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Optimizing dietary restriction for genetic epistasis analysis and gene discovery in C. elegans.

Mair W, Panowski SH, Shaw RJ, Dillin A - PLoS ONE (2009)

Bottom Line: Dietary restriction (DR) increases mammalian lifespan and decreases susceptibility to many age-related diseases.Here we define a DR method that better fulfills criteria required for an invertebrate DR protocol to mirror mammalian studies.In contrast to previous reports, we find that DR can robustly extend the lifespan of worms lacking the AMP-activated protein kinase catalytic subunit AAK2 or the histone deacetylase SIR-2.1, highlighting the importance of first optimizing DR to identify universal regulators of DR mediated longevity.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.

ABSTRACT
Dietary restriction (DR) increases mammalian lifespan and decreases susceptibility to many age-related diseases. Lifespan extension due to DR is conserved across a wide range of species. Recent research has focused upon genetically tractable model organisms such as C. elegans to uncover the genetic mechanisms that regulate the response to DR, in the hope that this information will provide insight into the mammalian response and yield potential therapeutic targets. However, no consensus exists as to the best protocol to apply DR to C. elegans and potential key regulators of DR are protocol-specific. Here we define a DR method that better fulfills criteria required for an invertebrate DR protocol to mirror mammalian studies. The food intake that maximizes longevity varies for different genotypes and informative epistasis analysis with another intervention is only achievable at this 'optimal DR' level. Importantly therefore, the degree of restriction imposed using our method can easily be adjusted to determine the genotype-specific optimum DR level. We used this protocol to test two previously identified master regulators of DR in the worm. In contrast to previous reports, we find that DR can robustly extend the lifespan of worms lacking the AMP-activated protein kinase catalytic subunit AAK2 or the histone deacetylase SIR-2.1, highlighting the importance of first optimizing DR to identify universal regulators of DR mediated longevity.

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BDR and reproduction.a. BDR significantly reduces the rate of egg-production of wild type C. elegans. Median egg production in 7 hours; Control feeding = 35, BDR = 16, (Non-parametric Wilcoxon test, P<0.0001). b. Lifespan of male wild type C. elegans on control and BDR feeding regimes. BDR significantly extends the lifespan of male worms. Median Lifespan; Control = 23 days, BDR = 32 days. 39.1% extension (Log rank test, P<0.0001).
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pone-0004535-g002: BDR and reproduction.a. BDR significantly reduces the rate of egg-production of wild type C. elegans. Median egg production in 7 hours; Control feeding = 35, BDR = 16, (Non-parametric Wilcoxon test, P<0.0001). b. Lifespan of male wild type C. elegans on control and BDR feeding regimes. BDR significantly extends the lifespan of male worms. Median Lifespan; Control = 23 days, BDR = 32 days. 39.1% extension (Log rank test, P<0.0001).

Mentions: Similar to mammalian DR, BDR significantly reduces the rate of reproduction, as measured by egg production by hermaphrodites, compared to controls (Median eggs laid per adult worm in 7 hours: Control = 35, BDR = 16, Non-parametric Wilcoxon test, P<0.0001, Figure 2a). However, as is the case for DR in mammals and fruit flies [1], [41], lifespan extension under BDR is not the direct result of reduced egg production; BDR increases the lifespan of both wild type male C. elegans (Log rank test, P<0.0001. Figure 2b), and sterile normal lived hermaphrodite glp-4 mutants (data not shown).


Optimizing dietary restriction for genetic epistasis analysis and gene discovery in C. elegans.

Mair W, Panowski SH, Shaw RJ, Dillin A - PLoS ONE (2009)

BDR and reproduction.a. BDR significantly reduces the rate of egg-production of wild type C. elegans. Median egg production in 7 hours; Control feeding = 35, BDR = 16, (Non-parametric Wilcoxon test, P<0.0001). b. Lifespan of male wild type C. elegans on control and BDR feeding regimes. BDR significantly extends the lifespan of male worms. Median Lifespan; Control = 23 days, BDR = 32 days. 39.1% extension (Log rank test, P<0.0001).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2643252&req=5

pone-0004535-g002: BDR and reproduction.a. BDR significantly reduces the rate of egg-production of wild type C. elegans. Median egg production in 7 hours; Control feeding = 35, BDR = 16, (Non-parametric Wilcoxon test, P<0.0001). b. Lifespan of male wild type C. elegans on control and BDR feeding regimes. BDR significantly extends the lifespan of male worms. Median Lifespan; Control = 23 days, BDR = 32 days. 39.1% extension (Log rank test, P<0.0001).
Mentions: Similar to mammalian DR, BDR significantly reduces the rate of reproduction, as measured by egg production by hermaphrodites, compared to controls (Median eggs laid per adult worm in 7 hours: Control = 35, BDR = 16, Non-parametric Wilcoxon test, P<0.0001, Figure 2a). However, as is the case for DR in mammals and fruit flies [1], [41], lifespan extension under BDR is not the direct result of reduced egg production; BDR increases the lifespan of both wild type male C. elegans (Log rank test, P<0.0001. Figure 2b), and sterile normal lived hermaphrodite glp-4 mutants (data not shown).

Bottom Line: Dietary restriction (DR) increases mammalian lifespan and decreases susceptibility to many age-related diseases.Here we define a DR method that better fulfills criteria required for an invertebrate DR protocol to mirror mammalian studies.In contrast to previous reports, we find that DR can robustly extend the lifespan of worms lacking the AMP-activated protein kinase catalytic subunit AAK2 or the histone deacetylase SIR-2.1, highlighting the importance of first optimizing DR to identify universal regulators of DR mediated longevity.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America.

ABSTRACT
Dietary restriction (DR) increases mammalian lifespan and decreases susceptibility to many age-related diseases. Lifespan extension due to DR is conserved across a wide range of species. Recent research has focused upon genetically tractable model organisms such as C. elegans to uncover the genetic mechanisms that regulate the response to DR, in the hope that this information will provide insight into the mammalian response and yield potential therapeutic targets. However, no consensus exists as to the best protocol to apply DR to C. elegans and potential key regulators of DR are protocol-specific. Here we define a DR method that better fulfills criteria required for an invertebrate DR protocol to mirror mammalian studies. The food intake that maximizes longevity varies for different genotypes and informative epistasis analysis with another intervention is only achievable at this 'optimal DR' level. Importantly therefore, the degree of restriction imposed using our method can easily be adjusted to determine the genotype-specific optimum DR level. We used this protocol to test two previously identified master regulators of DR in the worm. In contrast to previous reports, we find that DR can robustly extend the lifespan of worms lacking the AMP-activated protein kinase catalytic subunit AAK2 or the histone deacetylase SIR-2.1, highlighting the importance of first optimizing DR to identify universal regulators of DR mediated longevity.

Show MeSH