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

TL;DR

This study shows that a drug used for Alzheimer's can improve lung function and immune health in aged mice by boosting acetylcholine levels.

Contribution

The study demonstrates that acetylcholinesterase inhibition can reverse age-related lung decline and enhance immune tissue in aged mice.

Findings

Donepezil treatment improved blood oxygen levels and voluntary activity in aged mice.

Treated mice showed reversal of alveolar enlargement and restoration of lung elasticity.

Donepezil increased bronchus-associated lymphoid tissue formation in aged mice.

Abstract

As people age, their lungs and immune system do not work as well as they used to. This makes older adults much more vulnerable to pneumonia, flu, and other breathing illnesses. Scientists know that levels of a natural chemical called acetylcholine, which helps control inflammation, drop with age, and that raising acetylcholine in older adults is linked to a lower risk of death. This study tested whether donepezil (an Alzheimer’s drug that increases acetylcholine) could improve lung and immune health in aged mice. Older mice that received donepezil were more active and had better blood oxygen levels, more elastic lungs, and healthier immune tissue in their lungs than untreated aged mice. These results suggest that a drug already approved for older patients might one day help protect lung function and immune defenses in people with age-related or chronic breathing problems.

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 a 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 that 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.

Figures