Alien Registration- Klimko, Joseph (Lewiston, Androscoggin County)

https://digitalmaine.com/alien_docs/27082/thumbnail.jp

Germline genetic inactivations that prolong reproductive lifespan.

<p>In the <i>rrf-1(pk1417)</i> mutant, RNAi predominantly operates in the germline. Ten of the identified genes increase reproductive lifespan when inactivated in the <i>rrf-1</i> mutants. The extension levels are comparable to that in wild type (<i>N2)</i>, except for <i>daf-2</i>, <i>nhx-2</i> and <i>moma-1</i>. The average of three independent experiments is shown, <i>p<0.05</i>.</p

Gene inactivations extending reproductive lifespan.

<p>32 gene inactivations extend reproductive lifespan more than 25% in the RNAi hypersensitive strain, <i>nre-1(hd20)lin-15b(hd126)</i> (A). 26 of those gene inactivations also significantly increase reproductive lifespan of wild type (<i>N2</i>) (B). The other six gene inactivations promote reproductive longevity only in the <i>nre-1(hd20)lin-15b(hd126)</i> strains. They may act in neurons or their RNAi inactivations are only effective in the RNAi hypersensitive background. The average of three independent experiments is shown, <i>p<0.05</i> except ^#.</p

Functional classification of reproductive longevity regulatory genes.

<p>(A) Identified reproductive longevity regulatory genes are placed into different groups based on their functional annotation using DAVID bioinformatics analysis. (B) The genetic interaction between the identified genes and insulin/IGF-1 and TGF-β signaling pathways. The identified genes were inactivated in <i>daf-2(e1370);sqt-3(e2117)</i>, <i>daf-16(mgDf47);sqt-3(e2117)</i> or <i>sma-2(e502);sqt-3(e2117)</i> mutants and examined for their effects on the onset of reproductive senescence. Yellow highlights gene inactivations that delay reproductive senescence in the mutants. Dark gray shows gene inactivations that fail to affect reproductive senescence of the mutants. All the experiments were performed at least twice independently. (C) <i>nhx-2</i> and <i>sgk-1</i>, two regulators of sodium reabsorption, modulate reproductive senescence independently of either insulin/IGF-1 or TGF-β signaling. 17 of the identified genes interact with both pathways. Eight and five genes function specifically in the TGF-β and the insulin/IGF-1 signaling pathway, respectively. (D) <i>nhx-2</i> and <i>sgk-1</i> regulate reproductive lifespan additively with caloric restriction. <i>sgk-1</i> and <i>nhx-2</i> were inactivated in the <i>eat-2(ad465)</i> mutant, a genetic model of caloric restriction in <i>C. elegans</i>. Compared to wild type (<i>N2</i>), the <i>eat-2(ad465)</i> mutant reproduces 24% longer, * <i>p<0.05</i>. RNAi inactivation of either <i>sgk-1</i> or <i>nhx-2</i> further enhances the reproductive lifespan extension in the <i>eat-2(ad465)</i> mutant, ### <i>p<0.001</i>. The average of three independent experiments is shown. (E) Inactivation of <i>nhx-2</i> and <i>sgk-1</i> are additive on reproductive lifespan extension. The <i>sgk-1(mg455)</i> null mutation and the <i>nhx-2</i> RNAi inactivation prolong reproductive lifespan by 85% and 154%, respectively. The <i>nhx-2</i> RNAi inactivation further extends the reproductive lifespan of the <i>sgk-1</i> mutant by 75%. <i>p<0.0001</i> in all cases.</p

Gene inactivations that promote somatic longevity.

<p>(A–C) RNAi inactivation of <i>daf-2</i>, <i>R07H5.9</i> and <i>C05E11.6</i> decrease RoA by 48%, 15% and 14%, respectively, without a significant effect on IMR. The mean lifespan is significantly increased by 55%, 11% and 10%, respectively (<i>p<0.001</i>). (D and E) Inactivation of <i>nhx-2</i> and <i>sgk-1</i> reduce IMR by 87% and 45%, respectively, but does not significantly affect RoA. The mean lifespan is increased by 30% and 21%, respectively (<i>p<0.001</i>). (F) <i>C44B7.12</i> inactivation reduces IMR by 91%, but increases RoA by 44%. The mean lifespan is not significantly affected. This is one example to represent 20 genes in the Group 3.</p

Reproductive longevity regulatory genes modulate somatic longevity.

<p>(A) The mortality rate curve of the control animals fed with bacteria expressing no dsRNA. The slope of the curve defines the demographic rate of aging (RoA), and the intercept with the y-axis shows initial mortality rate (IMR). (B–D) The effects of the reproductive senescence genes on somatic aging-related parameters, including IMR (B), RoA (C), and mean lifespan (D). Three gene inactivations including <i>daf-2</i>, <i>R07H5.9</i> and <i>C05E11.6</i> (Group 1), reduce RoA without affecting IMR and increase mean lifespan significantly. Inactivation of <i>sgk-1</i> or <i>nhx-2</i> (Group 2), two regulators of sodium reabsorption, reduces IMR with no effect on RoA and extends mean lifespan. There are also 20 other gene inactivations (Group 3) that reduce IMR, but increase RoA and do not alter mean lifespan. Six gene inactivations have no effect on somatic longevity (Group 4). For IMR and RoA, the average with standard deviation of three independent experiments is shown; for mean lifespan extension, three independent experiments were combined for analysis.</p