Naibedya Dutta, Daniel Hicks, Edgar Esparza, Anna Entin, Priyadharshini Vijayakumar, Caitlin M Lange, Tripti Nair, Elijah A Roditi, Athena Alcala, Maxim Averbukh, Matthew Vega, Rebecca Aviles Barahona, Caitlin McTygue, Veronica Kuo, Juri Kim, Herbert Anson, Aeowynn J Coakley, George Wang, Steven E Pilley, Max A Thorwald, Whitaker Cohn, Sean P Curran, Nicolas Brouilly, Caroline Kumsta, Rachel N Arey, Peter J Mullen, Gilberto Garcia, Ryo Higuchi-Sanabria
Longevity and stress resilience require precise coordination of gene expression programs across tissues. Here, we demonstrate that overexpression of the chromatin reader bet-1 specifically in neurons of Caenorhabditis elegans promotes organismal longevity and stress resistance via cell-nonautonomous signaling. Neuronal bet-1 elicits a neurotransmitter-dependent signal that activates the conserved stress-responsive transcription factor HSF-1 in the intestine, enhancing proteostasis, oxidative stress resistance, metabolic remodeling, and immune defense. Life span extension by neuronal bet-1 requires both hsf-1 and daf-16 in neurons but only requires hsf-1 in peripheral tissues. Using bulk RNA sequencing, we reveal distinct prolongevity pathways that include enhanced heat-shock response, proteostasis, increased actin stability, and resistance to pathogens, which likely together coordinate the prolongevity effects of neuronal bet-1 Our findings establish BET-1 as a potent nonautonomous regulator of aging and stress response, highlighting chromatin readers as upstream modulators of intertissue signaling and systemic resilience.