The regulation of cancer and aging by methionine

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Project Summary Age-related diseases, including cancer, are the major causes of morbidity and mortality in Western society. While cancer in the genetically heterogeneous human population primarily occurs in the aged, cancer research to-date has primarily utilized young, inbred animals. As the effect of aging and host factors on cancer development and progression has grown increasingly evident, the limitations of this approach have become clear. Understanding how aging impacts cancer development, progression, and the response to interventions will provide mechanistic insights into the prevention and treatment of cancer as individuals grow older, and eventually will permit the development of new pharmacological approaches to this age-associated disease that will enable healthy aging. Here, we build on recent work by our team and others demonstrating that restricting dietary protein, or restriction of specific dietary amino acids, can extend the lifespan and healthspan of mice. We will utilize methionine restriction (MR), a dietary intervention that extends longevity and improves metabolic health in mice, and which in mouse xenograft studies has been shown to slow the progression of certain cancers, including breast cancer, the most common cancer in older women. Limitations of MR research to date include the fact that the effect of MR on healthspan is limited in scope, that the effects of MR have been studied only in a few young mouse strains, and that the cancer studies done to-date have exclusively relied on young hosts. Understanding how MR affects the healthspan, longevity, and natural development of breast cancer during the aging of genetically heterogeneous mice will provide valuable new insights into the potential application of MR-based interventions for the health, longevity and treatment of cancer in the genetically heterogeneous human population. We will use cutting edge techniques to isolate and characterize cancer initiating cells (CICs), examine how changes in levels of methionine and its metabolites affect the epigenome. We will use two breast tumor models to examine how host age impacts CICs, tumor growth and/or metastasis and the response to MR. Finally, we will determine the role of specific molecular sensors of methionine metabolites in the epigenetic and anti-cancer effects of MR during aging. The proposed work will address long- standing questions regarding the molecular mechanisms by which dietary components regulate healthy aging and cancer.