Nobiletin as a Geroprotective Flavonoid: Mechanisms of Action, Therapeutic Potential, and Challenges of Bioavailability

Flavonoids are a diverse group of naturally occurring polyphenolic compounds found in plant-based foods and are known for their broad-spectrum biological activities. Among them, nobiletin, a polymethoxylated flavone derived from citrus peels, has gained attention for its multifaceted role in promoting healthy ageing and mitigating age-related diseases. This review explores the chemical properties, mechanisms of action, therapeutic potential, and challenges related to nobiletin. The focus is placed on its antioxidant, anti-inflammatory, neuroprotective, cardioprotective, and metabolic regulatory effects, as well as its capacity to enhance mitophagy, modulate circadian rhythms, and prevent ferroptosis. Despite promising preclinical results across various models, including in vitro cell lines, C. elegans, and mice, the clinical translation of nobiletin is hindered by poor oral bioavailability, complex extraction, and limited human data. Novel delivery systems, such as nanoemulsions and phospholipid-based carriers, offer potential solutions to enhance its bioavailability. As research advances, nobiletin emerges as a promising candidate for geroprotective therapy, warranting further investigation through well-designed clinical trials to extend healthspan and prevent age-associated pathologies.