Biology of Aging
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This study investigated the role of insulin signaling pathways in regulating longevity in C. elegans. It found that neuronal and intestinal tissues play important roles in mediating the increased lifespan seen in insulin pathway mutants. Restoring the insulin receptor DAF-2 specifically in neurons or intestine partially rescued longevity, while restoring the FOXO transcription factor DAF-16 ubiquitously, in neurons alone, or intestine alone all increased lifespan in insulin mutants. The results demonstrate that neuronal and intestinal tissues contribute independently to increased longevity through insulin signaling.
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Biology of Aging
- 1. Insulin Signaling in C. elegans regulates both endocrine and cell-autonomous outputs
- 2. Insulin mutants have increased lifespan Increased Lifespan
- 3. AGE-1 PDK DAF-16 Nucleus DAF-2 Insulin Signaling Pathway Overview Dauer Lifespan Stress Resistance
- 4. Which tissues are important for longevity? Neuronal? Intestinal?
- 5. Neuronal IntestinalRic-18 promoter Gly or Spl promoter Ubiquitous Dpy promoter Promoters used in this paper
- 6. Neuronal IntestinalRic-18 promoter Gly or Spl promoter Ubiquitous Dpy promoter age-1 mutant daf-16 mutant Experimental Overview
- 7. Fig 1
- 8. Table 1
- 9. Table 2
- 10. Table 3
- 11. Table 4
- 12. Fig 3
- 13. Table 5 Promoter Parental genotype Developmental phenotype (25°C) Rescue development (Y/P/N) Dauers (%) Adults (%) n Fertile Sterile age-1(mg44) m+z- 100.0 0.0 0.0 133 age-1(mg305) 100.0 0.0 0.0 183 ric-19 mg44; bvEx120 1.3 79.6 19.1 152 Y mg44; bvEx122 0.0 93.4 6.6 198 Y mg44; bvEx123 1.9 87.5 10.6 104 Y mg44; bvEx125 0.9 50.5 48.6 111 Y/P mg44; bvEx128 0.9 86.0 13.1 107 Y unc-4 mg305; bvEx78 22.4 11.4 66.2 210 P unc-25 mg305; bvEx68 92.2 2.2 5.6 90 N/P flp-1 mg44; bvEx47 10.1 9.6 80.3 208 P mg305; bvEx47 2.0 60.1 37.9 198 Y spl-1 mg44;bvEx87 0.0 28.6 71.4 28 P mg305;bvEx88 25.9 0.9 73.2 112 P mg44; bvEx90 0.0 75.0 25.0 52 Y mg305;bvEx90 1.3 72.7 26.0 231 Y gly-19 mg305;bvEx117 36.6 0.7 62.7 279 P
- 14. Which tissue is important for daf-16? Fig 4A
- 15. Table 6 Genotype Mean (days) Std error (n) Expt. % Increase P vs controla daf-16(+); age-1(+) 15.3 0.74 38 1 31 daf-16(+); age-1(+) 19.2 0.48 85 2 41 daf-16(+); age-1(+) 16.8 0.30 49 3 29 daf-16(+); age-1(+) 19.7 1.12 36 4b 25 age-1(mg109) m+z- 22.2 0.51 33 3 46 age-1(mg109) m+z- 35.5 1.86 23 4b 59 daf-16(mg242); age-1(mg109) 10.6 0.31 42 1 daf-16(mg242); age-1(mg109) 11.3 0.67 21 2 daf-16(mg242); age-1(mg109) 11.9 0.18 42 3 daf-16(mg242); age-1(mg109) 14.7 0.19 61 4b
- 16. Table 6: Ubiquitous daf-16 Ubiquitous daf-16 (Pdpy-30:daf-16) daf-16(-); age-1(-); bvEx130 15.7 0.59 25 3 25 <0.0001, <0.0001 daf-16(-); age-1(-); bvEx130 19.5 0.90 29 4b 25 <0.0001, <0.0001
- 17. Table 6 Neuronal daf-16 (Pric-19:daf-16) daf-16(-);age-1(- ); bvEx94 13.0 0.41 46 1 18 <0.0001, <0.0001 daf-16(-);age-1(- ); bvEx94 12.8 0.41 33 3 7 0.0023, 0.0037 daf-16(-);age-1(- ); bvEx94 16.0 0.71 28 4b 8 0.0043, 0.0883 daf-16(-);age-1(- ); bvEx92 11.1 0.32 35 1 0.2902, 0.2660 daf-16(-);age-1(- ); bvEx93 12.8 0.36 46 1 17 <0.0001, <0.0001 daf-16(-);age-1(- ); bvEx96 11.3 0.48 40 1 6 0.0578, 0.2336 daf-16(-);age-1(- ); bvEx98 11.8 0.50 24 1 10 0.0744, 0.0499
- 18. Table 6: Intestinal daf-16 Intestinal daf-16 (Pgly-19:daf-16, Pspl-1:daf-16) daf-16(+); bvEx103 18.5 0.36 76 2 −4 0.0160, 0.0256 daf-16(+); bvEx105 19.3 0.43 79 2 0 0.6309, 0.5742 daf-16(-); age-1(-); bvEx#13 11.9 0.88 7 1 11 0.1244, 0.2050 daf-16(-); age-1(-); bvEx#P1 12.3 0.65 19 1 14 0.0278, 0.0300
- 19. Table 6: Neuronal and Intestinal daf-16 Neuronal + intestinal daf-16 (Pric-19:daf-16 + Pgly-19:daf-16) daf-16(-); age-1(-); bvEx113 14.5 0.45 62 2 22 <0.0001, <0.0001 daf-16(-); age-1(-); bvEx113 14.6 0.46 39 3 18 <0.0001, <0.0001 daf-16(-); age-1(-); bvEx113 18.0 0.61 53 4b 18 <0.0001, <0.0001 daf-16(-); age-1(-); bvEx114 14.9 0.61 31 2 24 <0.0001, <0.0001 daf-16(-); age-1(-); bvEx114 14.1 0.48 40 3 16 <0.0001, <0.0001 daf-16(-); age-1(-); bvEx114 19.3 0.98 28 4b 24 <0.0001, <0.0001
- 20. Altered FIRE response to fasting in insulin pathway mutants Wt Well Fed Wt 6hr Fast Cytoplasm Nucleus daf-2 6hr Fast age-1 6hr Fast daf-16; age-1 6hr Fast Cytoplasm Cytoplasm Nucleus Pan-neuronal age-1 in age-1 Intestine age-1 in age-1 Cytoplasm Nucleus Fasting Induced Redistribution of Esterase Activity Figure 5
- 21. Pan-neuronal Motorneuron Intestine Table 7 Pan-neuronal Ubiquitous Pan-neuron and Intestine FIRE response with tissue-restricted age-1 and daf-16 expression
- 22. Fig 6
- 23. Fig 7
Editor's Notes
- Upon binding of ligand the daf-2 receptor is activated phosphorylating age-1 which then leads to the phosphorylation of daf-16. In this state the transcription factor is prevented from entering the nucleus. When daf-2 signaling is blocked either by lack of ligand or mutation in the daf-2 receptor or age-1 – phosphorylation of daf-16 does not occur and it can then enter the nucleus and transcribe genes involved in dauer formation lifespan and stress resistance.
- This is what they are trying to sort out. One lab reported that daf-2/age-1 mutations in the neurons were necessary for lifespan extension while another was reporting that daf-16 mutations in the intestine was necessary for lifespan extension. (I think I have this right) So they are trying to figure out which genes are important where.
- They took age-1 and daf-16 mutants and are using transgenics to selectively express wt protein in specific tissues to see if wt expression can be rescued.