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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.


Reproductive longevity regulatory genes modulate somatic longevity.(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 daf-2, R07H5.9 and C05E11.6 (Group 1), reduce RoA without affecting IMR and increase mean lifespan significantly. Inactivation of sgk-1 or nhx-2 (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.
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pgen-1004752-g005: Reproductive longevity regulatory genes modulate somatic longevity.(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 daf-2, R07H5.9 and C05E11.6 (Group 1), reduce RoA without affecting IMR and increase mean lifespan significantly. Inactivation of sgk-1 or nhx-2 (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.

Mentions: To characterize the interaction between reproductive aging and somatic aging, we inactivated the 32 genes in the nre-1(hd20)lin-15b(hd126) RNAi hypersensitive strain, and examined their effects on organismal lifespan and on age-specific patterns of mortality. In the fitted mortality rate curve under the Gompertz-Makeham model (Figure 5A), the slope of the curve defines the demographic rate of aging (RoA) showing the rate of increase in mortality with age; whereas the intercept with the y-axis defines initial mortality rate (IMR) or “frailty” that represents the mortality rate at the defined time zero, in this case young adulthood and is related to the baseline mortality [24].


Gene pathways that delay Caenorhabditis elegans reproductive senescence.

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

Reproductive longevity regulatory genes modulate somatic longevity.(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 daf-2, R07H5.9 and C05E11.6 (Group 1), reduce RoA without affecting IMR and increase mean lifespan significantly. Inactivation of sgk-1 or nhx-2 (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.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004752-g005: Reproductive longevity regulatory genes modulate somatic longevity.(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 daf-2, R07H5.9 and C05E11.6 (Group 1), reduce RoA without affecting IMR and increase mean lifespan significantly. Inactivation of sgk-1 or nhx-2 (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.
Mentions: To characterize the interaction between reproductive aging and somatic aging, we inactivated the 32 genes in the nre-1(hd20)lin-15b(hd126) RNAi hypersensitive strain, and examined their effects on organismal lifespan and on age-specific patterns of mortality. In the fitted mortality rate curve under the Gompertz-Makeham model (Figure 5A), the slope of the curve defines the demographic rate of aging (RoA) showing the rate of increase in mortality with age; whereas the intercept with the y-axis defines initial mortality rate (IMR) or “frailty” that represents the mortality rate at the defined time zero, in this case young adulthood and is related to the baseline mortality [24].

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.