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.