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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.


Related in: MedlinePlus

Gene inactivations extending reproductive lifespan.32 gene inactivations extend reproductive lifespan more than 25% in the RNAi hypersensitive strain, nre-1(hd20)lin-15b(hd126) (A). 26 of those gene inactivations also significantly increase reproductive lifespan of wild type (N2) (B). The other six gene inactivations promote reproductive longevity only in the nre-1(hd20)lin-15b(hd126) 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, p<0.05 except #.
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pgen-1004752-g001: Gene inactivations extending reproductive lifespan.32 gene inactivations extend reproductive lifespan more than 25% in the RNAi hypersensitive strain, nre-1(hd20)lin-15b(hd126) (A). 26 of those gene inactivations also significantly increase reproductive lifespan of wild type (N2) (B). The other six gene inactivations promote reproductive longevity only in the nre-1(hd20)lin-15b(hd126) 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, p<0.05 except #.

Mentions: Out of 18,413 gene inactivations screened, 58 candidates were identified that extend reproductive longevity of sqt-3 mutant animals (Figure S1C and Table S1). These gene inactivations were further examined in wild type and in an RNAi hypersensitive strain, nre-1(hd20)lin-15b(hd126) where RNAi potency is enhanced, especially in neurons [19]. We found that 32 gene inactivations prolong reproductive lifespan by more than 25% in the nre-1(hd20)lin-15b(hd126) background (Figure 1A and Table S2), and increase late reproduction of progeny after the first 3 days of adulthood (Figure S2). Twenty-six of the gene inactivations extend reproductive lifespan nearly equivalently in the enhanced neuronal RNAi background and in wild type; the 6 genes that show phenotypes only in the enhanced neuronal RNAi strain background may act in neurons because wild type C. elegans generally does not silence neuronal gene functions by RNAi (Figure 1B and Table S3).


Gene pathways that delay Caenorhabditis elegans reproductive senescence.

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

Gene inactivations extending reproductive lifespan.32 gene inactivations extend reproductive lifespan more than 25% in the RNAi hypersensitive strain, nre-1(hd20)lin-15b(hd126) (A). 26 of those gene inactivations also significantly increase reproductive lifespan of wild type (N2) (B). The other six gene inactivations promote reproductive longevity only in the nre-1(hd20)lin-15b(hd126) 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, p<0.05 except #.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256158&req=5

pgen-1004752-g001: Gene inactivations extending reproductive lifespan.32 gene inactivations extend reproductive lifespan more than 25% in the RNAi hypersensitive strain, nre-1(hd20)lin-15b(hd126) (A). 26 of those gene inactivations also significantly increase reproductive lifespan of wild type (N2) (B). The other six gene inactivations promote reproductive longevity only in the nre-1(hd20)lin-15b(hd126) 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, p<0.05 except #.
Mentions: Out of 18,413 gene inactivations screened, 58 candidates were identified that extend reproductive longevity of sqt-3 mutant animals (Figure S1C and Table S1). These gene inactivations were further examined in wild type and in an RNAi hypersensitive strain, nre-1(hd20)lin-15b(hd126) where RNAi potency is enhanced, especially in neurons [19]. We found that 32 gene inactivations prolong reproductive lifespan by more than 25% in the nre-1(hd20)lin-15b(hd126) background (Figure 1A and Table S2), and increase late reproduction of progeny after the first 3 days of adulthood (Figure S2). Twenty-six of the gene inactivations extend reproductive lifespan nearly equivalently in the enhanced neuronal RNAi background and in wild type; the 6 genes that show phenotypes only in the enhanced neuronal RNAi strain background may act in neurons because wild type C. elegans generally does not silence neuronal gene functions by RNAi (Figure 1B and Table S3).

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.


Related in: MedlinePlus