Summary: In Caenorhabditis elegans, the programmed repression of the heat shock response (HSR) accompanies the transition to reproductive maturity, leaving cells vulnerable to environmental stress and protein aggregation with age. To identify the factors driving this event, we performed an unbiased genetic screen for suppressors of stress resistance and identified the mitochondrial electron transport chain (ETC) as a central regulator of the age-related decline of the HSR and cytosolic proteostasis. Mild downregulation of ETC activity, either by genetic modulation or exposure to mitochondria-targeted xenobiotics, maintained the HSR in adulthood by increasing HSF-1 binding and RNA polymerase II recruitment at HSF-1 target genes. This resulted in a robust restoration of cytoplasmic proteostasis and increased vitality later in life, without detrimental effects on fecundity. We propose that low levels of mitochondrial stress regulate cytoplasmic proteostasis and healthspan during aging by coordinating the long-term activity of HSF-1 with conditions preclusive to optimal fitness. : Using the nematode Caenorhabditis elegans, Labbadia et al. demonstrate that low levels of mitochondrial stress caused by exposure to RNAi or xenobiotics can restore HSF-1 function with age, thereby maintaining cytosolic proteostasis, enhancing stress resistance, and prolonging healthspan, all without detrimental effects on development or reproduction. Keywords: HSF-1, heat shock response, mitochondria, proteostasis, aging, stress resistanc
