Gordon Lithgow at Health Extension Salon #7

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Dr. Lithgow, from the Buck Institute, presents evidence from his lab that multiple age-related diseases share a common root in cellular aging processes, and furthermore that interventions designed to affect the aging process could prevent or delay such diseases.

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Gordon Lithgow at Health Extension Salon #7

  1. 1. The Buck Institute forResearch on AgingInterdisciplinary Research Center on Geroscience
  2. 2. Kathleen Casey-Kirschling
  3. 3. Kathleen Casey-Kirschling1st Jan, 1946, 00.01AM
  4. 4. The Choice
  5. 5. Mechanisms of aging and disease are tightly linkedAging can be slowed
  6. 6. cardiovascular diseaseParkinson’s DiseaseHuntington’s DiseaseAlzheimer’s Diseasediabetessarcopeniaosteoperosisosteoarthritismacular degenerationadult cancer
  7. 7. tuberculosissmall poxpoliosyphilisGerman measlesmumpschicken poxpertussisdiphtheriatenatusflu
  8. 8. cardiovascular diseaseParkinson’s DiseaseHuntington’s DiseaseAlzheimer’s Diseasediabetessarcopeniaosteoperosisosteoarthritismacular degenerationadult cancer
  9. 9. Agingcardiovascular diseaseParkinson’s DiseaseHuntington’s DiseaseAlzheimer’s Diseasediabetes sarcopeniaosteoporosisosteoarthritismacular degenerationadult cancer
  10. 10. What is aging?
  11. 11. Longevity Variation• Roundworm – 15 days• Fruit Fly – 50 days• Mouse – 2-3 years• Naked mole rate – 30+ years• Human - 82 years• Bowhead whales – 180 years• Quahog clam - 220 years
  12. 12. Ocean quahog(Arctica islandica)507 yr
  13. 13. Famous people born at the same timeas currently living clamsMary Queen of Scots(1542-1587)
  14. 14. Why is aging a risk factor for disease?
  15. 15. How are we getting to the answer?
  16. 16. age-1
  17. 17. Age (days)0 5 10 15 20 25 30 35FractionAlive0.00.20.40.60.81.00 5 10 15 20 25 30 35 40 45 50 55 60age-1Wild type (N2)Copyright – Gordon J. Lithgow
  18. 18. • Surprisingly easy to modulate aging andincrease “healthspan”• Surprisingly large effects on lifespan• Surprisingly similar genes in very differentspecies• A wide variety of biochemical andphysiological processes (100s of genes)• Complex
  19. 19. Aging as a loss of homeostasis
  20. 20. The Tolerance Zone
  21. 21. Optimal Reproduction/HealthDiseaseDeath
  22. 22. Sub optimalDiseaseDeath
  23. 23. Homeostatic mechanisms
  24. 24. Aged homeostatic mechanisms
  25. 25. Small moleculesEnhancedhomeostasis
  26. 26. Heat shockNutritional fluctuationsOsmolarityHeavy metals/oxidantsOxidative stressEndocrine pathwaysInsulin-like, steroidhormonesIntracellular damageand repair signalingMetabolic controlAging outcomesInfection/inflammationHomeostatic factors are targets for interventions inaging
  27. 27. Can drugs be found that slow aging orpostpone age-related disease?
  28. 28. Rapamycin
  29. 29. Some promising drug candidates
  30. 30. Protein homeostasis
  31. 31. Jens Tyedmers, Axel Mogk and Bernd BukauNature Reviews, Molecular Cell Biology volume 11, 2010Protein homeostasis
  32. 32. Human diseases caused by a failure inprotein homeostasis
  33. 33. Does maintaining protein qualitydetermine normal aging?
  34. 34. Dyes that bind amyloidthioflavin T
  35. 35. Suppression of worm Alzheimer’s+ThtControlChris Link, U Colorado
  36. 36. Alavez et al. Nature 2011
  37. 37. 800,000 and 21www.nature.com (2008)
  38. 38. Parallel screening(NPL-640 from TimTec(Newark, DE)RPS-O Aβ DAF-16localizationSASPPGC1αNFkappaBMetalresistancecheckpointMammalian cellsC. elegans
  39. 39. LithiumAshland, Oregons Lithia Park
  40. 40. Lithium suppresses the accumulation ofinsoluble proteins during agingYoungControlDay11ControlYoungLithiumDay11Lithium
  41. 41. 0 5 10 15 20 250.000.250.500.751.000mM5mM10mM20mM50mM100mMDaysFractionSurvivingLithiumMcColl et al. J. Biol. Chem. 2008
  42. 42. A ray of sunshine from a petri dishVitamin D
  43. 43. Now what?
  44. 44. The Nobel Prize in Physiology or Medicine 2002"for their discoveries concerning genetic regulation of organdevelopment and programmed cell deathSydney Brenner Robert Horovitz John Suslston

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