Safranal-Standardized Saffron Extract Improves Metabolic, Cognitive, and Anxiolytic Outcomes in Aged Mice via Hypothalamic–Amygdalar Peptide Modulation

<i>Background</i>: Population aging increases susceptibility to cognitive decline, anxiety, and metabolic dysregulation, yet safe and effective interventions remain limited. Saffron (<i>Crocus sativus</i> L.) has been traditionally used to enhance mood and cognition, and its main metabolites, crocins and safranal, exert neuroprotective, anxiolytic, and metabolic effects. However, variability in extract composition and frequent adulteration hinder reproducibility. <i>Objectives</i>: To clarify the efficacy of genuine saffron preparations in aging, we investigated a saffron extract standardized for safranal and crocin content (SSE). <i>Methods</i>: Safranal bioavailability was first characterized in rats, followed by an evaluation of behavioral, neuroendocrine, and metabolic outcomes after 35 days of oral SSE administration (25 or 200 mg/kg/day) in 25-month-old male C57BL/6 mice. Behavioral performance was assessed using open field and novel object recognition tests, while molecular analyses targeted neuropeptides in the hypothalamus and amygdala, hippocampal plasticity markers, cortical inflammatory proteins, and hepatic lipid metabolism genes. <i>Results</i>: SSE administration induced a rapid but transient increase in the plasma's safranal, confirming its bioavailability. In aged mice, the low dose prevented age-related weight loss and modulated hepatic lipid metabolism, whereas the high dose reduced anxiety-like behavior and improved recognition memory. The anxiolytic effects are consistent with elevated hypothalamic <i>Npy</i>, an anxiolytic peptide, reduced amygdalar <i>Crh</i>, a key mediator of stress and anxiety, and decreased hypothalamic <i>Hcrt,</i> an arousal modulator. The improvement in memory is associated with modulation of the cortical and hippocampal inflammatory and endocannabinoid proteins involved in neural plasticity. <i>Conclusions</i>: These findings highlight content-standardized saffron extracts as a promising multi-target nutraceuticals for healthy aging.