Mechanistic understanding of host-microbe interactions in regulating stress response and lifespan

Summary/Abstract Host-microbe interaction plays a critical role in regulating the host’s nutrition, development, immune system, and aging. Whether it is the microbe or its host, both have evolved to deal with systemic or environmental stresses such as temperature, redox imbalance, xenobiotics, etc. However, this ability of host organisms to respond to stress declines as they age, which is associated with aging-related diseases. Considering microbes live in close proximity to the host and experience the same stresses, the question arises as to whether microbial stress responses may modify the host's stress response and longevity. Addressing this question could significantly contribute to developing novel therapeutic paradigm targeting the microbial stress signaling for regulating host stress responses and promoting healthy aging. Using laboratory adaptive evolution, we evolved bacteria that resist oxidative stress and found that worms grown on these genetically modified bacteria could live longer and resist oxidative stress. This preliminary data provided the basis for our central hypothesis that alteration in the bacterial stress response can change its metabolism, in turn regulating worms' metabolism, stress response and lifespan. The specific research aims for this proposal are to (1) Characterize the role of stress evolved bacteria on worm’s stress tolerance and lifespan; (2) Elucidate the role that bacterial iron-sulfur homeostasis plays in regulating worm metabolism and longevity; and (3) Investigate bacterial- host mitochondrial signaling in stress and lifespan regulation. Successful completion of this project will highlight how microbial stress signaling is tied to host stress response and longevity, paving the way for formulation of genetically modified probiotics for slowing aging and age-related diseases. Through this career development award, I will gain a deeper understanding of the stress response and metabolism, as well as acquire new techniques to study the host-microbe interaction in order to establish an independent career which will investigate how microbial genetic variation affects host stress responses and longevity. In conjunction with my mentorship team, the University of Michigan offers an excellent environment for my training for this proposal and my transition to an independent career.