Gao X, Sanderson SM, Dai Z, Reid MA, Cooper DE, Lu M, Richie JP Jr, Ciccarella A, Calcagnotto A, Mikhael PG, Mentch SJ, Liu J, Ables G, Kirsch DG, Hsu DS, Nichenametla SN, Locasale JW.
Nature. 2019 Aug;572(7769):397-401
Nutrition exerts considerable effects on health, and dietary interventions are commonly used to treat diseases of metabolic aetiology. Although cancer has a substantial metabolic component1, the principles that define whether nutrition may be used to influence outcomes of cancer are unclear2. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. By contrast, whether specific dietary interventions can influence the metabolic pathways that are targeted in standard cancer therapies is not known. Here we show that dietary restriction of the essential amino acid methionine-the reduction of which has anti-ageing and anti-obesogenic properties-influences cancer outcome, through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and is the target of a variety of cancer interventions that involve chemotherapy and radiation. Methionine restriction produced therapeutic responses in two patient-derived xenograft models of chemotherapy-resistant RAS-driven colorectal cancer, and in a mouse model of autochthonous soft-tissue sarcoma driven by a G12D mutation in KRAS and knockout of p53 (KrasG12D/+;Trp53-/-) that is resistant to radiation. Metabolomics revealed that the therapeutic mechanisms operate via tumour-cell-autonomous effects on flux through one-carbon metabolism that affects redox and nucleotide metabolism-and thus interact with the antimetabolite or radiation intervention. In a controlled and tolerated feeding study in humans, methionine restriction resulted in effects on systemic metabolism that were similar to those obtained in mice. These findings provide evidence that a targeted dietary manipulation can specifically affect tumour-cell metabolism to mediate broad aspects of cancer outcome.
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.
Access the full paper here.
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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Several interventions have been identified that significantly extend healthy lifespan in mammals. Caloric restriction, for example, has been shown to improve healthspan in a variety of organisms, including rodents. Conversely, animals fed a diet with a normal caloric content, but with limiting amounts of the essential amino acid methionine, are up to 45% longer-lived than control animals. These and many other studies collectively demonstrate that alterations in nutrition and metabolism can have profound effects on healthy aging.
While studies are ongoing using conventional and established approaches to explore the molecular mechanisms underlying healthspan-extending interventions, many powerful new techniques are also being developed (e.g., genome engineering, high-throughput sequencing, DNA methylomics) that can be used to great effect for studies of healthy aging.
To explore the interplay between aging, nutrition, and metabolism, as well as the important role that novel technologies will play in current and future studies, Orentreich Foundation for the Advancement of Science and The Sackler Institute for Nutrition Science at The New York Academy of Sciences are bringing together several preeminent researchers in these fields. The event will take place Friday, December 2, 2016 from 12:30 PM – 6:30 PM at The New York Academy of Sciences (7 World Trade Center, 40th Floor, New York, NY, USA).
Attendance for this event is limited in order to facilitate high level discussions and interactions. For additional information on the symposium, speakers, and registration, visit the NYAS website.