1. Endocrine regulation of development and lifespan Weiqing Li (weiqing@u.washington.edu) Department of Biological Structure University of Washington, Seattle Conj 542

2. Cell differentiation Cell renewal Cell maintenance

3. Measures of Lifespan in a Population age (yr) proportion surviving mortality rate age-specific survival age-specific mortality Steve Austad

4. grow fast and reproduce stop growing live long delay reproduction conserve energy turn on stress responses good environments: live normally adverse environments: protect your body (somatic maintenance) Reproductive growth versus survival

5. Insulin signaling serves as a conserved survival pathway C. elegans MouseDrosophila environmental cues, diet sensory signal InsR PI3K Akt-1, 2 DAF-16 (FOXO) dAkt InsR PI3K dFOXO InsR, IGF1R PI3K Akt, SGK FOXO1 FOXO3 FOXO4 development metabolism longevity stress responses

6. Does steroid signaling serve as another conserved survival pathway? C. elegans MouseDrosophila environmental cues, diet cholesterol transporters steroid processing enzymes development metabolism longevity stress responses ecdyson steroid hormones hormone receptor DAF-12 hormone receptor cholesterol transporter steroid processing enzymes? cholesterol synthesis or trafficking? steroid hormones regulating metabolism &/or reproduction? hormone receptors regulating metabolism &/or reproduction? other steroid or steroid-like? ? ?

7. Development and Aging

8. Adverse environmental conditions slower growth smaller body size longer lifespan

9. Dwarf mice live longer (4 years and 12 days old — roughly the equivalent of a 136-year-old human) R. Miller, Michigan

10. Snell Dwarf Mice Live 40% Longer R. Miller

11. Ames dwarf mice Snell dwarf mice Reduced growth hormone (GH) and insulin-like growth factor IGF-1 Reduced growth and body size 35-70% Lifespan extension GHR/GHBP-KO mice Reduced growth And body size 40-55% Lifespan extension Reduced IGF-1 and insulin IGF1R(KO)/+ Slight reduction of body weight 33% Lifespan extension in females Reduced IGF-1 receptors Bartke, 2005

12. Low IGF-1 Levels in Young Adults Predict Long Lifespan

13. Mice live longer when the insulin receptor is knocked out in the fat tissue Khan et al., Science 299: 572, 2003 FIRKO mice Wild-type mice

14. Tatar & Antebi, 2003

15. embryo L1L2L3L4adult normal environment growth arrest increased fat extended lifespan dauer adverse environment L3 dauer Adverse environmental cues induce dauer arrest in C. elegans

16. adverse environments developmental diapause extended lifespan impaired reproduction ??? reduced insulin signaling reduced steroid signaling? reduced insulin signaling reduced steroid signaling reduced insulin signaling active steroid signaling

17. insulin receptor-like development aging & etc. metabolism insulin-like ligands: DAF-28 and INS1-39 IST-1 AAP-1 PDK-1 kinases PTEN lipid phosphatase FOXO transcription factor IRS-1 P55 PI3K PI’s PI3P’s A conserved insulin signaling pathway in C. elegans

18. development aging & etc. metabolism insulin-like ligands: DAF-28 and INS1-39 IST-1 AAP-1 PDK-1 kinases insulin receptor-like PTEN lipid phosphatase FOXO transcription factor IRS-1 P55 PI3K PI’s PI3P’s on off A conserved insulin signaling pathway in C. elegans

19. The down-regulation of the insulin pathway results in extended lifespan

20. Environment and Aging

21. ASI ASJ ciliated endings nerve ring ASI ASJ Pdaf-28 (insulin)::GFP Ciliated sensory neurons are exposed to sense the environment http://www.wormatlas.org/handbook/ amphid

22. sensory neuron -by laser ablation - mutants with defective sensory neurons extended lifespan (largely blocked in daf-16/FOXO(-)) Sensory perception influences lifespan Alcedo & Kenyon, 2004Apfeld & Kenyon, 1999

23. Reproduction and Aging

24. http://www.wormatlas.org/handbook/anatomyintro/anatomyintro.htm

25. Z1Z4 Z2 Z3 glp-1(-): defective germ-line, extended lifespan Ablation of Z2, Z3: lifespan extended Ablation of Z1,Z2, Z3, Z4: lifespan not extended Ablation of Z2, Z3 in daf-16(-): lifespan not extended DTC Depletion of germ-line stem cells extends lifespan Kenyon lab (UCSF)

26. gonad intestine when the germ-line is developing normal lifespan extended lifespan The germ-line long-living signal is mediated by steroid and insulin signaling when germ-line cells are depleted (laser ablation or glp-1) nuclear DAF-16:GFP cytoplasmic DAF-16:GFP Cynthia Kenyon

27. gonad intestine when the germ-line is developing normal lifespan extended lifespan The germ-line long-living signal is mediated by steroid and insulin signaling when germ-line cells are depleted (laser ablation or glp-1) steroids cytochrome P-450 oxygenase nuclear receptor Adam Antebi, Cynthia Kenyon

28. nutritional cues ? impaired germline steroid signaling insulin signaling extended lifespan

29. Stress resistance and Aging

30. Long-lived mutants of C. elegans are resistant to multiple forms of stress Heat Exposure (minutes) 0200400600800 0.0 0.2 0.4 0.6 0.8 1.0 Wild-type age-1 daf-2 Days After UV Exposure 0246810 Survival 0.0 0.2 0.4 0.6 0.8 1.0 Wild-type age-1 daf-2 Data: Johnson, Lithgow, Murakami, Larsen, others Survival

31. Diabetes vs. Lifespan Extension down-regulation of insulin signaling anti-aging diabetes

32. Tatar & Antebi, 2003

33. Diabetes -- a genetic disease? 1. Some racial/ethnic groups are at higher risk; 2. Familial history: if you have one relative who has diabetes, your risk goes up to 40%, instead of normal 7.3%; if your have two relatives who have diabetes, your risk goes up to 60-80%, instead of normal 7.3%; 3. Polygenic traits.

34. The diseases of affluence diabetes, hypertention, heart disease, stroke. Obesity Diabetes blindness, kidney failure, heart diseases, stroke, nerve problems, premature death.

35. Environmental factors: too much food, food of high energy, lack of exercise. More??? Genetic factors: ?????? External and internal determinants

36. The diseases of affluence in China (before and after economic booming) Obesity 1979 1992 2002 20052015 30 million 60 Million 90 Million (7.1%) 200 million? Diabetes 1%3% 2.6% -- ?

37. diabetes China urban area of China 3% 6.4% overweight22.8% 30% obesity 7.1% 12.3% 19.8% 7.3% US

39. Environmental factors: too much food, food of high energy, lack of exercise. more??? Genetic factors: ?????? External and internal determinants

40. Living environments over time: frequency of famine, change of food composition, etc. Selection for genetic backgrounds?

41. Environment with abundant food diabetic survivors? Environment with frequent famine

42. Reviews: 1.Bartke (2005) Mini Review: Role of the Growth Hormone/Insulin-Like Growth Factor System in Mammalian Aging. Endocrinology 2. Tatar & Antebi (2003) The Endocrine Regulation of Aging by Insulin-like Signals. Science 3. Kenyon (2001) A conserved Regulatory System for Aging. Cell 4. Baumeister et al. (2006) Endocrine signaling in Caenorhabditis elegans controls stress response and longevity. Journal of Endocrinology Paper: Berdichevsky et al. (2006) C. elegans SIR-2.1 Interacts with 14-3-3 Proteins to Activate DAF- 16 and Extend Life Span. Cell