Brown Seaweed Phlorotannins: Chemical Diversity, Sustainable Extraction, Selective Quantification, Ageing-Related Bioactivities, and Phlorotannin-First Biorefinery Potential.

Phlorotannins are the characteristic phenolic metabolites of brown seaweeds and represent one of the most chemically diverse, analytically challenging, and industrially promising classes of marine polyphenols. Unlike terrestrial phenolics, phlorotannins are formed from phloroglucinol units and occur as complex mixtures of fucols, phlorethols, fuhalols, fucophlorethols, eckols, and related oligomeric or polymeric structures whose composition varies strongly with species, tissue, season, habitat, extraction protocol, and purification strategy. This review critically examines brown seaweed phlorotannins across five major dimensions: chemical diversity and species-dependent availability; extraction, enrichment, and sustainable solvent strategies, including natural deep eutectic solvents (NADES); analytical challenges and advances in selective quantification, highlighting the non-specific nature of Folin-Ciocalteu assays and the emerging value of selective qNMR-based quantification; and biological relevance to ageing-associated processes such as oxidative stress, inflammation, glycation, metabolic dysfunction, neurodegeneration, and skin ageing. The review further evaluates translational barriers, including poor standardization, uncertain bioavailability, matrix interference, limited compound-specific standards, and insufficient in vivo and clinical validation. Finally, a phlorotannin-first brown seaweed biorefinery framework is proposed, in which the phenolic fraction is recovered early as a high-value stream before sequential valorization of polysaccharides, proteins, pigments, minerals, and residual biomass. This integrated perspective highlights the need to move from crude "total phenolic" descriptions toward chemically defined, functionally validated, and industrially scalable phlorotannin systems.