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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. IV. The anti-aging effect of dietary restriction

  3. 1 x 109 1 .8 .6 .4 .2 0 Dietary restriction (DR) extends lifespan in C. elegans eat-2(-): a genetic model of dietary restriction N2 1 eat-2(ad1116) .8 Fraction alive .6 1 x 1011 Fraction Alive 1 x 1010 .4 1 x 108 N2 .2 Adult age (days) 0 35 0 5 10 15 20 25 30 Adult age (days) nutrient transporters mutants (nuc, pept) Klass et al., Mech Ageing Dev. (1977) Lakowski et al., PNAS (1998) Fei et al., JBC (2003) Meissner et al., JBC (2004)

  4. Metabolic rate not changed in eat-2 Houthoofd et al., (2002) Possible mechanisms? Rate of living theory: DR reduces metabolic rate Energy consumption increase in eat-2 Hsu and Feng Lab unpubilshed

  5. Public and private DR mechanisms

  6. Genes involved in the longevity response to DR in C. elegans Autophagy, Protein synthesis, Stress response, …. etc. Kenyon,Nature,(2010)

  7. 1 1 1 1 sams-1(RNAi) rab-10(RNAi) drr-2(RNAi) drr-1(RNAi) Control Control Control Control .8 .8 .8 .8 .6 .6 .6 .6 .4 .4 .4 .4 .2 .2 .2 .2 0 0 0 0 0 0 5 5 10 10 15 15 20 20 25 25 30 30 35 35 40 40 0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40 Time (days) Time (days) Time (days) Time (days) DR response (drr) genes Fraction Alive Fraction Alive Hansen et al, PLoS Genetics, 2005

  8. daf-16(-) 30 0 5 10 15 20 25 1 N2 eat-2(-) .8 .6 Fraction Alive .4 .2 0 0 5 10 15 20 25 30 35 40 Adult age (days) 0 10 20 30 40 50 60 DR response (drr) genes Phenocopies DR animals (size, reproduction, etc.). The lifespan extension phenotypes are daf-16-independent. RNAi knock-down does not further extend eat-2 lifespan. D. mRNA levels are reduced in eat-2(-) versus N2 worms. Hansen, Hsu et al, PLoS Genetics, 2005

  9. mRNA levels of drr genes are reduced in eat-2vs N2 worms Ratio of mRNA levels in eat-2 vs. N2

  10. Average brood size/worm ± SEM (no. of worms) Treatment P value 0.003 Control sams-1 275 ± 7 (23) 241 ± 9 (15) RNAi of drr genes delay progeny production A Number of progeny/worm Adult age (hours) B

  11. Dietaryrestriction may increase lifespan by reducing the mRNA levels of drr genes.

  12. Dietary restriction may increase lifespan by reducing the mRNA levels of drr genes. DRR-2 SAMS-1

  13. DRR-2 = eIF4H Inactivating translation initiation extends lifespan Johnson, Kenyon, Kapahi, Lee, Ruvkun, Tavernarakis Labs

  14. drr-2 encodes a worm homolog of eIF4H Cytosol Input Polysome N2 EQ19 N2 EQ19 WB: Anti-GFP WB: Anti-b-actin Relative 35S incorporation Ching et al, Aging Cell, 2010 Control S6K/rsks-1 (RNAi) eIF4H/drr-2 (RNAi) eIF4H/drr-2 o.e.

  15. intestine ventral nerve cord neuron vulva pharynx canal cells canal cell processes tail ganglion nerve ring spermatheca spermatheca pharynx neurons and canal cells vulva epithelium intestine ventral nerve cord neurons spermatheca tail ganglion neurons canal cell processes Where does DRR-2 act to mediate DR?

  16. dorsal coelomocytes ventral coelomocytes Where does DRR-2 act to mediate DR? Day 10 adult

  17. Is the reduction of drr-2/eIF4H expression level required for DR to extend lifespan?

  18. N2 EQ192 EQ191 1 1 eat-2(ad1116) .8 .8 .6 .6 .4 .4 .2 .2 0 0 eat-2(-) lifespan extension is suppressed by drr-2/eIF4H over-expression N2 EQ19 Fraction alive Fraction alive P=0.32 P<0.0001 Adult age (days) Adult age (days) Ching et al, Aging Cell, 2010

  19. Lifespan extension by solid phase DR is suppressed by drr-2/eIF4H over-expression Ching et al, Aging Cell, 2010

  20. Lifespan extension by solid phase DR is suppressed by drr-2/eIF4H over-expression

  21. Lowering the expression of drr-2/eIF4His required for TOR to extend lifespan Ching et al, Aging Cell, 2010

  22. Lowering the expression of drr-2/eIF4His NOT required for S6Kto extend lifespan

  23. PHA-4 (FoxA) is NOT required for drr-2/eIF4Hto extend lifespan

  24. Model for DRR-2 in DR Nutrient TOR/let-363 Raptor/daf-15 ? S6K/rsks-1 eIF4H/drr-2 eIF4E/ife-2 eIF4G/ifg-1 FOXA/pha-4 INCREASED LIFESPAN Ching et al, Aging Cell, 2010

  25. SAMS-1: S-adenosylmethioninesynthetase

  26. What’s SAMS? SAMS S-adenosylmethonine (SAM) Methionine restriction in rodents also extends lifespan !

  27. What’s SAMS? 1. Transmethylation 2. Transsulfuration (Met -> Cys) 3. Aminopropylation (polyamine synthesis)

  28. There are five SAMS isoforms in worms: SAMS-1 SAMS-2 SAMS-3/SAMS-4 SAMS-5

  29. sams expression levels in sams-1(RNAi) animals mRNA levels sams-1 sams-2 sams-3/4 sams-5 Control RNAi Control RNAi

  30. RANi of sams-1and sams-5 extend lifespan Control Control sams-1(RNAi) sams-1(RNAi) sams-2(RNAi) sams-3(RNAi) sams-5(RNAi) sams-4(RNAi) Fraction alive Adult age (days) Adult age (days)

  31. Deletion mutations of sams-1 and sams-5 extend lifepsan Control Control sams-1(ok2947) sams-5(gk145) Fraction alive Adult age (days)

  32. Is the reduction of sams-1 expression level required for DR to extend lifespan?

  33. eat-2(-) lifespan extension is partially suppressed by sams-1 over-expression N2 eat-2(ad1116) sams-1 o.e. 1 sams-1 o.e. in eat-2(ad1116) .8 .6 Fraction Alive .4 .2 P<0.0001 0 35 0 5 10 15 20 25 30 Adult age (days) Ching & Hsu, unpublished

  34. N2 sams-1 o.e. Lifespan extension by solid phase DR is suppressed by sams-1 over-expression Mean lifespan (days) 107 108 109 1010 1011 1012 Bacteria concentration (bacteria/mL) Ching & Hsu, unpublished

  35. Is the reduction of sams-1 expression level required for TOR signaling to regulate lifespan?

  36. Lifespan extension by TOR+Raptor knock-down is suppressed by sams-1 over-expression vector vector TOR/let-363(RNAi); Raptor/daf-15(RNAi) TOR/let-363(RNAi); Raptor/daf-15(RNAi) Fraction Alive P=0.001 P=0.75 N2 EQ2 (sams-1 o.e.) 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Adult age (days) Ching & Hsu, unpublished

  37. 1 1 1 .8 .8 .8 0 0 0 0 10 10 10 10 20 20 20 20 30 30 30 30 40 35 35 40 .6 .6 .6 .4 .4 .4 .2 .2 .2 0 0 0 sams-1 may function in parallel to S6K & PHA-4 to influence lifespan Fraction alive P<0.0001 P=0.0075 N2 pha-4(zu225) vector vector S6K/rsks-1(RNAi) S6K/rsks-1(RNAi) Fraction alive P=0.0005 P=0.032 EQ2 (sams-1 o.e.) N2 Adult age (days) vector vector Ching & Hsu, unpublished sams-1(RNAi) sams-1(RNAi)

  38. SAMS-1 Model Nutrient TOR/let-363 Raptor/daf-15 S6K/rsks-1 SAMS-1 FOXA/pha-4 INCREASED LIFESPAN

  39. sams-1 acts upstream of drr-2

  40. Nutrient Model TOR/let-363 Raptor/daf-15 S6K/rsks-1 sams-1 eIF4H/drr-2 HIF-1 FOXA/pha-4 IRE-1 Longevity Ching & Hsu, unpublished

  41. The expression pattern of SAMS-1 Body-wall muscles head muscles Intestinal nuclei sams-1p::sams-1::gfp Ching & Hsu, unpublished

  42. The expression level of sams-1 is reduced in DR animals sams-1::gfp Control DR Confirmed by qRT-PCR Ching & Hsu, unpublished

  43. The expression level of sams-1 is reduced in TOR/let-363(RNAi) animals TOR/let-363 + Raptor/daf-15 RNAi * * Relative mRNA level (%) ** qRT-PCR

  44. The nuclear accumulation of sams-1 in intestinal cells is reduced in eat-2(-) animals Intestinal nuclei sams-1::gfp sams-1::gfp, eat-2 (ad1116) Ching & Hsu, unpublished

  45. The nuclear accumulation of sams-1 in intestinal cells is reduced in sDR animals Control DR (17hr) % nuclear SAMS-1 DR (Hours) Ching & Hsu, unpublished

  46. let-363/TOR RNAi The nuclear accumulation of sams-1 is reduced in TOR (RNAi) animals sams-1::gfp control bacteria sams-1::gfp Ching & Hsu, unpublished

  47. The nuclear accumulation of sams-1 is reduced in TOR (RNAi) animals % nuclear SAMS-1 TOR RNAi (Hours) Ching & Hsu, unpublished

  48. Where does SAMS-1 act to influence longevity?

  49. Conditional knock-down of sams-1: the rde-1 system N2 on VC N2 on sams-1 RNAi Ching & Hsu, unpublished

  50. Conditional knock-down of sams-1: the rde-1 system VC Intestine specific sams-1 RNAi Ching & Hsu, unpublished

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