The Insulin like signaling (ILS) pathway and the peroxisomal beta oxidation (PBO) are highly conserved central metabolic gateways that regulate the uptake of glucose and amino acids and the breakdown of fatty acids in all animals. ILS has been widely associated with lifespan control across species (1); PBO has not been directly connected with lifespan modifications but our and other laboratories work showed that small molecular products of C. elegans PBO can trigger pro-health and anti-ageing effects (ascarosides #2, #3, #8, ncas#3 (2, unpublished)). Crossing
daf-22(
ok693) worms lacking the CoA C-acetyltransferase DAF-22 and
daf-2(
e1370) mutants in which the function of the insulin receptor tyrosine kinase domain is compromised, we generated a
d2d22 double mutant, which exhibits an extremely high long lifespan, almost double the lifespan of the already long-lived
daf-2(
e1370) worms.
d2d22 double mutants further exhibit slow development, an extended fertility period, reduced number of progeny, and formation of large triglyceride containing droplets during adulthood. Comparative metabolomic and transcriptomic analyses of wild type,
daf-2,
daf-22 and
d2d22 mutants at different ages reveal small molecules and transcripts with starkly altered abundances in the long-lived strains. Accompanying proteomic analysis will provide further insight into the biosynthesis and regulatory aspects of those compounds. Selected compounds and mutants are tested in bioassays for developmental pace and lifespan. Integration of the all-omics data will facilitate the creation of a C. elegans pathway map of age-related small molecules. 1. Michelangela Barbieri, ... Giuseppe Paolisso. Am J Physiol Endocrinol Metab. 2003 Nov;285(5): E1064-71. Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. DOI: 10.1152/ ajpendo.00296.2003 2. Ludewig AH, ... Schroeder FC. Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5522-7. Pheromone sensing regulates Caenorhabditis elegans lifespan and stress resistance via the deacetylase SIR-2.1. doi: 10.1073/pnas.1214467110.