Unraveling the Molecular Basis of Stress Adaptation and Longevity in C. elegans Through the Lens of Heat Hormesis
Aging is a fundamental process in which organisms experience a progressive decline in cellular function, making them more susceptible to age-related diseases. While stress and environmental stimuli are often linked to accelerated aging, accumulating evidence suggests that fine-tuning stress adaptation can enhance resilience and promote longevity. Hormesis, a concept describing the dose-dependent, bi-phasic effect where low levels of stress confer beneficial effects, has emerged as a promising avenue in aging research. Among its various forms, heat hormesis, triggered by mild heat stress, has gained interest due to its association with sauna therapy, a popular wellness practice. This dissertation explores the molecular basis of how animals adapt to early-life mild stress experiences, triggering "memory-like" mechanisms that promote long-term survival benefits, using Caenorhabditis elegans (C. elegans) as a model organism.
Through multiomics approaches and functional screening, I uncovered dynamic transcriptomic and chromatin changes throughout a heat hormesis regimen. This longitudinal analysis captured key time points: immediately after mild stress exposure, following the recovery period, and upon subsequent high-level stress challenges. Significantly, I identified several novel regulators, previously unlinked to hormesis, essential for enhancing stress resistance. These discoveries connect heat hormesis to broader biological processes, including methionine incorporation, piRNA-mediated regulation, integration of developmental cues and stress signals, epigenetic memory formation via pioneer transcription factors, and chromosome architecture regulation through the dosage compensation complex.
To provide a broader perspective, I explored the varying physiological and molecular responses to hormetic heat stress, revealing its effects on reproductive activity and uncovering strain-specific mechanisms influencing longevity benefits. These findings suggest that heat hormesis benefits are shaped by a complex interplay of stress and broader biological context.
Beyond these molecular insights, this dissertation highlights the translational potential of harnessing hormesis to promote healthy aging. By reviewing the literature and clarifying the benefits and mechanisms of various heat hormesis regimens, it provides a foundation for developing precision stress management strategies to optimize healthspan and longevity. This work contributes to the growing body of knowledge on stress adaptation and offers valuable insights into precision approaches for promoting healthy aging.