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Endocrine regulation of development and lifespan

Endocrine regulation of development and lifespan. Weiqing Li (weiqing@u.washington.edu). Department of Biological Structure. University of Washington, Seattle. Conj 542. Cell differentiation Cell renewal Cell maintenance. Measures of Lifespan in a Population. age-specific survival.

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Endocrine regulation of development and lifespan

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  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-specific survival proportion surviving age (yr) age-specific mortality mortality rate Steve Austad

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

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

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

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

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

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

  14. Tatar & Antebi, 2003

  15. Adverse environmental cues induce dauer arrest in C. elegans normal environment L3 embryo L1 L2 L3 L4 adult dauer • growth arrest • increased fat • extended lifespan adverse environment dauer

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

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

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

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

  20. Environment and Aging

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

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

  23. Reproduction and Aging

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

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

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

  27. The germ-line long-living signal is mediated by steroid and insulin signaling when germ-line cells are depleted (laser ablation or glp-1) when the germ-line is developing gonad cytochrome P-450 oxygenase nuclear receptor steroids intestine extended lifespan normal lifespan 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 1 . 0 1 . 0 W i l d - t y p e a g e - 1 0 . 8 0 . 8 d a f - 2 0 . 6 0 . 6 Survival Survival 0 . 4 0 . 4 W i l d - t y p e a g e - 1 0 . 2 0 . 2 d a f - 2 0 . 0 0 . 0 0 2 0 0 4 0 0 6 0 0 8 0 0 0 2 4 6 8 1 0 H e a t E x p o s u r e ( m i n u t e s ) D a y s A f t e r U V E x p o s u r e Data: Johnson, Lithgow, Murakami, Larsen, others

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

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

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

  36. The diseases of affluence in China (before and after economic booming) 2005 2015 1992 2002 1979 200 million? 90 Million (7.1%) 60 Million 30 million Obesity -- 2.6% -- 1% 3% ? Diabetes

  37. urban area of China US China 19.8% 7.1% obesity 12.3% overweight 22.8% 30% 7.3% 6.4% diabetes 3%

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

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

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

  41. 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

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