Signals produced by a few cells within a single tissue can regulate lifespan and functional aging throughout an
animal. These signaling molecules may exert nonautonomous effects at target tissues to induce their protective
mechanisms against age-dependent degeneration. Conversely, nonautonomous signals such as insulin/IGF-like
hormones may promote somatic functions that favor growth and reproduction, but while being permissive to
somatic degeneration. While nonautonomous signaling in aging regulation has been best characterized in terms
of centrally produced hormones, and more recently with cytokines and SASP, provocative data from several
model systems suggest there are critical, nonautonomous regulators of aging yet to be described. Accordingly,
this proposal focuses on small neuropeptide like molecules secreted from specialized cells of the intestine – gut
peptides. Enteroendocrine cells of animal guts, including those of Drosophila and humans, produce many gut
peptides that have system-wide impacts on behavior, digestion and metabolism. Working with Drosophila, we
propose that gut peptides can also affect lifespan and somatic functional aging by nonautonomous signaling
across the organism. In Drosophila, gut peptide production appears change with age, some increasing and
others decreasing. We also found that depleting a nutrient sensitive transcription factor in fly enteroendocrine
cells was sufficient to block longevity extension by dietary restriction, while inducing this factor appears to
increase the ability of dietary restriction to slow aging. We propose that gut peptides secreted from these cells
provides a mechanism to regulate aging and in particular in response to diet. The work has three objectives.
First is to fully characterize changes in the secretion of gut peptides from fly intestines with age and in response
to dietary restriction, and to assay their transcriptional controls. From our identified age-dynamic gut peptides,
we will use genetic manipulations to robustly infer which gut have the capacity to nonautonomously control life
span and functional aging at target tissues. The second goal is to determine if gut peptides modulate aging
through direct signaling at target tissues, and notably through G-Protein Coupled Receptors at these tissues.
The third aim explores if gut peptides nonautonomously modulate aging by affecting production of a secondary,
relay hormone, such as insulin/IGF or juvenile hormone, which in turn control systemic functional aging. Together
these aims will describe a novel tissue function for the intestine in aging control through systemic signaling, and
provide a model to explore these highly conserved gut peptides in mammals during aging and in response to
dietary restriction.