Did you know that kidney disease is one of the major causes of early mortality, morbidity, and rising medical costs in the United States? Now, more than ever, it is crucial to find a way to delay or avoid this devastating disease. OFAS and other researchers have proven that methionine restriction extends the lifespan of several species, and although studies have been conducted on various rodent organs, the effects of MR on kidneys are not well known. A study conducted by the Orentreich Foundation’s Associate Science Director, Dr. Gene Ables, has shown that MR reduced the effects of kidney injury by suppressing inflammation and fibrosis mechanisms. This, in turn, delays the progression of kidney disease.
When protein is ingested, protein waste products are created. Healthy kidneys have millions of nephrons that filter this waste, which then leaves the body in urine. Unhealthy kidneys lose the ability to remove protein waste, and it starts to build up in the blood. One way to prevent this is by putting patients with chronic kidney disease on low-protein diets. Methionine restrictive diets offer the alternative of simulating a low-protein diet without actually reducing overall protein intake, which is done through the increased consumption of plant-based foods instead of animal-based foods. It is recommended that future studies that investigate the effects of MR on kidney function should be done with older mice in order to include the effects of age and provide more insight.
FASEB J. 2017 Oct.
Methionine restriction (MR) extends the lifespan across several species, such as rodents, fruit flies, roundworms, and yeast. MR studies have been conducted on various rodent organs, such as liver, adipose tissue, heart, bones, and skeletal muscle, to elucidate its benefits to the healthspan; however, studies of the direct effect of MR on kidneys are lacking. To investigate the renal effects of MR, we used young and aged unilateral nephrectomized and 5/6 nephrectomized (5/6Nx) mice. Our studies indicated that MR mice experienced polydipsia and polyuria compared with control-fed counterparts. Urine albumin, creatinine, albumin-to-creatinine ratio, sulfur amino acids, and electrolytes were reduced in MR mice. Kidneys of MR mice up-regulated genes that are involved in ion transport, such as Aqp2, Scnn1a, and Slc6a19, which indicated a response to maintain osmotic balance. In addition, we identified renoprotective biomarkers that are affected by MR, such as clusterin and cystatin C. Of importance, MR attenuated kidney injury in 5/6Nx mice by down-regulating inflammation and fibrosis mechanisms. Thus, our studies in mice show the important role of kidneys during MR in maintaining osmotic homeostasis. Moreover, our studies also show that the MR diet delays the progression of kidney disease.—Cooke, D., Ouattara, A., Ables, G. P. Dietary methionine restriction modulates renal response and attenuates kidney injury in mice.
Our work at the Orentreich Foundation for the Advancement of Science has proven that methionine restriction (MR) extends lifespan and has many beneficial effects on various systems in animal models. Rodent MR models have shown improved cardiovascular function, bone development, insulin sensitivity, stress tolerance, and glucose metabolism, as well as a reduction in body mass and cancer development. Some of these effects have also been documented in invertebrate organisms, such as yeast, nematodes, and fruit flies.
In order for these effects to translate to humans, it is crucial to have access to the appropriate food sources. Building on their previous research, Associate Science Director Gene Ables and Senior Scientist Jay Johnson utilized information from the US National Nutrient Database to compile a list of various food sources that contain methionine content in order to give individuals an idea of what foods are best for a low-methionine diet. It was revealed that food sources for beef contained the highest content of methionine, followed by other animal-based sources such as poultry, fish, and dairy, whereas food like nuts, vegetables, cereals, and fruit contained less methionine. According to the data found, in order to achieve MR, a person has to eat more plant-based food and less animal-based food. This supports the idea that a vegan diet, which is naturally low in methionine, could be beneficial to healthspan.
Mattocks DA, Mentch SJ, Shneyder J, Ables GP, Sun D, Richie JP Jr, Locasale JW, Nichenametla SN
Exp Gerontol. 2017 Feb;
Despite well-documented evidence for lifespan extension by methionine restriction (MR), underlying mechanisms remain unknown. As methionine can alter S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), the substrate and product of DNA methyltransferase-1 (DNMT1), we hypothesized that MR diet alters DNA methylation. Young (8-week-old) and adult (1-year-old) male C57BL/6J mice were fed diets with different levels of methionine (0.12%-MR, 0.84%-CD) for 12weeks. Functional indicators of DNA methylation, including global methylation (GM), gene-specific methylation (GSM) and LINE-1 methylation; and biochemical factors affecting DNA methylation, SAH, SAM, and DNMT1 were assessed in different tissues. MR altered DNA methylation depending on the age of intervention. While MR had no effect on hepatic GM in young animals, it increased GM by 27% over CD in adults (p<0.01). In comparison with young animals, hepatic GM levels were 17% lower in CD adults (p<0.05), but not different in MR adults. The MR-induced increase in hepatic GM was associated with a 38% decrease in SAH levels in adults (p<0.001), with SAH and GM levels being negatively correlated (r2=0.33, p<0.001). No changes were observed in DNMT protein levels in liver. In adipose tissue, MR caused a 6% decline in GM in adults (p<0.05), a corresponding 2-fold increase in SAH (p<0.05), and a 2-fold decrease in DNMT1 (p<0.01). MR caused both increases and decreases in GSM of liver and adipose. No changes were observed in LINE-1. Together, these findings provide evidence for protective effects of MR diet on hepatic DNA hypomethylation in adults, apparently mediated by SAH. These findings also indicate that altered DNA methylation might be playing a role in benefits conferred by MR diet.
Past research has shown that dietary methionine restriction (MR) improves healthspan in part by reducing fat and increasing insulin sensitivity in rodent models. OFAS Senior Scientist Julie Hens, PhD, lead her team in a study to determine whether MR slows down tumor progression in xenograft breast cancer mouse model and breast cancer cell lines. There were two groups of mice, those on an MR diet (0.12% methionine content) and those on a control-fed (CF) diet (0.86% methionine content). The mice on the MR diet not only had reduced weights and less fat, but also had smaller tumors compared to those that were on the CF diet. The MR mice showed a decrease in proliferation and an increase in apoptosis in cells that comprise the mammary glands and xenograft tumors, thus providing evidence that MR can hinder cancer progression by affecting the cell cycle.
In a clinical setting, if MR can delay the progression of cancer, this would provide more time for current cancer therapies to work, and this could provide a more optimistic and healthier outlook for cancer patients.
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