Winardi Kevin, Mach John, McKay Matthew J, Molloy Mark P, Mitchell Sarah J, MacArthur Michael R, McKenzie Catriona, Le Couteur David G, Hilmer Sarah N
Laboratory of Ageing and Pharmacology, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, New South Wales, Australia.
Bowel Cancer and Biomarker Laboratory, School of Medical Science, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
Aging Cell. 2025 Jan;24(1):e14357. doi: 10.1111/acel.14357. Epub 2024 Oct 27.
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.
多重用药（同时使用≥5种药物）在老年人中极为普遍，用于治疗慢性病，且与不良老年结局相关，包括身体和认知功能障碍、跌倒、衰弱、住院和死亡。减药（停药）是管理多重用药的一种潜在策略。多重用药造成损害以及减药可能有益的广泛分子变化尚不清楚，并且在老年患者的组织中进行严格研究也不可行。因此，在一项随机对照试验中，我们从中年（12个月）到老年（26个月）对雄性C57BL/6J（B6）小鼠给予常用慢性药物（羟考酮、奥昔布宁、西酞普兰、辛伐他汀或美托洛尔）的治疗剂量作为单一疗法或联合使用（多重用药），并在21个月龄起的一个亚组中逐渐减少用药。我们通过蛋白质组学以及转录组学和组织学比较了药物相关的肝脏效应。我们发现单一疗法对肝脏蛋白质组学的影响有限，但多重用药则出现了显著变化（93%为多重用药所特有）。多重用药改变了参与免疫、药物、胆固醇和氨基酸代谢的肝脏蛋白质表达，同时血清药物水平高于单一疗法。减药不仅逆转了一些效应，还在肝脏蛋白质组中引起了不可逆的新变化。此外，我们的研究确定了几个与临床相关的不良老年结局相关的肝脏蛋白质共表达模块，如活动能力、衰弱和日常生活活动。这项研究突出了衰老、慢性多重用药和减药后复杂的分子变化。对这些机制途径的进一步探索可能为老年人多重用药和减药的管理提供信息。
