JNK Acts as A Conserved Regulator Prevents Healthy Aging by Attenuating Proteostasis Stress During Aging

Stress-activated C-JUN N-terminal kinases(JNKs), which belong to the mitogen-activated protein kinase (MAPK) family, are evolutionarily conserved signaling modules that orchestrate protective responses to adverse environmental conditions. It has been extensively provedthat increasing JNK activity can delay aging and extend lifespan in lower model organisms such as C. elegans and Drosophila . However, there is a lack of evidence regarding the role and determine context of JNK in aging and longevity regulation in mammals. In this study, we found that brain-specific low-level activation of JNK in mice significantly attenuates age-dependent body-weight gain, and prevents age-related locomotor and cognitive decline. In addition, JNK activation reduces cellular senescence and neuroinflammation in the brains ofmiddle-aged mice. Mechanistically, mild, yet not robust, activation of JNK significantly induced the expression of translational repressor 4EBP1 and the energy sensor AMP kinase (AMPK), while concurrently inhibiting the overall rate of protein biosynthesis in both human and mouse models. Thus, our results uncover a conserved role of JNK in preventing healthy aging possibly by regulating the expression of 4EBP1 and AMPK, along with translation rates.