Measures of Lifespan in a Population age (yr) proportion surviving mortality rate age-specific survival age-specific mortality Steve Austad
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
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
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? ? ?
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
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
The down-regulation of the insulin pathway results in extended lifespan
Environment and Aging
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
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)
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
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
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
Diabetes vs. Lifespan Extension down-regulation of insulin signaling anti-aging diabetes
Tatar & Antebi, 2003
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.
Environmental factors: too much food, food of high energy, lack of exercise. More??? Genetic factors: ?????? External and internal determinants
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% -- ?
diabetes China urban area of China 3% 6.4% overweight22.8% 30% obesity 7.1% 12.3% 19.8% 7.3% US
Environmental factors: too much food, food of high energy, lack of exercise. more??? Genetic factors: ?????? External and internal determinants
Living environments over time: frequency of famine, change of food composition, etc. Selection for genetic backgrounds?
Environment with abundant food diabetic survivors? Environment with frequent famine
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