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Why we age Osher 106962

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: kaeber@uw.edu (Matt); shamieh@uw.edu (Lara); osher@kaeberleinlab.org (class).

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Why we age Osher 106962

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  1. 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: kaeber@uw.edu (Matt); shamieh@uw.edu (Lara); osher@kaeberleinlab.org (class)

  2. 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.

  3. Today’s topics • Introductions and ice breakers • Intro to aging-related research • Overview of human and cellular physiology • Possible molecular causes of aging

  4. 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?

  5. Introduction to aging-related research 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. Bob Hope (1903-2003) http://www.biology-online.org/dictionary/Aging

  6. 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. Bob Hope (1903-2003) http://www.biology-online.org/dictionary/Aging

  7. Average life span has increased recently Oeppen and Vaupel. Science 296:1029 2006.

  8. “Maximum” life span has probably not changed

  9. 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.

  10. Different people age differently vs.

  11. Different people age differently vs. 11/26/1939 12/18/1943

  12. Different people age differently vs. 11/26/1939 12/18/1943 Aging is influenced by both genetic and environmental components

  13. Hutchison Gilford Progeria (Mutations in nuclear structure gene) • Werner Syndomes (Mutations in a DNA repair gene) Progeroid diseases – aging quickly? Hutchinson Gilford Progeria

  14. Jeanne Calment – aging slowly? • 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 http://en.wikipedia.org/wiki/Jeanne_Calment

  15. 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

  16. Slowing aging should slow progression of multiple age-associated diseases Neurodegeneration Frailty Cancer AGING Stroke Wrinkles Type II Diabetes Heart Disease Arthritis

  17. What if aging could be slowed?

  18. What if aging could be slowed? Many different ways to do this have been discovered in lab animals!

  19. Weindruch and Sohal, 1997 Dietary restriction slows aging DR Ad lib • Dietary restriction slows aging in yeast, worms, flies, mice, rats, spiders, fish, andrhesus monkeys (note the change in both median and maximum survival) • Delays onset of most (all?) age-associated disease • Does it work in humans?

  20. Rapamycin increases mouse life span Nature July 16, 2009 • 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 Rapamycin http://www.nia.nih.gov/ResearchInformation/ScientificResources/InterventionsTestingProgram.htm

  21. Disconnect between funding and payoff

  22. ???

  23. 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

  24. 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.

  25. 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.

  26. 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 Repair Longevity Growth, fecundity, Aging

  27. 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

  28. A brief review of human and cell physiology

  29. Pathologies of Aging Neurodegeneration Frailty Cancer AGING Stroke Wrinkles Type II Diabetes Heart Disease Arthritis

  30. Systems of the Human Body Decline With Age skeletal cardiovascular muscular nervous Is there an underlying coordinated decline across systems of the body?

  31. Age-Related Decline in Individual Organs is Also Observed

  32. Organelles of the Human Cell

  33. Close-Up Schematic of the Human Nucleus Hutchinson-Gilford progeria is caused by a defect in nuclear structure

  34. What Causes Aging?

  35. Possible molecular causes of aging Telomere Shortening Cellular Senescence Advanced GlycationEndproducts DNA Damage Free Radicals / Reactive Oxygen Species Mitochondrial Damage

  36. 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

  37. Telomeres and Aging Two studies show a direct correlation between telomere length and life expectancy Both are controversial studies One study showed an inverse correlation between telomere length and stress

  38. What Causes Aging? Telomere Shortening Cellular Senescence Advanced GlycationEndproducts DNA Damage Free Radicals / Reactive Oxygen Species Mitochondrial Damage

  39. Cellular Senescence

  40. What Causes Aging? Telomere Shortening Cellular Senescence Advanced GlycationEndproducts DNA Damage Free Radicals / Reactive Oxygen Species Mitochondrial Damage

  41. Advanced GlycationEndproducts (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 proteins AGEs 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

  42. Role of AGEs in Diabetes

  43. Role of AGEs in Diabetes

  44. What Causes Aging? Telomere Shortening Cellular Senescence Advanced GlycationEndproducts DNA Damage Free Radicals / Reactive Oxygen Species Mitochondrial Damage

  45. DNA Damage and Aging When damage is not repaired, it results in an increase in mutations that may lead to aging and cancer

  46. Premature Human Aging Diseases and DNA Damage Werner’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 XerodermaPigmentosum is caused by a defect in DNA repair proteins Leads to a marked increase in skin cancers at a young age Little boy with Cockayne Syndrome – aged 9

  47. What Causes Aging? Telomere Shortening Cellular Senescence Advanced GlycationEndproducts DNA Damage Free Radicals / Reactive Oxygen Species Mitochondrial Damage

  48. Free Radicals and Reactive Oxygen Species (ROS)

  49. Mitochondria – The Powerhouse of the Cell

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