From Agro-Food By-Products to Precision Nutraceuticals: Bioactive Compounds, Molecular Mechanisms, Bioavailability and Clinical Translation

The valorization of agro-food by-products represents a potential strategy to address both environmental sustainability and the growing demand for innovative health-promoting products. Traditionally considered waste materials, agro-food residues are now recognized as valuable sources of bioactive compounds, including polyphenols, flavonoids, carotenoids, terpenoids, peptides, and other phytochemicals with potential nutraceutical applications. This review aims to provide a critical synthesis of the transition from agro-food by-product recovery to the development of evidence-based precision nutraceuticals. Particular attention is given to the chemical diversity of bioactive compounds obtained from representative agro-food sources, including citrus, olive, grape, tomato, and pomegranate residues, highlighting their biological activities and therapeutic potential. The molecular mechanisms underlying their health-promoting effects are discussed, focusing on key pathways involved in oxidative stress (Nrf2), inflammation (NF-κB), metabolic regulation (AMPK/SIRT1), mitochondrial homeostasis, autophagy/mitophagy, and apoptosis. Beyond the description of biological activities, this review critically addresses the main challenges limiting the translation of agro-food-derived bioactives into effective nutraceutical products, including bioavailability, bioaccessibility, intestinal metabolism, standardization of extracts, variability of raw materials, dose optimization, and the gap between preclinical findings and clinical evidence. The translational bottleneck is examined in detail, emphasizing the need for robust clinical validation and regulatory compliance. Finally, future perspectives are discussed, highlighting the potential of emerging technologies, including precision extraction, omics approaches, artificial intelligence, and personalized nutrition, to overcome current limitations and to enable the development of sustainable, safe, and effective nutraceutical interventions. By integrating advances in food science, molecular pharmacology, and human health research, this review provides a comprehensive perspective on how agro-food by-products can be transformed into scientifically validated nutraceutical platforms, supporting the development of sustainable and personalized strategies for disease prevention and health promotion. Despite promising preclinical evidence, clinical validation remains limited: most human studies are small, of short duration, and none have evaluated hard clinical endpoints.