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.

Grant Number: 5K99AG083058-02
NIH Institute/Center: NIH
Principal Investigator: Ajay Bhat