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Gene pathways that delay Caenorhabditis elegans reproductive senescence.

Wang MC, Oakley HD, Carr CE, Sowa JN, Ruvkun G - PLoS Genet. (2014)

Bottom Line: Of these 32 gene inactivations, we also found that 19 increase reproductive lifespan through their effects on oocyte activities, 8 of them coordinate oocyte and sperm functions to extend reproductive lifespan, and 5 of them can induce sperm humoral response to promote reproductive longevity.Furthermore, we examined the effects of these reproductive aging regulators on somatic aging.We found that 5 of these gene inactivations prolong organismal lifespan, and 20 of them increase healthy life expectancy of an organism without altering total life span.

View Article: PubMed Central - PubMed

Affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.

ABSTRACT
Reproductive senescence is a hallmark of aging. The molecular mechanisms regulating reproductive senescence and its association with the aging of somatic cells remain poorly understood. From a full genome RNA interference (RNAi) screen, we identified 32 Caenorhabditis elegans gene inactivations that delay reproductive senescence and extend reproductive lifespan. We found that many of these gene inactivations interact with insulin/IGF-1 and/or TGF-β endocrine signaling pathways to regulate reproductive senescence, except nhx-2 and sgk-1 that modulate sodium reabsorption. Of these 32 gene inactivations, we also found that 19 increase reproductive lifespan through their effects on oocyte activities, 8 of them coordinate oocyte and sperm functions to extend reproductive lifespan, and 5 of them can induce sperm humoral response to promote reproductive longevity. Furthermore, we examined the effects of these reproductive aging regulators on somatic aging. We found that 5 of these gene inactivations prolong organismal lifespan, and 20 of them increase healthy life expectancy of an organism without altering total life span. These studies provide a systemic view on the genetic regulation of reproductive senescence and its intersection with organism longevity. The majority of these newly identified genes are conserved, and may provide new insights into age-associated reproductive senescence during human aging.

No MeSH data available.


Functional classification of reproductive longevity regulatory genes.(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 daf-2(e1370);sqt-3(e2117), daf-16(mgDf47);sqt-3(e2117) or sma-2(e502);sqt-3(e2117) 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) nhx-2 and sgk-1, 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) nhx-2 and sgk-1 regulate reproductive lifespan additively with caloric restriction. sgk-1 and nhx-2 were inactivated in the eat-2(ad465) mutant, a genetic model of caloric restriction in C. elegans. Compared to wild type (N2), the eat-2(ad465) mutant reproduces 24% longer, * p<0.05. RNAi inactivation of either sgk-1 or nhx-2 further enhances the reproductive lifespan extension in the eat-2(ad465) mutant, ### p<0.001. The average of three independent experiments is shown. (E) Inactivation of nhx-2 and sgk-1 are additive on reproductive lifespan extension. The sgk-1(mg455)  mutation and the nhx-2 RNAi inactivation prolong reproductive lifespan by 85% and 154%, respectively. The nhx-2 RNAi inactivation further extends the reproductive lifespan of the sgk-1 mutant by 75%. p<0.0001 in all cases.
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pgen-1004752-g002: Functional classification of reproductive longevity regulatory genes.(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 daf-2(e1370);sqt-3(e2117), daf-16(mgDf47);sqt-3(e2117) or sma-2(e502);sqt-3(e2117) 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) nhx-2 and sgk-1, 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) nhx-2 and sgk-1 regulate reproductive lifespan additively with caloric restriction. sgk-1 and nhx-2 were inactivated in the eat-2(ad465) mutant, a genetic model of caloric restriction in C. elegans. Compared to wild type (N2), the eat-2(ad465) mutant reproduces 24% longer, * p<0.05. RNAi inactivation of either sgk-1 or nhx-2 further enhances the reproductive lifespan extension in the eat-2(ad465) mutant, ### p<0.001. The average of three independent experiments is shown. (E) Inactivation of nhx-2 and sgk-1 are additive on reproductive lifespan extension. The sgk-1(mg455) mutation and the nhx-2 RNAi inactivation prolong reproductive lifespan by 85% and 154%, respectively. The nhx-2 RNAi inactivation further extends the reproductive lifespan of the sgk-1 mutant by 75%. p<0.0001 in all cases.

Mentions: Functional annotation analysis classified these newly identified genes into different categories, such as signaling transduction, gene expression/translation control, metabolic maintenance, ion transport and innate immunity defense (Figure 2A). To further understand the regulatory mechanisms of these genes, we examined their interactions with the known reproductive longevity pathways regulated by insulin/IGF-1 and TGF-β signaling [7], [8], [9]. Mutations in the insulin/IGF-1 receptor, daf-2(e1370), cause increased reproductive lifespan, which is fully suppressed by a mutation in the negatively regulated FoxO transcription factor, daf-16(mgDf47)[7]. To analyze the functions of the identified genes in insulin/IGF-1 signaling, we inactivated the newly identified reproductive senescence genes in the sqt-3(e2117) strains carrying either daf-2(e1370) or daf-16(mgDf47) mutation, performed the similar temperature switching procedure as shown above, and examined whether reproductive senescence could be delayed. As shown in Figure 2B, ten gene inactivations delay reproductive senescence in the background with either daf-2 or daf-16 mutation, suggesting that these genes regulate reproductive senescence independently from insulin/IGF-1 signaling. Among the other 22 genes, nine of them act independently of daf-16, but their inactivations have no additive effects with the daf-2 mutation; the effects of four genes are dependent on daf-16, but are additive to daf-2; and the other nine gene inactivations fail to delay reproductive senescence in either mutant background. These 22 genes are likely acting in insulin/IGF-1 signaling, but at different positions in the pathway.


Gene pathways that delay Caenorhabditis elegans reproductive senescence.

Wang MC, Oakley HD, Carr CE, Sowa JN, Ruvkun G - PLoS Genet. (2014)

Functional classification of reproductive longevity regulatory genes.(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 daf-2(e1370);sqt-3(e2117), daf-16(mgDf47);sqt-3(e2117) or sma-2(e502);sqt-3(e2117) 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) nhx-2 and sgk-1, 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) nhx-2 and sgk-1 regulate reproductive lifespan additively with caloric restriction. sgk-1 and nhx-2 were inactivated in the eat-2(ad465) mutant, a genetic model of caloric restriction in C. elegans. Compared to wild type (N2), the eat-2(ad465) mutant reproduces 24% longer, * p<0.05. RNAi inactivation of either sgk-1 or nhx-2 further enhances the reproductive lifespan extension in the eat-2(ad465) mutant, ### p<0.001. The average of three independent experiments is shown. (E) Inactivation of nhx-2 and sgk-1 are additive on reproductive lifespan extension. The sgk-1(mg455)  mutation and the nhx-2 RNAi inactivation prolong reproductive lifespan by 85% and 154%, respectively. The nhx-2 RNAi inactivation further extends the reproductive lifespan of the sgk-1 mutant by 75%. p<0.0001 in all cases.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4256158&req=5

pgen-1004752-g002: Functional classification of reproductive longevity regulatory genes.(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 daf-2(e1370);sqt-3(e2117), daf-16(mgDf47);sqt-3(e2117) or sma-2(e502);sqt-3(e2117) 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) nhx-2 and sgk-1, 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) nhx-2 and sgk-1 regulate reproductive lifespan additively with caloric restriction. sgk-1 and nhx-2 were inactivated in the eat-2(ad465) mutant, a genetic model of caloric restriction in C. elegans. Compared to wild type (N2), the eat-2(ad465) mutant reproduces 24% longer, * p<0.05. RNAi inactivation of either sgk-1 or nhx-2 further enhances the reproductive lifespan extension in the eat-2(ad465) mutant, ### p<0.001. The average of three independent experiments is shown. (E) Inactivation of nhx-2 and sgk-1 are additive on reproductive lifespan extension. The sgk-1(mg455) mutation and the nhx-2 RNAi inactivation prolong reproductive lifespan by 85% and 154%, respectively. The nhx-2 RNAi inactivation further extends the reproductive lifespan of the sgk-1 mutant by 75%. p<0.0001 in all cases.
Mentions: Functional annotation analysis classified these newly identified genes into different categories, such as signaling transduction, gene expression/translation control, metabolic maintenance, ion transport and innate immunity defense (Figure 2A). To further understand the regulatory mechanisms of these genes, we examined their interactions with the known reproductive longevity pathways regulated by insulin/IGF-1 and TGF-β signaling [7], [8], [9]. Mutations in the insulin/IGF-1 receptor, daf-2(e1370), cause increased reproductive lifespan, which is fully suppressed by a mutation in the negatively regulated FoxO transcription factor, daf-16(mgDf47)[7]. To analyze the functions of the identified genes in insulin/IGF-1 signaling, we inactivated the newly identified reproductive senescence genes in the sqt-3(e2117) strains carrying either daf-2(e1370) or daf-16(mgDf47) mutation, performed the similar temperature switching procedure as shown above, and examined whether reproductive senescence could be delayed. As shown in Figure 2B, ten gene inactivations delay reproductive senescence in the background with either daf-2 or daf-16 mutation, suggesting that these genes regulate reproductive senescence independently from insulin/IGF-1 signaling. Among the other 22 genes, nine of them act independently of daf-16, but their inactivations have no additive effects with the daf-2 mutation; the effects of four genes are dependent on daf-16, but are additive to daf-2; and the other nine gene inactivations fail to delay reproductive senescence in either mutant background. These 22 genes are likely acting in insulin/IGF-1 signaling, but at different positions in the pathway.

Bottom Line: Of these 32 gene inactivations, we also found that 19 increase reproductive lifespan through their effects on oocyte activities, 8 of them coordinate oocyte and sperm functions to extend reproductive lifespan, and 5 of them can induce sperm humoral response to promote reproductive longevity.Furthermore, we examined the effects of these reproductive aging regulators on somatic aging.We found that 5 of these gene inactivations prolong organismal lifespan, and 20 of them increase healthy life expectancy of an organism without altering total life span.

View Article: PubMed Central - PubMed

Affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.

ABSTRACT
Reproductive senescence is a hallmark of aging. The molecular mechanisms regulating reproductive senescence and its association with the aging of somatic cells remain poorly understood. From a full genome RNA interference (RNAi) screen, we identified 32 Caenorhabditis elegans gene inactivations that delay reproductive senescence and extend reproductive lifespan. We found that many of these gene inactivations interact with insulin/IGF-1 and/or TGF-β endocrine signaling pathways to regulate reproductive senescence, except nhx-2 and sgk-1 that modulate sodium reabsorption. Of these 32 gene inactivations, we also found that 19 increase reproductive lifespan through their effects on oocyte activities, 8 of them coordinate oocyte and sperm functions to extend reproductive lifespan, and 5 of them can induce sperm humoral response to promote reproductive longevity. Furthermore, we examined the effects of these reproductive aging regulators on somatic aging. We found that 5 of these gene inactivations prolong organismal lifespan, and 20 of them increase healthy life expectancy of an organism without altering total life span. These studies provide a systemic view on the genetic regulation of reproductive senescence and its intersection with organism longevity. The majority of these newly identified genes are conserved, and may provide new insights into age-associated reproductive senescence during human aging.

No MeSH data available.