Sulfur amino acid restriction-induced changes in redox-sensitive proteins are associated with slow protein synthesis rates
Nichenametla SN, Mattocks DAL, Malloy VL, Pinto JT
Ann. N. Y. Acad. Sci. 2018 Jan;
The mechanisms underlying life span extension by sulfur amino acid restriction (SAAR) are unclear. Cysteine and methionine are essential for the biosynthesis of proteins and glutathione (GSH), a major redox buffer in the endoplasmic reticulum (ER). We hypothesized that SAAR alters protein synthesis by modulating the redox milieu. Male F344-rats were fed control (CD: 0.86% methionine without cysteine) and SAAR diets (0.17% methionine without cysteine) for 12 weeks. Growth rates, food intake, cysteine and GSH levels, proteins associated with redox status and translation, and fractional protein synthesis rates (FSRs) were determined in liver. Despite a 40% higher food intake, growth rates for SAAR rats were 27% of those fed CD. Hepatic free cysteine in SAAR rats was 55% compared with CD rats. SAAR altered tissue distribution of GSH, as hepatic and erythrocytic levels were 56% and 196% of those in CD rats. Lower GSH levels did not induce ER stress (i.e., unchanged expression of Xbp1s , Chop, and Grp78), but activated PERK and its substrates eIF2-α and NRF2. SAAR-induced changes in translation-initiation machinery (higher p-eIF2-α and 4E-BP1, and lower eIF4G-1) resulted in slower protein synthesis rates (53% of CD). Proteins involved in the antioxidant response (NRF2, KEAP1, GCLM, and NQO1) and protein folding (PDI and ERO1-α) were increased in SAAR. Lower FSR and efficient protein folding might be improving proteostasis in SAAR.
One of the negative aspects of aging is the decreased ability to maintain normal cellular functions, which eventually manifests as disease. Optimal maintenance of DNA methylation is critical for normal cellular functions, but, as organisms age, the number of methyl groups on DNA drops. This may result in the development of disorders such as cancer, impaired glucose/lipid metabolism, and cardiovascular diseases.
The two major dietary sources of methyl groups in animals are methionine and choline. Past research has shown that rats and mice fed diets low in methionine (MR) but optimal in choline are less susceptible to aging-associated diseases and outlive mice on regular diets. In this study, Senior Scientist Dr. Sailendra Nichenametla and his team hypothesized that an MR diet induces changes in DNA methylation, which ultimately contributes to its beneficial effects. Dr. Nichenametla investigated this hypothesis in mice of two different ages (young and adult) by feeding each either a control diet (normal levels of choline and methionine; CF) or an MR diet (normal choline levels, but 80% less methionine).
Findings from this study suggest that an MR diet, despite containing comparatively fewer methyl groups, prevents loss of DNA methylation in the liver. While seeming paradoxical, these findings are plausible and highlight the complexity of biological systems. A decrease in a number of methyl groups coming from methionine may not have an effect because of the presence of choline, which also contributes to methyl groups. However, the MR diet results in lower levels of S-adenosylhomocysteine (SAH). Previous studies found that SAH levels increase during aging.
Here at OFAS, we strive to provide insight into the mechanistic basis of lifespan extension by MR diet through our research. Based on our findings, we conclude that an MR diet improves the efficiency of DNA methylation maintenance systems in adult mice, but has no effect in young mice, likely due to the fact that young animals already have lower levels of SAH compared to adult mice. With this study, we are one step closer to finding ways to slow down the process of aging-associated diseases such as cancer.
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