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.

1. The Buck Institute for
Research on Aging
Interdisciplinary Research Center on Geroscience

2. Kathleen Casey-Kirschling

3. Kathleen Casey-Kirschling
1st Jan, 1946, 00.01AM

4. The Choice

5. Mechanisms of aging and disease are tightly linked
Aging can be slowed

6. cardiovascular disease
Parkinson’s Disease
Huntington’s Disease
Alzheimer’s Disease
diabetes
sarcopenia
osteoperosis
osteoarthritis
macular degeneration
adult cancer

7. tuberculosis
small pox
polio
syphilis
German measles
mumps
chicken pox
pertussis
diphtheria
tenatus
flu

9. cardiovascular disease
Parkinson’s Disease
Huntington’s Disease
Alzheimer’s Disease
diabetes
sarcopenia
osteoperosis
osteoarthritis
macular degeneration
adult cancer

10. Aging
cardiovascular disease
Parkinson’s Disease
Huntington’s Disease
Alzheimer’s Disease
diabetes sarcopenia
osteoporosis
osteoarthritis
macular degeneration
adult cancer

11. What is aging?

12. 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

13. Ocean quahog
(Arctica islandica)
507 yr

14. Famous people born at the same time
as currently living clams
Mary Queen of Scots
(1542-1587)

15. Why is aging a risk factor for disease?

16. How are we getting to the answer?

18. age-1

19. Age (days)
0 5 10 15 20 25 30 35
FractionAlive
0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20 25 30 35 40 45 50 55 60
age-1Wild type (N2)
Copyright – Gordon J. Lithgow

20. • Surprisingly easy to modulate aging and
increase “healthspan”
• Surprisingly large effects on lifespan
• Surprisingly similar genes in very different
species
• A wide variety of biochemical and
physiological processes (100s of genes)
• Complex

21. Aging as a loss of homeostasis

22. The Tolerance Zone

23. Optimal Reproduction/Health
Disease
Death

24. Sub optimal
Disease
Death

25. Homeostatic mechanisms

26. Aged homeostatic mechanisms

27. Small molecules
Enhanced
homeostasis

28. Heat shock
Nutritional fluctuations
Osmolarity
Heavy metals/oxidants
Oxidative stress
Endocrine pathways
Insulin-like, steroid
hormones
Intracellular damage
and repair signaling
Metabolic control
Aging outcomes
Infection/inflammation
Homeostatic factors are targets for interventions in
aging

29. Can drugs be found that slow aging or
postpone age-related disease?

30. Rapamycin

31. Some promising drug candidates

32. Protein homeostasis

33. Jens Tyedmers, Axel Mogk and Bernd Bukau
Nature Reviews, Molecular Cell Biology volume 11, 2010
Protein homeostasis

34. Human diseases caused by a failure in
protein homeostasis

35. Does maintaining protein quality
determine normal aging?

36. Dyes that bind amyloid
thioflavin T

38. Suppression of worm Alzheimer’s
+ThtControl
Chris Link, U Colorado

39. Alavez et al. Nature 2011

43. 800,000 and 21
www.nature.com (2008)

44. Parallel screening
(NPL-640 from TimTec
(Newark, DE)
RPS-O Aβ DAF-16
localization
SASPPGC1α
NFkappaB
Metal
resistance
checkpoint
Mammalian cellsC. elegans

45. Lithium
Ashland, Oregon's Lithia Park

46. Lithium suppresses the accumulation of
insoluble proteins during aging
YoungControl
Day11Control
YoungLithium
Day11Lithium

47. 0 5 10 15 20 25
0.00
0.25
0.50
0.75
1.00
0mM
5mM
10mM
20mM
50mM
100mM
Days
FractionSurviving
Lithium
McColl et al. J. Biol. Chem. 2008

48. A ray of sunshine from a petri dish
Vitamin D

49. Now what?

52. The Nobel Prize in Physiology or Medicine 2002
"for their discoveries concerning 'genetic regulation of organ
development and programmed cell death'
Sydney Brenner Robert Horovitz John Suslston