To investigate the hypothesis that elevated serum anticholinergic activity is independently associated with delirium in ill elderly persons, the authors performed a cross-sectional study of 67 acutely ill older medical inpatients. The presence of delirium was evaluated with the Confusion Assessment Method, and the presence of many delirium symptoms was measured by the Delirium Symptom Interview. Demographic data and clinical characteristics that may be important for the development of delirium were also collected. Logistic regression techniques demonstrated that elevated serum anticholinergic activity was independently associated with delirium. Among the subjects with delirium, a greater number of delirium symptoms was associated with higher serum anticholinergic activity.

Polypharmacy (use of ≥5 medications) and increasing Drug Burden Index (DBI) score (measure of person’s total exposure to anticholinergic/sedative medications) are associated with impaired physical function in observational studies of older adults. Deprescribing, the supervised withdrawal of medications for which harms outweigh benefits for an individual, may be a useful intervention. Current knowledge is limited to clinical observational studies that are unable to determine causality. Here, we establish a preclinical model that investigates the effects of chronic polypharmacy, increasing DBI, and deprescribing on global health outcomes in aging. In a longitudinal study, middle-aged (12 months) male C57BL/6J (B6) mice were administered control feed or feed and/or water containing polypharmacy or monotherapy with different DBI scores. At 21 months, each treatment group was subdivided (stratified by frailty at 21 months) to either continue on treatment for life or to have treatment withdrawn (deprescribed). Frailty and physical function were evaluated at 12, 15, 18, and 24 months, and were analyzed using a mixed modeling approach. Polypharmacy with increasing DBI and monotherapy with citalopram caused mice to become frailer, less mobile, and impaired their strength and functional activities. Critically, deprescribing in old age reversed a number of these outcomes. This is the first preclinical study to demonstrate that chronic polypharmacy with increasing DBI augments frailty and impairs function in old age, and that drug withdrawal in old age reversed these outcomes. It was not the number of drugs (polypharmacy) but the type and dose of drugs (DBI) that caused adverse geriatric outcomes.

Our findings suggest that serum anticholinergic activity may play a role in delirium in medical inpatients. The relationships between SAA and delirium in medical patients and between total SAA and medication use warrant further study.

SummaryWhile age‐related insulin resistance and hyperinsulinemia are usually considered to be secondary to changes in muscle, the liver also plays a key role in whole‐body insulin handling and its role in age‐related changes in insulin homeostasis is largely unknown. Here, we show that patent pores called ‘fenestrations’ are essential for insulin transfer across the liver sinusoidal endothelium and that age‐related loss of fenestrations causes an impaired insulin clearance and hyperinsulinemia, induces hepatic insulin resistance, impairs hepatic insulin signaling, and deranges glucose homeostasis. To further define the role of fenestrations in hepatic insulin signaling without any of the long‐term adaptive responses that occur with aging, we induced acute defenestration using poloxamer 407 (P407), and this replicated many of the age‐related changes in hepatic glucose and insulin handling. Loss of fenestrations in the liver sinusoidal endothelium is a hallmark of aging that has previously been shown to cause deficits in hepatic drug and lipoprotein metabolism and now insulin. Liver defenestration thus provides a new mechanism that potentially contributes to age‐related insulin resistance.