Dietary restriction (DR), reduced nutritional uptake without causing malnutrition, has proven to be the most powerful intervention extending life span from yeast to humans. Mechanisms underlying the specific health benefits of DR are largely unknown. Work in rodents has led to conflicting results as to whether DR impacts the health parameter of paramount importance to aging human populations, resistance to pathogenic infection. Progress has been hindered partly by the complexity of the mammalian immune system. I chose Drosophila as a model system because the architecture of its innate immune response strongly reflects the mammalian system and it is a well-established model for DR and its impact on aging. I discovered that an acute protein restriction (PR) greatly improves survival of animals infected with human pathogenic bacteria, independent of the amount of carbohydrate in the diet and its overall caloric content. Using a range of genetic and pharmacologic approaches, I determined that the target of rapamycin (TOR) pathway mediates these protective effects of PR on Drosophila innate immunity. Myc, a key effector transcription factor, is sufficient to provide the beneficial effects of PR on immunological healthspan in an infectious disease setting. PR executes its protective effects by stabilizing Myc through TOR, establishing a PR-TOR-Myc signaling pathway that improves survivorship following pathogenic infection. This study details, for the first time, the nature of changes in nutrient signaling in response to PR. In this application, I am proposing to investigate how aging processes regulate the PR-responsive signaling (i.e. PR-TOR-Myc) and to identify Myc target genes that constitute a pro-immune network. As has been reported for other diet-dependent phenotypes such as mortality rate, PR acts acutely (within 48 hours) to protect the animals from upcoming pathogenic infections. This rapid response to PR opens up an exciting possibility that short-term diet interventions would provide an effective means of boosting immunity and reducing the mortality risks from opportunistic infections during times when normal immune function is compromised, including advanced age.
A decline in immunity with age contributes significantly to increased mortality in the elderly population. The goal of this application is to identify the pro-immune regulatory network whereby protein restriction strengthens innate immunity through nutrient signaling pathways. Mechanistic details obtained from this proposed study are expected to serve as a framework for developing safe and effective pharmacological interventions that increase human immunological healthspan.