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The role of Sirt1 in restricted energy intake

Published online by Cambridge University Press:  28 January 2009

Luisa Wakeling  and
Dianne Ford
Luisa Wakeling
Affiliation:
Newcastle University, Newcastle upon Tyne, UK
Dianne Ford
Affiliation:
Newcastle University, Newcastle upon Tyne, UK
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Abstract

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Proceedings of the Nutrition Society , Volume 67 , Issue OCE8: Summer Meeting 30 June–3 July 2008 , May 2008 , E405
Copyright
Copyright © The Authors 2009

Dietary restriction (DR) increases lifespan in a range of evolutionarily-distinct species(Reference McCay, Crowell and Maynard1–Reference Jiang, Jaruga, Repnevskaya and Jazwinski4). The polyphenol resveratrol may be a dietary mimetic of some effects of DR(Reference Baur, Pearson and Price5). The pivotal role of the mammalian histone deacetylase (HDAC) Sirt1, and its homologue in other organisms, in mediating the effects of both DR and resveratrol on lifespan and ageing suggest that it may be the common conduit through which these dietary interventions influence ageing(Reference Howitz, Bitterman and Cohen6, Reference Cohen, Miller and Bitterman7). The novel hypothesis is proposed that effects of both DR and resveratrol relevant to lifespan extension include maintenance of DNA methylation patterns through Sirt1-mediated histone deacetylation. Changes in methylation status of the genome with aging are well-documented(Reference Singhal, Mays-Hoopes and Eichhorn8–Reference Wilson, Smith, Ma and Cutler10). The effects of manipulating histone acetylation by Sirt1 overexpression and resveratrol treatment on methylation of the LINE-1 retrotransposon, a surrogate marker of global DNA methylation, were examined in human intestinal Caco-2 cells, using a published combined bisulfite restriction analysis (COBRA) assay(Reference Yang, Estécio, Doshi, Kondo, Tajara and Issa11).

Treatment of cells with the HDAC inhibitor trichostatin A (0.3 μm for 48 h) resulted in an 18% reduction in LINE-1 methylation (n 16–30; P<0.001; Figure), supporting limited published evidence that manipulation of histone acetylation status can affect DNA methylation(Reference Cervoni and Szyf12). Sirt1 expression was undetectable by RT–PCR in Caco-2 cells and was substantially increased 72 h after transfection with a Sirt1 expression construct. Neither Sirt1 overexpression nor resveratrol (10 μm for 48 h) alone affected DNA methylation in Caco-2 cells, but together increased LINE-1 methylation by 30% (n 17–30; P<0.001, Figure), in support of the hypothesis. Future studies should investigate changes in histone acetylation and locus-specific changes in DNA methylation in this model system and determine the effects of DR and resveratrol in rodents on DNA methylation profiles to identify candidate genomic targets.

Figure. Effects of Sirt1 and resveratrol on LINE-1 methylation in Caco-2 cells. LINE-1 methylation was measured by densitometric analysis of SYBR green-stained COBRA gels. Data are normalised means with their standard errors (n 16–42). *P<0.05, **P<0.01, ***P<0.001 by one-way ANOVA then Bonferroni's multiple comparisons test.

References

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Figure 0

Figure. Effects of Sirt1 and resveratrol on LINE-1 methylation in Caco-2 cells. LINE-1 methylation was measured by densitometric analysis of SYBR green-stained COBRA gels. Data are normalised means with their standard errors (n 16–42). *P<0.05, **P<0.01, ***P<0.001 by one-way ANOVA then Bonferroni's multiple comparisons test.