Hormetic Stress Responses in Aging: From Molecular Mechanisms to Clinical Translation

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Abstract
Aging is characterized by a progressive decline in physiological resilience and increased susceptibility to chronic diseases, including neurodegenerative disorders. Emerging evidence indicates that low-dose stressors (collectively termed hormetic stimuli) activate adaptive cellular responses that enhance stress resistance, promote repair mechanisms, and ultimately extend healthspan. This narrative review synthesizes current knowledge on hormesis in the context of aging, with a focus on key molecular pathways including nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuins, autophagy, and mitohormesis. We examine how lifestyle interventions (physical exercise, caloric restriction, mild thermal stress) and emerging pharmacological agents induce beneficial adaptive responses, while critically evaluating their translational potential in clinical and public health settings. Special emphasis is placed on the role of hormesis in counteracting neurodegeneration, the utility of autophagy and systemic aging biomarkers (epigenetic clocks, inflammaging scores) for precision dosing, and the limitations imposed by inter-individual variability, age-related decline in adaptive capacity, and risks of overexposure. Importantly, this review distinguishes experimentally demonstrated hormetic responses from broader adaptive stress responses and critically evaluates situations in which hormetic mechanisms may be insufficient, maladaptive, or clinically inappropriate. Understanding the delicate balance between beneficial and detrimental stress responses is essential for leveraging hormesis as a robust strategy to counteract aging and age-related diseases. We further propose a multilevel framework integrating molecular mechanisms with clinical outcomes, positioning hormesis as a key determinant of adaptive resilience (stress resistance, mitochondrial function, HRV, VO2max) in aging.

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