Nutritional co-therapy with vitamin D and L-theanine reduces unpredictable mild chronic stress (UCMS) in aged mice by restoring alpha-oscillations, dopamine levels and behavioral improvement.

Late-life depression (LLD) arises from the confluence of neurochemical dysfunction, oxidative stress, and neural network disintegration, presenting a formidable therapeutic challenge. Here, we demonstrated that combined vitamin D (Vit D) and L-theanine (L-thea) administration exerts multimodal neurorestorative effects in an aged murine model of unpredictable chronic mild stress (UCMS), addressing the core triad of LLD pathology: dopaminergic decline, redox imbalance, and thalamocortical dyssynchrony. Using a comprehensive battery of behavioral assays (Open Field Test, Elevated Plus Maze, Hole Board Test, Tail Suspension Test, Forced Swim Test, Sucrose Preference Test), we observed profound anxiogenic and anhedonic phenotypes in the UCMS-exposed mice, accompanied by elevated immobility and suppressed exploratory drive. Co-treatment with L-theanine (2 mg/kg) and vitamin D (500 IU/kg) robustly reversed these deficits, surpassing the efficacy of monotherapy (P < 0.05). Electrophysiologically, Vit D + L-thea restored alpha oscillations (8-13 Hz power: 2.33-fold increase vs. UCMS, P < 0.0001), indicating recovered thalamocortical coherence, which is a biomarker of cognitive-emotional integration. Amperometric brain homogenate analysis revealed dopaminergic recovery (Δcurrent = 1.99 μA vs. UCMS 0.66 μA), paralleled by supra-normalized antioxidant defenses as evidenced by significant reductions in MDA and enhancements in endogenous antioxidant enzymes (SOD, catalase, P < 0.0001). These convergent outcomes underscore multimodal therapeutic action of combination, targeting the GABA-glutamate balance, dopaminergic tone, oxidative stress, and cortical oscillatory stability. This combination presents a transformative approach for LLD, particularly in frail, treatment-resistant populations, where polypharmacy risks prevail. Our study bridges nutritional neuroscience and geriatric psychiatry, offering a path to resilience against the converging tides of stress and aging.