Abstract
Heat hormesis describes the beneficial adaptations resulting from transient exposure to mild heat stress, which enhances stress resilience and promotes healthy aging. While heat hormesis is widely observed, much remains to be learned about its molecular basis. This study bridges a critical knowledge gap through a comprehensive multiomic analysis, providing key insights into the transcriptomic and chromatin accessibility landscapes throughout a heat hormesis regimen in Caenorhabditis elegans. We uncover highly dynamic, dose-dependent molecular responses to heat stress and reveal that while most initial molecular changes induced by mild stress revert to baseline, key differences emerge in response to subsequent heat shock challenge that likely contribute to physiological benefits. We further demonstrate that heat hormesis extends life span specifically in wild-type animals, but not in germline-less mutants, likely due to transient disruption of germline activities during mild heat exposure, which appears sufficient to trigger pro-longevity mechanisms. This finding points to tissue-specific responses in mediating the physiological outcomes of heat hormesis. Importantly, we identify several highly conserved regulators of heat hormesis that likely orchestrate gene expression to enhance stress resilience. Among these regulators, some (MARS-1/MARS1, SNPC-4/SNAPc, FOS-1/c-Fos) are broadly required for heat-hormesis-induced benefits, whereas others (ELT-2/GATA4, DPY-27/SMC4) are uniquely important in specific genetic backgrounds. This study advances our understanding of stress resilience mechanisms, points to multiple new avenues for future investigations, and provides a molecular framework for promoting healthy aging through strategic mid-life stress management.