Mild activation of the mitochondrial unfolded protein response increases lifespan without increasing resistance to stress

The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway that responds to mitochondrial insults by altering gene expression to recover mitochondrial homeostasis. The mitoUPR is mediated by the stress-activated transcription factor ATFS-1 (activating transcription factor associated with stress 1). Constitutive activation of ATFS-1 increases resistance to exogenous stressors but paradoxically decreases lifespan. In this work, we determined the optimal levels of expression of activated ATFS-1 with respect to lifespan and resistance to stress by treating constitutively active <i>atfs-1(et17</i>) worms with different concentrations of RNA interference (RNAi) bacteria targeting <i>atfs-1</i>. We observed the maximum lifespan of <i>atfs-1(et17</i>) worms at full-strength <i>atfs-1</i> RNAi, which was significantly longer than wild-type lifespan. Under the conditions of maximum lifespan, <i>atfs-1(et17</i>) worms did not show enhanced resistance to stress, suggesting a trade-off between stress resistance and longevity. The maximum resistance to stress in <i>atfs-1(et17</i>) worms occurred on empty vector. Under these conditions, <i>atfs-1(et17</i>) worms are short-lived. This indicates that constitutive activation of ATFS-1 can increase lifespan or enhance resistance to stress but not both, at the same time. Overall, these results demonstrate that constitutively active ATFS-1 can extend lifespan when expressed at low levels and that this lifespan extension is not dependent on the ability of ATFS-1 to enhance resistance to stress.