Genes Dev. 2026 Aug 6. doi: 10.1101/gad.353559.125. Online ahead of print.
ABSTRACT
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.
PMID:42562575 | DOI:10.1101/gad.353559.125