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

Transient events during development can exert long-lasting effects on organismal lifespan. Here we 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-depositing 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 marked rearrangements of the organismal lipid landscape and a significant decrease in mitochondrial β-oxidation and that both lipid and metabolic changes contribute to the protective effects of HSF-1 against amyloid toxicity. Together, these findings link developmental changes in the histone landscape, HSF-1 activity and lipid metabolism to protection against age-associated amyloid toxicities later in life. Using C. elegans, Oleson et al. demonstrate that developmental exposure to reactive oxygen species protects against amyloid toxicity later in life, mediated by disruption of the H3K4me3 epigenetic machinery through HSF-1-dependent shifts in lipid metabolism.