Genistein as a potential hormetic regulator of proteostasis in neurodegeneration and aging

Abstract

As global populations increase in age, the incidence of neurodegenerative diseases and dementia is rising; however, symptomatic and disease-modifying therapies deliver only modest benefits. This gap has fueled interest in aging-targeted interventions spanning lifestyle, nutrition, and pharmacology to attenuate neurodegeneration, preserve cognition, and, ideally, restore function. Although plant-derived bioactive compounds have been linked to resilience against cognitive aging, their underlying mechanisms remain elusive, limiting their clinical translation to preventive measures. Genistein, a soy-derived isoflavone consumed at high levels in Asian diets, has evolved as a potential multi-target modulator across neurodegenerative pathologies; however, its mechanistic basis is not fully understood. This review integrates preclinical and clinical evidence to propose a proteostasis-centered framework for genistein action, emphasizing how it may tune stress responses and quality control pathways that fail during aging and neurodegeneration. Genistein is discussed as a pleiotropic regulator of proteostasis with reported effects on molecular chaperones, the ubiquitin-proteasome system, and autophagy-lysosome pathways. It is also linked to endoplasmic reticulum (ER)-stress signaling via Ca 2+ homeostasis, thereby accelerating the clearance of proteotoxic substrates and mitigating excitotoxicity and oxidative injury. However, its hormetic and context-dependent actions underscore the need to define optimal dosing windows, target engagement, and modulators. Collectively, we anticipate that this review will stimulate proteostasis-focused mechanistic studies on genistein and support the therapeutic development for aging proteinopathies.