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The genetic and environmental factors that influence aging and longevity

The genetic and environmental factors that influence aging and longevity. Ao -Lin Hsu, Ph.D. Dept. of Internal Medicine - Geriatric Medicine and Geriatrics Center Dept. of Molecular & Integrative Physiology University of Michigan Medical School aolinhsu@umich.edu.

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The genetic and environmental factors that influence aging and longevity

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  1. The genetic and environmental factors that influence aging and longevity Ao-Lin Hsu, Ph.D. Dept. of Internal Medicine - Geriatric Medicine and Geriatrics Center Dept. of Molecular & Integrative Physiology University of Michigan Medical School aolinhsu@umich.edu

  2. III. The role of heat-shock response in aging

  3. Extended Lifespan is often correlated with increased stress resistance ROS Heat UV Johnson et al, ExpGerontol36, 1609-1617 (2007)

  4. Mild heat-shock pre-treatment increases lifespan Cypseret al, ExpGerontol (2006)

  5. Normal worm Day 7 Normal worm Day 15 Heat-shock factor-1 (HSF-1) may prevent C. elegans from aging prematurely Garigan et al.,Genetics 161, 1101, (2002)

  6. Normal worm Day 7 Normal worm Day 15 hsf-1(RNAi) Day 7 Heat-shock factor-1 (HSF-1) may prevent C. elegans from aging prematurely Garigan et al.,Genetics 161, 1101, (2002)

  7. N2 control N2 on hsf-1(RNAi) 0 10 20 30 40 HSF-1 knockdown promotes aging Fraction alive Days a a a a a

  8. What is Heat-shock factor ?

  9. Heat-shock response is responsible for: • Assist in protein folding and refolding • Solubilize aggregates • Sequester overloaded and damaged proteins • Target damaged proteins to degradation • Interfere with apoptotic program Protein Homeostasis !

  10. Activation of HSF-1 HSF-1 Trimerization domain Transactivation domain 1. Polymerization 2. Nuclear localization Cytoplasm 3. Posttranslational Modification 4. DNA binding & Transcription Nucleus hsp HSPs: molecular chaperones, proteases

  11. N2 control hsf-1 over-expressing line N2 on hsf-1(RNAi) 0 10 20 30 40 HSF-1 regulates longevity Fraction alive Days a a a a a

  12. HSF-1 regulates longevity, and thermotolerance, too hsf-1 over-expressing line

  13. Insulin/IGF-1 signaling function during early adulthood to regulate aging Insulin/IGF-1 Signaling CR Mitochondrial Function Larval Development Early Adulthood (Day 1 ~ 6) Late Adulthood Kenyon and other labs

  14. When does HSF-1 function to regulate lifespan? a a a

  15. hsf-1 RNAi Short-lived empty vector L3 L4 Short-lived? Day1 adult Day2 adult

  16. HSF-1 also function during adulthood to regulate aging 1 vector vector .8 .6 Fraction alive .4 hsf-1(RNAi) hsf-1(RNAi) .2 0 0 5 10 15 20 25 Days

  17. vector vector D2 vector hsf-1(RNAi) 1 D1 vector hsf-1(RNAi) L4 .8 vector hsf-1(RNAi) L3 vector hsf-1(RNAi) .6 Fraction alive hsf-1(RNAi) hsf-1(RNAi) .4 .2 0 0 5 10 15 20 25 Days HSF-1 also function during adulthood to regulate aging

  18. HSF-1 HSF-1 signaling function during early adulthood to regulate aging Insulin/IGF-1 Signaling CR Mitochondrial Function Larval Development Early Adulthood (Day 1 ~ 6) Late Adulthood Kenyon and other labs

  19. wild type 1 daf-2 (-) daf-16 (-);daf-2 (-) DAF-2 .5 (Insulin/IGF-1receptor) 0 0 20 40 60 80 Days DAF-16 (Forkhead transcription factor) L O N G E V I T Y Insulin/IGF-1 signaling regulates aging

  20. daf-2 on control daf-2 on hsf-1 RNAi N2 on hsf-1 RNAi Fraction alive N2 on control 80 0 20 40 60 Days Inhibition of hsf-1 completely prevents daf-2 mutations from extending lifespan Hsu et al, Science (2003)

  21. a a a a N2 on daf-16 (RNAi) 1 hsf-1 over-expressing line hsf-1 over-expressing line on daf-16 (RNAi) .8 Fraction alive .6 .4 .2 0 0 5 10 15 20 25 30 35 40 45 Days hsf-1 overexpression extends lifespan in a daf-16 dependent manner Hsu et al, Science (2003)

  22. Both DAF-16 and HSF-1 are needed for daf-2 mutations to promote longevityHow do they do that?

  23. Model #1 DAF-2 HSF-1 DAF-16 Longevity Working Models

  24. Reduction of hsf-1 does not affect the nuclear localization of DAF-16 daf-16::gfp in daf-2 (-);daf-16 (-) backgroud

  25. Model #1 Model #2 DAF-2 DAF-16 HSF-1 HSF-1 X DAF-16 Longevity They might have common targets! Longevity Working Models DAF-2 ? ?

  26. mtl-1 Barsyte et al., Faseb J., (2001) sod-3 Honda et al., Faseb J., (1999) 4 4 4 shsps (hsp16.1) 3 3 3 2 2 2 1 1 1 0 0 0 Murphy et al., Nature, (2003) HSF-1 is required for a subset of daf-16 targets to be up-regulated in daf-2 mutants Relative mRNA level N2 daf-16 (-) daf-2 (-) daf-2 on hsf-1 RNAi Hsu et al, Science (2003) a a a

  27. a a a mtl-1 Barsyte et al., Faseb J., (2001) sod-3 Honda et al., Faseb J., (1999) 4 4 4 shsps (hsp16.1) 3 3 3 2 2 2 1 1 1 0 0 0 Murphy et al., Nature, (2003) HSF-1 is required for a subset of daf-16 targets to be up-regulated in daf-2 mutants Relative mRNA level N2 daf-16 (-) daf-2 (-) daf-2 (-) on hsf-1 RNAi Hsu et al, Science (2003)

  28. a a a hsp-70 GuhaThakurta et al., (2002) unc-33 GuhaThakurta et al., (2002) shsps (hsp16.1) Murphy et al., (2003) DAF-16 is required for a subset of hsf-1 targets to be up-regulated after heat-shock Relative mRNA level heat-shock N2 Heat-shocked daf-16 N2 Hsu et al, Science (2003)

  29. a a a hsp-70 GuhaThakurta et al., (2002) unc-33 GuhaThakurta et al., (2002) shsps (hsp16.1) Murphy et al., (2003) DAF-16 is required for a subset of hsf-1 targets to be up-regulated after heat-shock Relative mRNA level heat-shock N2 Heat-shocked daf-16 (-) N2 Hsu et al, Science (2003)

  30. DAF-2 DAF-16 Working Model HSF sod-3 hsp-70 shsps, and more mtl-1 unc-33 Aging

  31. a a a a RNAi of shsps suppress the lifespan extension by both daf-2 mutation and hsf-1 over-expression Fraction alive hsf-1 over-expressing line Hsu et al, Science (2003)

  32. 76 60 How might HSF-1 and DAF-16 regulate their commontargets? IP: aGFP WB: aHSF 1. A 2. HSF B 3. C VC daf-2(-)

  33. How might sHSPs regulate the rate of aging? Protein Homeostasis?

  34. % of total animals sip-1 ctl-1 hsf-1 daf-16 mtl-1 sod-3 control hsp-70 hsp-16.1 hsp-12.6 hsp-16.49 Q40::YFP L4/YA Small heat-shock protein (sHSP) activity delays polyglutamine protein aggregation Hsu et al, Science (2003) Morley et al. PNAS 99, 10417 (2002)

  35. daf-2 mutations might delay both aging andage-related disease by up-regulating HSF-1 and sHSPsactivity a a a

  36. DAF-2 DAF-16 IIS pathway function together with HSF-1 to regulate longevity Heat-shock HSF-1 shsps, and more Aging Hsu et al, Science (2003)

  37. DAF-2 ? DAF-16 Heat-shock HSF-1 common targets Heat-shock response Aging

  38. Does DAF-2 regulate HSF-1 activity?

  39. Activation of HSF-1 HSF-1 Trimerization domain Transactivation domain 1. Polymerization 2. Nuclear localization Cytoplasm 3. Posttranslational Modification 4. DNA binding & Transcription Nucleus hsp HSPs: molecular chaperones, proteases

  40. HSF-1 nuclear localization is regulated by DAF-2 Chiang et al, Cell , (2012)

  41. HSF-1 post-translational modification is regulated by DAF-2 N2 daf-2(i) HS HSF-1 b-actin Chiang et al, Cell , (2012)

  42. N2 daf-2(-) Unlabeled probes - - HS + + 17 61 58 123 1 HSF-1 DNA-binding activity is regulated by DAF-2 Chiang et al, Cell , (2012)

  43. HSF-1 trans-activating activity is regulated by DAF-2 Chiang et al, Cell , (2012)

  44. How might DAF-2 regulate HSF-1 activity and heat-shock response?

  45. ddl-1(RNAi) Control 1 1 .8 .8 .6 .6 Cum. Survival .4 .4 .2 .2 0 0 0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40 Time (days) Time (days) Two potential HSF-1 regulatorsDDL-1 and DDL-2 ddl, (daf-16 dependent longevity) ddl-1 is a homolog of human coil-coil domain containing protein (CCDC53) ddl-2is a homolog of human WASH2 protein Lifespan assay on ddl-1 and ddl-2 RNAi ddl-2(RNAi) Control ddl-1 and ddl-2 negatively regulate lifespan

  46. ddl-1 and ddl-2 influence lifespan in a daf-16 dependent manner Insulin/IGFR Hansen, Hsu, et al, PLOS Genetics (2005) Yeast-two hybrid interactome: DDL-1 interacts with DDL-2 and HSB-1 CCDC53 binds to HSBP1 Vidal Lab

  47. ddl-1 and ddl-2knockdown animals are more resistant to stress

  48. Does DDL-1/2 influence longevity by negatively regulating HSF-1 activity?

  49. 1 1 1 1 ddl-1(RNAi) ddl-2(RNAi) Control Control .8 .8 .8 .8 .6 .6 .6 .6 .4 .4 .4 .4 A. B. .2 .2 .2 .2 0 0 0 0 0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40 Time (days) ddl-1(RNAi) ddl-2(RNAi) Control Control C. D. 0 2.5 5 7.5 10 12.5 15 17.5 20 22.5 0 2.5 5 7.5 10 12.5 15 17.5 20 22.5 Time (days) Time (days) ddl-1 and ddl-2 influence longevity in a HSF-1 dependent manner N2 Fraction alive Time (days) hsf-1(sy441) Fraction alive

  50. 1 .8 .6 .4 .2 0 0 2 4 6 8 10 12 14 16 Deletion of hsb-1 extends lifespan in a hsf-1 dependent manner N2 N2 on hsf-1 RNAi hsb-1(-) hsb-1(-) on hsf-1 RNAi 1 .8 .6 Fraction alive .4 .2 0 0 10 20 30 40 50 Age (days)

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