A major goal of aging research is to understand the underlying relationship between nutritional intake, metabolism, and healthy aging. Low-glycemic index diets have been shown to reduce risk of age-related metabolic diseases such as diabetes and cardiovascular disease, and reduced caloric intake via dietary restriction (DR) increases healthspan across species. One potential approach for supporting healthy aging is via interventions that engage healthspan-promoting metabolism. Our previous work demonstrated that DR increases healthspan in a manner that requires gluconeogenic gene expression. In mammals, the glucagon signaling pathway promotes glucose production in the liver by stimulating glycogenolysis and gluconeogenesis. We reason that glucagon signaling, like DR, may have an overall positive impact on healthspan. To investigate this, we screened for potential glucagon receptors in Caenorhabditis elegans, and found one candidate,
pdfr-1, which is required for the induction of gluconeogenic gene expression under DR and for the long lifespan of dietary-restricted animals. In the mammalian glucagon signaling pathway, the G protein alpha subunit coupled to the glucagon receptor activates adenylate cyclase, which increases cAMP levels to activate protein kinase A (PKA), which in turn inhibits glycolytic activity and promotes gluconeogenesis. Similar tocandidate glucagon receptor
pdfr-1, we found that a C. elegans adenylate cyclase ortholog,
acy-1, is required for increased lifespan under DR. We also found that disruption of
kin-2, which encodes the inhibitory subunit of the C. elegans PKA ortholog
kin-1, triggers biomarkers for the DR state and results in dramatic healthspan increases that mirror those seen under DR. Strikingly, an
acy-1 gain-of-function mutant phenocopies the healthspan benefits of
kin-2 animals, and
acy-1 and
kin-2 function in the same pathway to affect healthy aging. Finally, we show that both the DR transcription factor
pha-4 and the
pdfr-1 receptor are required for increased healthspan in
kin-2 and
acy-1(gf) animals, suggesting that these components make up a healthspan-promoting pathway that is engaged under dietary restriction and which parallels the mammalian glucagon signaling pathway.