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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.


Gene inactivations that promote somatic longevity.(A–C) RNAi inactivation of daf-2, R07H5.9 and C05E11.6 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 (p<0.001). (D and E) Inactivation of nhx-2 and sgk-1 reduce IMR by 87% and 45%, respectively, but does not significantly affect RoA. The mean lifespan is increased by 30% and 21%, respectively (p<0.001). (F) C44B7.12 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.
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pgen-1004752-g006: Gene inactivations that promote somatic longevity.(A–C) RNAi inactivation of daf-2, R07H5.9 and C05E11.6 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 (p<0.001). (D and E) Inactivation of nhx-2 and sgk-1 reduce IMR by 87% and 45%, respectively, but does not significantly affect RoA. The mean lifespan is increased by 30% and 21%, respectively (p<0.001). (F) C44B7.12 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.

Mentions: We found that the majority (25) of the identified reproductive senescence genes affect somatic mortality trajectories (Figure 5B–D). Based on their effects on different aging-related parameters, these genes can be classified into three groups. First, gene inactivations of three genes, including daf-2, R07H5.9 and C05E11.6 decrease RoA without affecting IMR (frailty) (Figure 5B–D, Figure 6A–C). As a result, the median and maximum lifespan (defined here as age at 1% estimated survival) are both significantly increased upon their inactivations (Figure 6A–C). Secondly, gene inactivation of the two sodium homeostasis regulatory genes nhx-2 and sgk-1, reduce IMR but not RoA (Figure 5B–D, Figure 6D and 6E). Their inactivations also lead to median and maximum lifespan extension (Figure 6D and 6E), which is consistent with previous findings [25], [26]. The third group includes 20 gene inactivations that decrease IMR, but increase RoA (Figure 5B–D). As a result, these genes have little effect on median lifespan and cause no change in maximum lifespan (Figure 5B–D, one example shown in Figure 6F). Together, these results suggest that most of the gene inactivations that delay reproductive senescence decrease the baseline probability of death and consequently postpone the age-associated rise in mortality.


Gene pathways that delay Caenorhabditis elegans reproductive senescence.

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

Gene inactivations that promote somatic longevity.(A–C) RNAi inactivation of daf-2, R07H5.9 and C05E11.6 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 (p<0.001). (D and E) Inactivation of nhx-2 and sgk-1 reduce IMR by 87% and 45%, respectively, but does not significantly affect RoA. The mean lifespan is increased by 30% and 21%, respectively (p<0.001). (F) C44B7.12 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.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004752-g006: Gene inactivations that promote somatic longevity.(A–C) RNAi inactivation of daf-2, R07H5.9 and C05E11.6 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 (p<0.001). (D and E) Inactivation of nhx-2 and sgk-1 reduce IMR by 87% and 45%, respectively, but does not significantly affect RoA. The mean lifespan is increased by 30% and 21%, respectively (p<0.001). (F) C44B7.12 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.
Mentions: We found that the majority (25) of the identified reproductive senescence genes affect somatic mortality trajectories (Figure 5B–D). Based on their effects on different aging-related parameters, these genes can be classified into three groups. First, gene inactivations of three genes, including daf-2, R07H5.9 and C05E11.6 decrease RoA without affecting IMR (frailty) (Figure 5B–D, Figure 6A–C). As a result, the median and maximum lifespan (defined here as age at 1% estimated survival) are both significantly increased upon their inactivations (Figure 6A–C). Secondly, gene inactivation of the two sodium homeostasis regulatory genes nhx-2 and sgk-1, reduce IMR but not RoA (Figure 5B–D, Figure 6D and 6E). Their inactivations also lead to median and maximum lifespan extension (Figure 6D and 6E), which is consistent with previous findings [25], [26]. The third group includes 20 gene inactivations that decrease IMR, but increase RoA (Figure 5B–D). As a result, these genes have little effect on median lifespan and cause no change in maximum lifespan (Figure 5B–D, one example shown in Figure 6F). Together, these results suggest that most of the gene inactivations that delay reproductive senescence decrease the baseline probability of death and consequently postpone the age-associated rise in mortality.

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.