In C. elegans many of the conserved pathways that stimulate adult longevity were first identified for their influence on formation of a long-lived larval stage called the dauer diapause, which animals enter under harsh conditions. Endocrine pathways play a critical role in mediating this life stage choice, and include steroid hormone, insulin/IGF, and TGF-beta signaling. We have focused in particular on how steroid hormone and insulin/IGF signaling coordinate longevity. DAF-12 is a steroid receptor transcription factor most related to vertebrate Vitamin-D, Liver-X, and Farnesoid-X receptors. Like its vertebrate cousins, DAF-12 transcriptional activity is turned on by bile acid-like steroids, in this case called the dafachronic acids (DA). Genetic and molecular studies suggest a model whereby in favorable environmental conditions, cues detected by the nervous system result in activation of insulin/IGF and TGF-beta signaling, thereby stimulating DA production and DAF-12 activation. Consequently animals progress through larval development, culminating in maturation and short life. Conversely in unfavorable environments, endocrine systems are shut down, and the unliganded DAF-12 receptor specifies dauer formation, organismal arrest and longevity.
Interestingly, the DA/DAF-12 module is conserved amongst parasitic nematodes, whose infective stage is analogous to dauer. Thus the study of these pathways has not only shed light on the biology of ageing, but may have therapeutic implications for treatment of pathogenic nematodes. By using a combination of genetics and biochemistry we are elucidating the dafachronic acid biosynthetic pathways and their regulation by physiologic signaling and environmental inputs during organismal commitments. Additionally we continue to genetically dissect components of dauer formation in order to identify novel molecular pathways that promote long life.