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Why we age Osher 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). - PowerPoint PPT Presentation
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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)
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
Different people age differently
vs.
11/26/1939 12/18/1943
Aging is influenced by both genetic and environmental components
Different people age differently
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
0
50
100
150
200
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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
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial Damage
Cellular Senescence
What Causes Aging?
Telomere Shortening
Cellular Senescence
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial 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
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial 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
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial 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
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial 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
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial Damage