Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer

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Daniel Herranz,

Maribel Muñoz-Martin,

Marta Cañamero,

Francisca Mulero,

Barbara Martinez-Pastor,

Oscar Fernandez-Capetillo

& Manuel Serrano

Abstract

Genetic overexpression of protein deacetylase Sir2 increases longevity in a variety of lower organisms, and this has prompted interest in the effects of its closest mammalian homologue, Sirt1, on ageing and cancer. We have generated transgenic mice moderately overexpressing Sirt1 under its own regulatory elements (Sirt1-tg). Old Sirt1-tg mice present lower levels of DNA damage, decreased expression of the ageing-associated gene p16Ink4a, a better general health and fewer spontaneous carcinomas and sarcomas. These effects, however, were not sufficiently potent to affect longevity. To further extend these observations, we developed a metabolic syndrome-associated liver cancer model in which wild-type mice develop multiple carcinomas. Sirt1-tg mice show a reduced susceptibility to liver cancer and exhibit improved hepatic protection from both DNA damage and metabolic damage. Together, these results provide direct proof of the anti-ageing activity of Sirt1 in mammals and of its tumour suppression activity in ageing- and metabolic syndrome-associated cancer.

Original Article

The Pharmacogenomics Journal advance online publication 13 April 2010; doi: 10.1038/tpj.2010.28

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Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs

D Wang¹, Y Guo², S A Wrighton², G E Cooke³ and W Sadee¹

1. ¹Department of Pharmacology, Program in Pharmacogenomics, School of Biomedical Science, Ohio State University, Columbus, OH, USA
2. ²Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
3. ³Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, OH, USA

Correspondence: Dr D Wang, Department of Pharmacology, Program in Pharmacogenomics, School of Biomedical Science, College of Medicine, Ohio State University, Columbus, OH 43210, USA. E-mail:wang.808@osu.edu

Received 12 October 2009; Revised 10 March 2010; Accepted 16 March 2010; Published online 13 April 2010.

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Abstract

Cytochrome P450 3A4 (CYP3A4) metabolizes ~50% of all clinically used drugs. Although CYP3A4 expression varies widely between individuals, the contribution of genetic factors remains uncertain. In this study, we measured allelic CYP3A4 heteronuclear RNA (hnRNA) and mRNA expression in 76 human liver samples heterozygous for at least one of eight marker SNPs and found marked allelic expression imbalance (1.6–6.3-fold) in 10/76 liver samples (13%). This was fully accounted for by an intron 6 SNP (rs35599367, C>T), which also affected mRNA expression in cell culture on minigene transfections. CYP3A4 mRNA level and enzyme activity in livers with CC genotype were 1.7- and 2.5-fold, respectively, greater than in CT and TT carriers. In 235 patients taking stable doses of atorvastatin, simvastatin, or lovastatin for lipid control, carriers of the T allele required significantly lower statin doses (0.2–0.6-fold, P=0.019) than non-T carriers for optimal lipid control. These results indicate that intron 6 SNP rs35599367 markedly affects expression of CYP3A4 and could serve as a biomarker for predicting response to CYP3A4-metabolized drugs.

Keywords:

polymorphism; gene expression; CYP3A4; statin; allelic expression imbalance; cytochrome P450