Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment

The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse hippocampal dysfunction by enhancing mitophagy and mitochondrial function. Two mouse models were used: 18-month-old C57BL/6 mice with established mitochondrial and cognitive deficits, and 5-month-old SAMP8 mice, an accelerated aging with cognitive decline starting from 6 months of age. UA was administered for 8 weeks, followed by assessments of ATP production, mitochondrial dynamics, mitophagy markers, synaptic proteins, and memory. In C57BL/6 mice, UA increased ATP, boosted proteins associated with fusion, antioxidant defense, and biogenesis, and reduced phosphorylated tau; however, these changes did not restore memory. In contrast, SAMP8 mice showed stronger effects: ATP rose sharply, mitochondrial stress and aberrant proteins decreased, and cognitive performance improved. These findings highlight UA effects as a preventive therapeutic agent, but are insufficient to reverse established cognitive decline, suggesting early mitophagy activation is critical to mitigate brain aging and neurodegeneration.