Research at OFAS

OFAS has spent years researching dietary methionine restriction (MR) as a means of extending lifespan. Our studies have shown that reducing intake of this essential amino acid can lead to a remarkable increase in maximum age. In addition, experimental animals maintained on this dietary intervention have lower body weight, less fat accretion, improved insulin sensitivity, and reduced incidence of age-related disease, including cancer. Having established the effects of MR, we now seek to understand the mechanisms by which they are accomplished.

 

Previous work at OFAS revealed that dietary MR protects mice from developing diabetes and obesity. Current projects focus on identifying and characterizing the molecular changes MR produces in different organs and how these changes affect whole-body physiology. In addition to examining MR’s mechanistic properties in the bones, we have also examined a paradoxical effect of MR in mice—that it increases levels of homocysteine, a marker for greater cardiovascular disease risk—and found that heart function was not affected. By determining the adaptive responses to MR, we are able to identify cells, pathways, and molecules that help to explain its lifespan-extending effects. Together, our studies imply that MR in humans will lead to lowered risk for developing metabolic diseases and improved healthspan. We have shown that MR in rodent models can improve insulin and glucose levels and reduce body fat, conditions related to diabetes and obesity.

Publications

MR may be an important strategy for inhibiting cancer growth, particularly in cancers that exhibit dependence on methionine for survival and proliferation. Current projects focus on how MR alters expression of genes that control cell migration in breast development and cancer. Mesenchymal and breast cancer cells grown in MR media are being examined to determine which molecular mechanisms MR alters. Future work will extend this research to examine changes in noncoding RNAs, further elucidating the mechanism of MR-induced longevity in the rodent model. We also hope to examine MR’s effect on other cancers.

Publications

A previous collaboration with National Cheng Kung University, Taiwan, showed that MR increased mouse bone elasticity. We joined with that team again for further investigations into MR’s effects on bone. At first glance, comparing animals of the same age and gender, it appears that MR reduces rat bone density and mineral content. However, when one takes into consideration MR’s effect on body size—lower weight and less fat—reductions in bone density either disappear or are actually improved in MR rats. In addition, MR mice have similar intrinsic strength properties to animals fed a standard diet. Further studies at OFAS have indicated that use of dietary MR to promote improved healthspan might best be limited to adults; in mice on an MR diet, adults appeared to be more resistant to MR’s effects on bone than young animals.

Publications

We recently collaborated with researchers at Cornell University to determine histone methylation status in MR mice; findings suggest that methionine availability may affect cellular chromatin state. Studies now in progress seek to establish the role of MR on DNA methylation, protein homeostasis, and its cysteine sparing effect. Using yeast and mammalian cell models, we also hope to identify novel molecules that are involved in the lifespan extension of effect of MR.

Publications

Several observational studies suggest that vegan or vegan-like diets, low in protein and thus in methionine, confer benefits against obesity, hypertension, type-2 diabetes, and cardiovascular mortality. However, there are no interventional studies confirming whether such benefits are due to low protein in general or, more specifically, to low methionine. We are currently conducting a study with Penn State University investigating whether MR provides beneficial effects in humans similar to those observed in laboratory animals.