Brain Aging, Neurohormesis and Neuronutrition: Defining Neuroprotective Strategies

Anastasiia Badaeva; Alexey Danilov; Anastasiia Kosareva; Carlotta Girlando; Antonio Trapanotto; Alena Sidenkova; Damiano Galimberti; Luay Rashan; Uwe Wenzel; Edward J. Calabrese; Vittorio Calabrese

doi:10.53941/alr.2025.100007

Abstract

Aging is accompanied by a decline in adaptive stress responses, increasing susceptibility to neurodegenerative processes driven by oxidative stress, mitochondrial dysfunction, impaired proteostasis, and chronic inflammation. Hormesis—a biphasic dose–response to low-intensity stressors—has emerged as a central biological strategy for enhancing cellular resilience across multiple systems, including the nervous system. This review highlights neurohormesis as a key mechanism of neuronal protection, wherein subtoxic stimuli activate cytoprotective pathways such as NRF2/ARE, heat shock proteins, and vitagene networks, promoting neuroplasticity and delaying cognitive decline. In parallel, the evolving discipline of neuronutrition offers a complementary strategy by utilizing specific nutrients and bioactive compounds (e.g., polyphenols, magnesium, omega-3 fatty acids) that act as mild stressors or modulators of adaptive signaling. These compounds influence mitochondrial bioenergetics, redox regulation, and neuroinflammatory pathways, often mediated through the gut–brain axis. The synergy between hormesis and neuronutrition provides a systems-level, personalized framework for promoting brain health, enhancing functional longevity, and preventing or attenuating age-related neurodegenerative disorders. In contrast to earlier reviews that have treated neurohormesis and neuronutrition in isolation, the present article offers a novel, systems-level integration of both paradigms under a unified strategy for personalized neuroprotection, with a specific emphasis on the gut-brain axis and microbiota as pivotal regulators of adaptive signaling.

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