The First International Mini-Symposium on Methionine Restriction and Lifespan

It has been 20 years since the Orentreich Foundation for the Advancement of Science, under the leadership Dr. Norman Orentreich, first reported that low methionine (Met) ingestion by rats extends lifespan (Orentreich et al., 1993). Since then, several studies have replicated the effects of dietary methionine restricted (MR) in delaying age-related diseases (Richie et al., 1994; Miller et al., 2005; Ables et al., 2012; Sanchez-Roman and Barja, 2013). We report the abstracts from the First International Mini-Symposium on Methionine Restriction and Lifespan held in Tarrytown, NY, September 2013. The goals were (1) to gather researchers with an interest in MR and lifespan, (2) to exchange knowledge, (3) to generate ideas for future investigations, and (4) to strengthen relationships within this community. The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed. The symposium also emphasized the value of other species, e.g., the naked mole rat, Brandt's bat, and Drosophila, in aging research. Overall, the symposium consolidated scientists with similar research interests and provided opportunities to conduct future collaborative studies (Figure 3)

Circulating Angiopoietins-1 and -2, Angiopoietin Receptor Tie-2 and Vascular Endothelial Growth Factor-A as Biomarkers of Acute Myocardial Infarction: a Prospective Nested Case-Control Study

<p>Abstract</p> <p>Background</p> <p>Angiogenesis is up-regulated in myocardial ischemia. However, limited data exist assessing the value of circulating angiogenic biomarkers in predicting future incidence of acute myocardial infarction (AMI). Our aim was to examine the association between circulating levels of markers of angiogenesis with risk of incident acute myocardial infarction (AMI) in men and women.</p> <p>Methods</p> <p>We performed a case-control study (nested within a large cohort of persons receiving care within Kaiser Permanente of Northern California) including 695 AMI cases and 690 controls individually matched on age, gender and race/ethnicity.</p> <p>Results</p> <p>Median [inter-quartile range] serum concentrations of vascular endothelial growth factor-A (VEGF-A; 260 [252] vs. 235 [224] pg/mL; p = 0.01) and angiopoietin-2 (Ang-2; 1.18 [0.66] vs. 1.05 [0.58] ng/mL; p < 0.0001) were significantly higher in AMI cases than in controls. By contrast, endothelium-specific receptor tyrosine kinase (Tie-2; 14.2 [3.7] vs. 14.0 [3.1] ng/mL; p = 0.07) and angiopoietin-1 levels (Ang-1; 33.1 [13.6] vs. 32.5 [12.7] ng/mL; p = 0.52) did not differ significantly by case-control status. After adjustment for educational attainment, hypertension, diabetes, smoking, alcohol consumption, body mass index, LDL-C, HDL-C, triglycerides and C-reactive protein, each increment of 1 unit of Ang-2 as a Z score was associated with 1.17-fold (95 percent confidence interval, 1.02 to 1.35) increased odds of AMI, and the upper quartile of Ang-2, relative to the lowest quartile, was associated with 1.63-fold (95 percent confidence interval, 1.09 to 2.45) increased odds of AMI.</p> <p>Conclusions</p> <p>Our data support a role of Ang-2 as a biomarker of incident AMI independent of traditional risk factors.</p

Methionine-Restricted C57BL/6J Mice Are Resistant to Diet-Induced Obesity and Insulin Resistance but Have Low Bone Density

<div><p>Dietary methionine restriction (MR) extends lifespan, an effect associated with reduction of body weight gain, and improvement of insulin sensitivity in mice and rats as a result of metabolic adaptations in liver, adipose tissue and skeletal muscle. To test whether MR confers resistance to adiposity and insulin resistance, C57BL/6J mice were fed a high fat diet (HFD) containing either 0.86% methionine (control fed; CF) or 0.12% methionine (methionine-restricted; MR). MR mice on HFD had lower body weight gain despite increased food intake and absorption efficiency compared to their CF counterparts. MR mice on HFD were more glucose tolerant and insulin sensitive with reduced accumulation of hepatic triglycerides. In plasma, MR mice on HFD had higher levels of adiponectin and FGF21 while leptin and IGF-1 levels were reduced. Hepatic gene expression showed the downregulation of <em>Scd1</em> while <em>Pparg</em>, <em>Atgl</em>, <em>Cd36</em>, <em>Jak2</em> and <em>Fgf21</em> were upregulated in MR mice on HFD. Restriction of growth rate in MR mice on HFD was also associated with lower bone mass and increased plasma levels of the collagen degradation marker C-terminal telopeptide of type 1 collagen (CTX-1). It is concluded that MR mice on HFD are metabolically healthy compared to CF mice on HFD but have decreased bone mass. These effects could be associated with the observed increase in FGF21 levels.</p> </div

MR mice on HFD were shorter and had lower bone mass.

<p> (<b>A</b>) Mouse measurements from the tip of the nose to the base of the tail. (<b>B</b>) Mouse body mass indexes (BMI) based on the calculations mentioned in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051357#s2" target="_blank">Methods</a> section. Statistical analysis used was One-way ANOVA followed by Bonferroni post-tests where ***p<0.001 is for CF vs MR at all time points and^ap<0.01 is the comparison between CF measurements at 11 and 4 weeks. (<b>C</b>) Accelerated rotarod experiments were conducted as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051357#s2" target="_blank">Methods</a> section. (<b>D</b>) Fixed rotarod experiments were conducted as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051357#s2" target="_blank">Methods</a> section. (<b>E</b>) Plasma N-terminal propeptide of type 1 procollagen (P1NP) as determined by ELISA. F. Plasma C-terminal telopeptide of type 1 collagen (CTX-1) as determined by ELISA. Data are expressed as the mean ± SD (n = 7–8 mice per feeding group) and Figs. C–F were analyzed by Student’s unpaired <i>t</i>-test. *p<0.05, **p<0.01, ***p<0.001.</p

Hepatic gene expression of MR mice on HFD corresponded with improved insulin sensitivity.

<p> (<b>A</b>) Hepatic gene expression analysis by Taqman qPCR using β-actin as the housekeeping gene. All data are expressed as the mean ± SD (n = 7–8 mice per feeding group) and analyzed by Student’s unpaired <i>t</i>-test. *p<0.05, ***p<0.001.</p

Blood biochemistry of HFD-fed CF and MR mice.

<p>Eight weeks old C57BL/6J mice were weight-matched and fed control fed (CF) on HFD (n = 7–8) and methionine-restricted (MR) on HFD (n = 7–8) diets for 14 weeks. Data are expressed as means ± SD and compared using Student’s unpaired <i>t</i>-test.</p>*<p>p<0.05,</p>**<p>p<0.01,</p>***<p>p<0.001.</p