Chronic polypharmacy, monotherapy, and deprescribing: Understanding complex effects on the hepatic proteome of aging mice

Polypharmacy (use of ≥5 concurrent medications) is highly prevalent among older adults to manage chronic diseases and is linked to adverse geriatric outcomes, including physical and cognitive functional impairments, falls, frailty, hospitalization, and mortality. Deprescribing (withdrawal) is a potential strategy to manage polypharmacy. The broad molecular changes by which polypharmacy causes harm and deprescribing may be beneficial are unknown and unfeasible to study rigorously in tissue from geriatric patients. Therefore, in a randomized controlled trial, we administered therapeutic doses of commonly used chronic medications (oxycodone, oxybutynin, citalopram, simvastatin, or metoprolol) as monotherapy or concurrently (polypharmacy) from middle-age (12 months) to old-age (26 months) to male C57BL/6J (B6) mice and deprescribed (gradually withdrew) treatments in a subset from age 21 months. We compared drug-related hepatic effects by applying proteomics along with transcriptomics and histology. We found that monotherapy effects on hepatic proteomics were limited but significant changes were seen with polypharmacy (93% unique to polypharmacy). Polypharmacy altered the hepatic expression of proteins involved in immunity, and in drug, cholesterol, and amino acid metabolism, accompanied by higher serum drug levels than monotherapies. Deprescribing not only reversed some effects but also caused irreversible and novel changes in the hepatic proteome. Furthermore, our study identified several hepatic protein co-expressed modules that are associated with clinically relevant adverse geriatric outcomes, such as mobility, frailty, and activities of daily living. This study highlights the complex molecular changes following aging, chronic polypharmacy, and deprescribing. Further exploration of these mechanistic pathways may inform management of polypharmacy and deprescribing in older adults.