Aging is the key risk factor in the development of various neurodegenerative diseases. The precise molecular links between metabolism, brain function, and aging are poorly understood. Using the simplified model organism C. elegans, we have discovered a potential link, which we propose to study in this grant.
There is a fundamental connection between metabolism, aging, and neural functions. Considering that the nervous system centrally coordinates organismal metabolism and therefore its sequale, understanding the precise mechanisms through which the nervous system assesses organismal energetic state is fundamental to understanding aging and age on-set diseases. Changes in flux through the tryptophan degradation pathway, also known as the kynurenine pathway, have been linked to a variety of neurodegenerative diseases such as Huntington's, Alzheimer's, multiple sclerosis and amyotrophic lateral sclerosis as well as psychiatric disorders such as schizophrenia and depression. Blocking the tryptophan degradation pathway at various points ameliorates murine, Drosophila, and C. elegans models of neurodegeneration or protein aggregation. How one amino acid degradation pathway affects such a broad range of neurological processes remains a mystery. In the course of studying C. elegans feeding regulatory pathways, we made the unexpected discovery that a specific kynurenine pathway metabolite, kynurenic acid, is locally produced within the animal's nervous system and serves as an endogenous measure of food availability. Our preliminary genetic and biochemical studies connect this metabolite through a glutamatergic signaling pathway to serotonin release, which in turn, modulates neuroendocrine secretions including that of insulin. This is accomplished through serotonergic inhibition of AMP-activated kinase in specific neurons. As tryptophan is an essential amino acid and various tryptophan- derived metabolites have neural signaling properties, I hypothesize that the kynurenine pathway metabolites are an ancient mechanism that links metabolism to neural functions including neuroendocrine secretions that coordinate the intertwined pathways of metabolism, protein homeostasis, and aging. I propose to use C. elegans to delineate the molecular circuits that link kynurenic acid levels to neuroendocrine mechanisms of aging and protein homeostasis. We will first establish the precise molecular links between kynurenic acid and insulin secretion from specific neurons, investigate the consequences of this neural pathway on organism-wide mechanisms of proteostasis, and define the regulatory relationships between the kynurenine pathway and various longevity mutants. Together, these studies will be a paradigm for how metabolism is sensed by the nervous system to regulate age related processes.