decreased and improper mitochondrial function

Recent studies have shown that free radicals attack, DRP-1 (a mitochondrial protein) that leads to mitochondrial fragmentation, damaging synapses and eventually leading to nerve cell death.

Mitochondrial Damage and Alzheimer’s Disease

The Causes of Aging are Interlinked:(It is hard to separate one from the other)

Telomere Shortening

Cellular Senescence


DNA Damage



Documents

Why we age Osher 106962