AREDS FORMULA COMBINED WITH SAFFRON, BILBERRY, AND ASTAXANTHIN: A NARRATIVE REVIEW OF MECHANISTIC RATIONALE, TRANSLATIONAL POTENTIAL, AND CLINICAL EVIDENCE IN AGE-RELATED MACULAR DEGENERATION

Rajendran, Sudesh Raj*, Ravetha, Tejas, Muzhumathi Susithra, Sneha1, Reethi

Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in adults over 50 years, affecting more than 196 million individuals worldwide. The AREDS2 formula, which contains lutein, zeaxanthin, vitamins C and E, zinc, and copper, remains the only evidence-based nutritional intervention proven to reduce the risk of AMD progression. However, AREDS2 does not address several established AMD pathological drivers, including photoreceptor neuroprotection, choroidal neovascularisation, mitochondrial dysfunction in the retinal pigment epithelium, NLRP3 inflammasome activation, and complement pathway dysregulation. This review synthesises the mechanistic rationale, translational evidence, and available clinical data for augmenting the AREDS2 formula with three bioactive compounds: saffron (Crocus sativus), bilberry (Vaccinium myrtillus), and astaxanthin, and evaluates their combined potential as a multimodal functional food strategy for AMD prevention and management. A structured narrative review was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Cochrane databases (January 2000–March 2025). Included studies comprised human randomised controlled trials, systematic reviews, meta-analyses, and mechanistic preclinical studies relevant to AMD and the three bioactives. Saffron's crocin and crocetin constituents provide photoreceptor neuroprotection via BDNF/TrkB and cAMP-PKA signalling, with clinical trials demonstrating significant electroretinographic improvement and visual acuity gains in early AMD. Bilberry anthocyanins reinforce retinal microvascular integrity, suppress NLRP3 inflammasome-mediated neuroinflammation, and accelerate rhodopsin regeneration. Astaxanthin provides superior lipid-phase singlet oxygen quenching at 6,000-fold the potency of vitamin E, with additional mitochondrial protective and anti-neovascular properties. The mechanistic profiles of all three bioactives are non-redundant with AREDS2 and address distinct, clinically validated AMD pathological pathways. The combination of AREDS2 with saffron, bilberry, and astaxanthin constitutes a mechanistically coherent, evidence-supported multimodal strategy for comprehensive AMD management. Dedicated combination randomised controlled trials with standardised endpoints are warranted to confirm clinical synergy and establish optimal dosing protocols.