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. 2014 Mar 13;6(5):836-43.
doi: 10.1016/j.celrep.2014.01.031. Epub 2014 Feb 27.

The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet

Sarah J Mitchell  1 , Alejandro Martin-Montalvo  2 , Evi M Mercken  2 , Hector H Palacios  2 , Theresa M Ward  2 , Gelareh Abulwerdi  2 , Robin K Minor  2 , George P Vlasuk  3 , James L Ellis  3 , David A Sinclair  4 , John Dawson  5 , David B Allison  5 , Yongqing Zhang  6 , Kevin G Becker  6 , Michel Bernier  2 , Rafael de Cabo  7
Affiliations

The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet

Sarah J Mitchell et al. Cell Rep. .

Abstract

The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 1 (SIRT1), an NAD(+)-dependent deacetylase, improves metabolism and confers protection against physiological and cognitive disturbances in old age. SRT1720 is a specific SIRT1 activator that has health and lifespan benefits in adult mice fed a high-fat diet. We found extension in lifespan, delayed onset of age-related metabolic diseases, and improved general health in mice fed a standard diet after SRT1720 supplementation. Inhibition of proinflammatory gene expression in both liver and muscle of SRT1720-treated animals was noted. SRT1720 lowered the phosphorylation of NF-κB pathway regulators in vitro only when SIRT1 was functionally present. Combined with our previous work, the current study further supports the beneficial effects of SRT1720 on health across the lifespan in mice.

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Figures

Figure 1
Figure 1. SRT1720 extends lifespan and improves health in mice fed a standard diet
(A) Kaplan-Meier survival curves for mice fed either a standard diet (SD) or high-fat diet (HFD) supplemented without or with SRT1720 (SD-SRT1720, HFD-SRT1720); (B) Average body weight over the study; (C) Average daily caloric intake over the study; (D) Percentage fat mass measured by nuclear magnetic resonance spectroscopy at 13 months of age; (E) Respiratory Exchange Ratio (RER); (F) Rotarod performance. Data are shown as mean ± SEM. * p≤0.05 compared to diet without SRT1720.
Figure 2
Figure 2. SRT1720 improves the quality of life of SD-fed mice
(A) Cataract formation as assessed by lens opacity classification; (B) Oral glucose tolerance test with area under the curve (inset); (C) The homeostatic model assessment calculation of insulin resistance (HOMA-IR) and serum biochemical markers. Data are shown as mean ± SEM. * p≤0.05 compared to SD diet without SRT1720.
Figure 3
Figure 3. SRT1720 elicits differential gene expression profiles in the liver and muscle of SD-fed mice
Principal component analysis (PCA) was performed on (A) liver and (B) skeletal muscle of SD-fed mice supplemented without and with SRT1720. (C) Parametric analysis of gene-set enrichment (PAGE) analysis was performed on microarray data. Columns show significantly up- (red) and down-regulated (blue) pathways following SRT1720 supplementation. (D) mRNA expression analysis in liver and skeletal muscle by quantitative real-time PCR. Relative expression values were normalized to those of SD-fed control mice. (E) Serum tumor necrosis factor alpha (TNF-α) concentrations in SD-fed mice supplemented or not with SRT1720. Data are shown as mean ± SEM. (F) Western blotting of liver lysates from SD-fed mice supplemented or not with SRT1720. Upper left panel, representative blots; remaining panels, Signals associated with bands of interest were normalized to GAPDH and plotted. * p≤0.05; ** p≤0.01; *** p≤0.001 when compared to SD-fed control animals.
Figure 4
Figure 4. SIRT1 dependence in SRT1720-mediated gene expression in MEF cells
Microarray data collected from untreated (UT) and SRT1720-treated wild-type (WT) and Sirt1-KO MEFs were used to illustrate enrichment of select genes. A larger list of genes can be found in Table S6.
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