why we age osher 106962
DESCRIPTION
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 PresentationTRANSCRIPT
![Page 1: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/1.jpg)
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)
![Page 2: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/2.jpg)
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.
![Page 3: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/3.jpg)
Today’s topics
• Introductions and ice breakers• Intro to aging-related research• Overview of human and cellular physiology• Possible molecular causes of aging
![Page 4: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/4.jpg)
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?
![Page 5: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/5.jpg)
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
![Page 6: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/6.jpg)
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
![Page 7: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/7.jpg)
Oeppen and Vaupel. Science 296:1029 2006.
Average life span has increased recently
![Page 8: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/8.jpg)
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
![Page 9: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/9.jpg)
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.
![Page 10: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/10.jpg)
Different people age differently
vs.
![Page 11: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/11.jpg)
vs.
11/26/1939 12/18/1943
Different people age differently
![Page 12: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/12.jpg)
vs.
11/26/1939 12/18/1943
Aging is influenced by both genetic and environmental components
Different people age differently
![Page 13: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/13.jpg)
Hutchinson Gilford Progeria
• Hutchison Gilford Progeria (Mutations in nuclear structure gene)
• Werner Syndomes (Mutations in a DNA repair gene)
Progeroid diseases – aging quickly?
![Page 14: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/14.jpg)
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
![Page 15: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/15.jpg)
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
![Page 16: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/16.jpg)
AGINGStroke
Arthritis
Wrinkles
Frailty
Heart Disease
Type IIDiabetes
Cancer
Neurodegeneration
Slowing aging should slow progression of multiple age-associated diseases
![Page 17: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/17.jpg)
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
![Page 18: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/18.jpg)
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!
![Page 19: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/19.jpg)
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
![Page 20: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/20.jpg)
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
![Page 21: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/21.jpg)
Disconnect between funding and payoff
0
1
2
3
4
5
6
7
8
9
Aging Cancer Heart Disease
Spending in billions
![Page 22: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/22.jpg)
0
50
100
150
200
250
300
350
400
450
500
Aging Cancer HeartDisease
Pentagon
Spending in billions
???
![Page 23: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/23.jpg)
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
![Page 24: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/24.jpg)
![Page 25: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/25.jpg)
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.
![Page 26: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/26.jpg)
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.
![Page 27: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/27.jpg)
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
![Page 28: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/28.jpg)
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
![Page 29: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/29.jpg)
A brief review of human and cell physiology
![Page 30: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/30.jpg)
Pathologies of Aging
AGINGStroke
Arthritis
Wrinkles
Frailty
Heart Disease
Type IIDiabetes
Cancer
Neurodegeneration
![Page 31: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/31.jpg)
Systems of the Human Body Decline With Age
Is there an underlying coordinated decline across systems of the body?
skeletal
muscular
cardiovascular
nervous
![Page 32: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/32.jpg)
Age-Related Decline in Individual Organs is Also Observed
![Page 33: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/33.jpg)
Organelles of the Human Cell
![Page 34: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/34.jpg)
Close-Up Schematic of the Human Nucleus
Hutchinson-Gilford progeria is caused by a defect in nuclear structure
![Page 35: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/35.jpg)
What Causes Aging?
![Page 36: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/36.jpg)
Possible molecular causes of aging
Telomere Shortening
Cellular Senescence
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial Damage
![Page 37: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/37.jpg)
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
![Page 38: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/38.jpg)
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
![Page 39: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/39.jpg)
What Causes Aging?
Telomere Shortening
Cellular Senescence
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial Damage
![Page 40: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/40.jpg)
Cellular Senescence
![Page 41: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/41.jpg)
What Causes Aging?
Telomere Shortening
Cellular Senescence
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial Damage
![Page 42: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/42.jpg)
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
![Page 43: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/43.jpg)
Role of AGEs in Diabetes
![Page 44: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/44.jpg)
Role of AGEs in Diabetes
![Page 45: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/45.jpg)
What Causes Aging?
Telomere Shortening
Cellular Senescence
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial Damage
![Page 46: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/46.jpg)
DNA Damage and Aging
When damage is not repaired, it results in an increase in mutations that may lead to aging and cancer
![Page 47: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/47.jpg)
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
![Page 48: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/48.jpg)
What Causes Aging?
Telomere Shortening
Cellular Senescence
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial Damage
![Page 49: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/49.jpg)
Free Radicals and Reactive Oxygen Species (ROS)
![Page 50: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/50.jpg)
Mitochondria – The Powerhouse of the Cell
![Page 51: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/51.jpg)
Free Radicals: A By-Product of the Electron Chain
![Page 52: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/52.jpg)
What Causes Aging?
Telomere Shortening
Cellular Senescence
Advanced Glycation Endproducts
DNA Damage
Free Radicals / Reactive Oxygen Species
Mitochondrial Damage
![Page 53: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/53.jpg)
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
![Page 54: Why we age Osher 106962](https://reader036.vdocuments.us/reader036/viewer/2022062410/568161ec550346895dd2210e/html5/thumbnails/54.jpg)
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