Gut stress-induced intercellular signaling networks promoting longevity and proteostasis

PROJECT SUMMARY
Cellular protein homeostasis (proteostasis) is essential to maintain the health of an entire organism throughout
life. Proteostasis collapse in aging organisms is a massive clinical problem as it underlies the development of
age-associated degenerative protein misfolding diseases in multiple organs, such as sarcopenia, metabolic
disorders or dementia. Centrally regulated signals produced by the nervous system such as hormones and
neuropeptides have been best characterized for their role in maintaining cell nonautonomous health. However,
the role of enteroendocrine cells, i.e. the gut, in producing secreted signals that have system-wide effects to
extend the health span of an animal is less well studied. Identifying intercellular signaling networks initiated by
the gut to prolong healthy tissue function throughout aging is therefore essential if we are to begin utilize such
signals for therapeutic strategies. The long-term goal of my lab is to develop molecular interventions that lever-
age intercellular signals initiated by the gut to promote healthy aging and long-term tissue health. We use C.
elegans for our work, as it is a tremendously useful system to identify and visualize the molecular mechanism
of intercellular signaling networks in the living organism. My lab discovered that mild gut stress, triggered by
knockdown of the molecular chaperone Hsp90 in the intestine, initiates the upregulation of protective protein
quality control responses in other tissues such as muscle. This results in lifespan extension and promotes
stress resilience throughout aging. We identified the cell membrane associated guanylate cyclase TXT-1 and
the homeodomain transcription factor CEH-58 as crucial mediators of gut-to-muscle signaling. Both compo-
nents function in the muscle to transduce extracellular signals received from the gut to activate protective re-
sponses. The overall objective is to determine how TXT-1 and CEH-58 initiate adaptive regulatory responses
in the muscle that promote health span. The central hypothesis is that intestine-specific reduction of Hsp90 ex-
pression activates a new intercellular signaling pathway that induces protective protein quality control re-
sponses in muscle cells (“gut-to-muscle signaling”). Our rationale is that by determining the molecular mecha-
nism of core components required for gut-to-muscle signaling we will have defined this new pathway and can
therapeutically target it to prolong health span. To test our central hypothesis, we will use genetic approaches
that allow for the visualization of intercellular and tissue-specific signals, as well as tissue-specific proteomic
and genomic methodologies in the following specific aims; Aim 1: Determine the molecular mechanism of core
components involved in gut-to-muscle signaling that promote proteostasis; Aim 2: Determine the gut stress-
induced antagonistic regulation of HSF-1 and CEH-58 at the transcriptional and molecular level; Aim 3: Define
the effects of constitutive and transient TCS activation on proteostasis and long-term health. In determining the
molecular mechanism of gut-to-muscle signaling, we expect to reveal fundamental new insights into the role of
the gut as a central organ that promotes organismal health span and counteracts age-associated illnesses.