Acetylcholinesterase Inhibition Reverses Age-Related Pulmonary Decline and Increases Bronchus-Associated Lymphoid Tissue Formation in Aged Mice

The age-related chronic, low-grade inflammation known as inflammaging contributes to tissue damage and disease. In the lungs inflammaging leads to abnormal tissue remodeling, reduced function, and decreased immunity. A key factor in inflammaging is declining acetylcholine signaling, which normally suppresses inflammation and promotes tissue repair. We tested whether increasing acetylcholine responsiveness could reverse age-related lung damage. Aged mice were treated with donepezil to increase acetylcholine availability. After six months blood oxygen saturation and voluntary activity were significantly improved. Histologically, treated mice showed reversal of alveolar enlargement (a hallmark of emphysema) and complete restoration of elastic fibers. Donepezil treatment also dramatically increased bronchus-associated lymphoid tissue (iBALT) formation. iBALT is the repository of tissue resident memory lymphocytes, including memory cholinergic lymphocytes that produce acetylcholine to suppress inflammation during secondary infections. The age-related loss of iBALT contributes to the increased risks associated with respiratory infection in the elderly. This indicates age-related lung function and respiratory immune deficits can be modulated by improving acetylcholine signaling. Repurposing an approved medication provides a direct pathway to clinical application for improving respiratory health and infection resistance during aging.