Early life changes in histone landscape protect against age-associated amyloid toxicities through HSF-1 dependent regulation of lipid metabolism

Abstract Recent studies revealed that early-in-life events can have highly beneficial long-term effects in animals. We now demonstrate that exposure of Caenorhabditis elegans to reactive oxygen species during development protects against amyloid-induced proteotoxicity later in life. We show that this protection is initiated by the inactivation of the redox sensitive H3K4me3 modifying COMPASS complex, and conferred by a substantial increase in the heat shock independent activity of heat shock factor 1 (HSF-1), a longevity factor known to act predominantly during C. elegans development. We show that depletion of HSF-1 leads to dramatic rearrangements of the organismal lipid landscape, and a significant decrease in mitochondrial β-oxidation. Both of these activities appear to majorly contribute to HSF-1’s protective effects against amyloid toxicity. In summary, our study reveals previously unknown links between developmental changes in the histone landscape, HSF-1 activity and lipid metabolism and the protection against age-associated amyloid toxicities later in life.