Abstract
Aging is a major risk factor for neurodegenerative diseases, yet the role of senescent microglia in age-related cognitive dysfunction remains incompletely understood. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been extensively studied for their significant potential in anti-aging. In this study, we demonstrated that hUC-MSCs ameliorate age-related cognitive decline and downregulate senescence-associated markers in the aged hippocampus. Furthermore, co-culture experiments showed that senescent microglia exacerbate neuronal senescence and neuroinflammation, while also suppressing the apoptosis of senescent neurons. These findings suggested that senescent microglia contribute to age-related cognitive decline by exacerbating neuronal damage and impairing senescent neurons' clearance. We also elucidated a novel mechanism by which hUC-MSCs alleviate age-related cognitive decline by targeting senescent microglia. Specifically, we showed that hUC-MSCs reduce senescence-associated markers, decrease lipid droplet accumulation, and restore phagocytic function in senescent microglia through the inhibition of the NF-κB-SREBP1 pathway. This pathway modulation attenuates neuronal damage and promotes the apoptosis of senescent neurons, facilitating the clearance of damaged neurons. These findings highlight the therapeutic potential of hUC-MSCs in age-related neurodegenerative disorders.