Probing polypharmacy, ageing and sex effects on physical function using different tests.

BACKGROUND: Ageing, sex and polypharmacy affect physical function. OBJECTIVES: This mouse study investigates how ageing, sex and polypharmacy interact and affect grip strength, balance beam and wire hang, correlating and comparing the different test results between and within subgroups. METHODS: Young (2.5 months) and old (21.5 months) C57BL/6 J male and female mice (n = 10-6/group) were assessed for physical function at baseline on grip strength, balance beam and wire hang with three trials of 60 s (WH60s) and one trial of 300 s (WH300s). Mice were randomised to control or diet containing a high Drug Burden Index (DBI, total anticholinergic and sedative drug exposure) polypharmacy regimen (metoprolol, simvastatin, citalopram, oxycodone and oxybutynin at therapeutic oral doses). Following 6-8 weeks of treatment, mice were reassessed. RESULTS: High DBI polypharmacy and control mice both showed age group differences on all tests (p < 0.05). Only control mice showed sex differences, with females outperforming males on the WH60s and balance beam for old mice, WH300s for young mice (p < 0.05). Polypharmacy reduced grip strength in all subgroups (p < 0.05) and only in old females reduced wire hang time and cumulative behaviour and balance beam time and %walked (p < 0.05). Physical function assessments were all correlated with each other, with differences between subgroups (p < 0.05), and mice within subgroups showed interindividual variability in performance. CONCLUSION: Age, sex and polypharmacy have variable effects on different tests, and behavioural measures are useful adjuvants to assessing performance. There was considerable within-group variability in change in measures over time. These findings can inform design and sample size of future studies.

Polypharmacy With High Drug Burden Index (DBI) Alters the Gut Microbiome Overriding Aging Effects and Is Reversible With Deprescribing.

Aging, medication use, and global function are associated with changes in the microbiome. However, their interrelationships and changes over time require further characterization. In a longitudinal aging mouse study, we investigated the effects of aging, chronic polypharmacy with a high Drug Burden Index (DBI, measure of total anticholinergic and sedative medication exposure) and gradual cessation (deprescribing) on the microbiome, further exploring any association with global outcomes. Chronic administration of high DBI polypharmacy attenuated the aging-related reduction in alpha diversity, which was not sustained after deprescribing. Beta diversity and LEfSe (Linear discriminant analysis Effect Size) features varied with age, polypharmacy, and deprescribing. Aging with and without polypharmacy shared decreases in Bifidobacteriaceae, Paraprevotellaceae, Bacteroidaceae, and Clostridiaceae, while only aging with polypharmacy showed increased LEfSe features. Microbiome diversity correlated with frailty, nesting, and open field performance. Polypharmacy deprescribing reversed changes that occurred with treatment. However, the microbiome did not recover to its pretreatment composition at 12 months, nor develop the same aging-related changes from 12 to 24 months as the control group. Overall, aging, chronic polypharmacy, and deprescribing differentially affected the diversity and composition of the gut microbiome, which is associated with frailty and function.

Polypharmacy and precision medicine.

Precision medicine is an approach to maximise the effectiveness of disease treatment and prevention and minimise harm from medications by considering relevant demographic, clinical, genomic and environmental factors in making treatment decisions. Precision medicine is complex, even for decisions about single drugs for single diseases, as it requires expert consideration of multiple measurable factors that affect pharmacokinetics and pharmacodynamics, and many patient-specific variables. Given the increasing number of patients with multiple conditions and medications, there is a need to apply lessons learned from precision medicine in monotherapy and single disease management to optimise polypharmacy. However, precision medicine for optimisation of polypharmacy is particularly challenging because of the vast number of interacting factors that influence drug use and response. In this narrative review, we aim to provide and apply the latest research findings to achieve precision medicine in the context of polypharmacy. Specifically, this review aims to (1) summarise challenges in achieving precision medicine specific to polypharmacy; (2) synthesise the current approaches to precision medicine in polypharmacy; (3) provide a summary of the literature in the field of prediction of unknown drug-drug interactions (DDI) and (4) propose a novel approach to provide precision medicine for patients with polypharmacy. For our proposed model to be implemented in routine clinical practice, a comprehensive intervention bundle needs to be integrated into the electronic medical record using bioinformatic approaches on a wide range of data to predict the effects of polypharmacy regimens on an individual. In addition, clinicians need to be trained to interpret the results of data from sources including pharmacogenomic testing, DDI prediction and physiological-pharmacokinetic-pharmacodynamic modelling to inform their medication reviews. Future studies are needed to evaluate the efficacy of this model and to test generalisability so that it can be implemented at scale, aiming to improve outcomes in people with polypharmacy.

Comparing Effects of Polypharmacy on Inflammatory Profiles in Older Adults and Mice: Implications for Translational Aging Research.

Aging and multimorbidity are associated with inflammation. Polypharmacy is common in older people with multimorbidity. Given the potential for interactions between polypharmacy and inflammation, the relationship between inflammation and polypharmacy were studied in older adults with multimorbidity and in healthy aging mice. A cross-sectional analysis of data from the 5-year wave of the Concord Health and Ageing in Men Project, a population-based study of community-dwelling men aged ≥70 years. Serum concentrations of 27 cytokines were measured using a multiplex immunoassay. Associations between polypharmacy (≥5 medications) and cytokines were evaluated using multivariable linear regression adjusting for age, frailty, comorbidities, and individual drug classes. Interaction between polypharmacy and Drug Burden Index (DBI-drugs with anticholinergic and sedative effects) was analyzed. Effects of polypharmacy and DBI on serum levels of 23 cytokines were determined in aging male mice treated with chronic polypharmacy or control. Compared to the nonpolypharmacy group (n = 495), CHAMP participants with polypharmacy (n = 409) had significantly higher concentrations of IL-8, IL-6, CCL3, Eotaxin, IL-1ra, IL-1ß, IP-10, and lower concentrations of anti-inflammatory cytokine IL-4. In fully-adjusted multivariable models, polypharmacy was positively associated with concentrations of IL-8 and CCL3. There were no significant differences in inflammatory profiles between control and polypharmacy-treated mice. The relationship was not influenced by DBI in men or in mice. Inflammatory markers associated with polypharmacy in older adults were not seen in healthy aged mice administered polypharmacy, and may be related to underlying diseases. The polypharmacy mouse model provides opportunities for mechanistic investigations in translational research.

Applying the AFRAID and FRIGHT Clocks to Novel Preclinical Mouse Models of Polypharmacy.

The Frailty Inferred Geriatric Health Timeline (FRIGHT) and Analysis of Frailty and Death (AFRAID) clocks were developed to predict biological age and lifespan, respectively, in mice. Their utility within the context of polypharmacy (≥5 medications), which is very common in older adults, is unknown. In male C57BL/6J(B6) mice administered chronic polypharmacy, monotherapy, and undergoing treatment cessation (deprescribing), we aimed to compare these clocks between treatment groups; investigate whether treatment affected correlation of these clocks with mortality; and explore factors that may explain variation in predictive performance. Treatment (control, polypharmacy, or monotherapy) commenced from age 12 months. At age 21 months, each treatment group was subdivided to continue treatment or have it deprescribed. Frailty index was assessed and informed calculation of the clocks. AFRAID, FRIGHT, frailty index, and mortality age did not differ between continued treatment groups and control. Compared to continued treatment, deprescribing some treatments had inconsistent negative impacts on some clocks and mortality. FRIGHT and frailty index, but not AFRAID, were associated with mortality. The bias and precision of AFRAID as a predictor of mortality varied between treatment groups. Effects of deprescribing some drugs on elements of the clocks, particularly on weight loss, contributed to bias. Overall, in this cohort, FRIGHT and AFRAID measures identified no treatment effects and limited deprescribing effects (unsurprising as very few effects on frailty or mortality), with variable prediction of mortality. These clocks have utility, but context is important. Future work should refine them for intervention studies to reduce bias from specific intervention effects.

Diurnal effects of polypharmacy with high drug burden index on physical activities over 23 h differ with age and sex.

Aging, polypharmacy (concurrent use of ≥ 5 medications), and functional impairment are global healthcare challenges. However, knowledge of the age/sex-specific effects of polypharmacy is limited, particularly on daily physical activities. Using continuous monitoring, we demonstrated how polypharmacy with high Drug Burden Index (DBI-cumulative anticholinergic/sedative exposure) affected behaviors over 23 h in male/female, young/old mice. For comparison, we also evaluated how different drug regimens (polypharmacy/monotherapy) influenced activities in young mice. We found that after 4 weeks of treatment, high DBI (HDBI) polypharmacy decreased exploration (reduced mean gait speed and climbing) during the habituation period, but increased it during other periods, particularly in old mice during the transition to inactivity. After HDBI polypharmacy, mean gait speed consistently decreased throughout the experiment. Some behavioral declines after HDBI were more marked in females than males, indicating treatment × sex interactions. Metoprolol and simvastatin monotherapies increased activities in young mice, compared to control/polypharmacy. These findings highlight that in mice, some polypharmacy-associated behavioral changes are greater in old age and females. The observed diurnal behavioral changes are analogous to drug-induced delirium and sundowning seen in older adults. Future mechanistic investigations are needed to further inform considerations of age, sex, and polypharmacy to optimize quality use of medicines.

Preclinical frailty assessments: Phenotype and frailty index identify frailty in different mice and are variably affected by chronic medications.

Use of different objective frailty assessment tools may improve understanding of the biology of frailty and allow evaluation of effects of interventions on frailty. Polypharmacy is associated with increased risk of frailty in epidemiologic studies, regardless of frailty definition, but the pathophysiology of the association is not well understood. This study aims to (1) assess and compare the prevalence of frailty from middle to old age following control, chronic polypharmacy or monotherapy treatment, when measured using the clinical frailty index assessment and the mouse frailty phenotype tools; and (2) to evaluate and compare the effects of chronic polypharmacy regimens with zero, low and high Drug Burden Index (DBI) and monotherapies from middle to old age on the rate of deficit accumulation on the frailty index, mean number of phenotype criteria, odds of being frail assessed by the frailty index or phenotype, and the time to onset of frailty assessed by the frailty index or phenotype. In a longitudinal study, middle-aged (12 months) male C57BL/6J(B6) mice were administered non medicated control feed and water, or therapeutic doses of different polypharmacy combinations or monotherapies in feed and/or water. Frailty assessments were performed at 12, 15, 18, 21 and 24 months. There was limited overlap between animals identified as frail using different frailty assessments. Polypharmacy has measurable and different effects on each frailty assessment. Long-term chronic administration of some polypharmacy and monotherapy therapeutic drug regimens increased the number of frailty deficits (clinical frailty index: low DBI polypharmacy (15 and 21 months), high DBI polypharmacy (15-21 months), oxycodone (15-18 months), oxybutynin (15-18 months), citalopram (15-21 months) and metoprolol monotherapy (15 months) and modified frailty phenotype assessment (over the whole duration of treatment, low DBI polypharmacy (adjusted Risk Ratio(aRR) = 1.97, 95% confidence interval (CI) 1.43-2.72), high DBI polypharmacy (aRR = 1.88; 95% CI 1.36-2.60), oxybutynin (aRR = 1.48; 95% CI 1.01-2.16) and citalopram monotherapy (aRR = 1.96; 95% CI 1.41-2.74), p < 0.05) . The odds of developing frailty measured with the clinical frailty index increased with high DBI polypharmacy (adjusted odds ratio (aOR) = 3.13; 95% CI 1.01-9.66) and when measured with the frailty phenotype assessment increased with low DBI polypharmacy (aOR = 4.38, 95% CI 1.40-13.74), high DBI polypharmacy (aOR = 3.43; 95% CI 1.12-10.50) and citalopram monotherapy (aOR = 4.63; 95% CI 1.39-15.54)). No treatment affected time to frailty using either frailty assessment. Analysis of the number of deficits on the frailty index or number of positive criteria on the frailty phenotype allows analysis of rate of change and provides greater sensitivity, while the odds of being frail analysis provided a clinically relevant indicator of whether mice had greater chance of reaching a cut-off for becoming frail with medication exposure than without. Our results are consistent with clinical studies, demonstrating that certain polypharmacy regimens induce frailty, with different relationships observed when using different frailty assessments and analyses.

Public Health Foundations for Radiology Resident Education: Healthcare Disparities in Radiology.

Increasing recognition within the medical literature and by the Accreditation Council for Graduate Medical Education has been attributed to the need for enhanced resident education on concepts related to public health and health equity. Despite increasing documentation of pervasive inequalities within the scope of radiology, dedicated curricula designed to improve cultural competency and understanding of healthcare disparities among radiology trainees remains sparse. With relatively fewer patient interactions, radiology trainees are particularly susceptible to insufficient contextual awareness of how socioeconomic factors influence patient health and behaviors, physician recommendations, and ultimately clinical outcomes. The purpose of this article is to provide a high-yield background of foundational health equity and disparity concepts for radiology trainees, from which additional educational curricula may be derived. Specifically, this article will discuss the fundamental socioeconomic factors known to contribute to discrepant access and use of imaging services, followed by areas in radiology with well-documented disparities of which trainees should be aware. Lastly, previous and current strategies for addressing disparities in radiology will be discussed with the ultimate goal of stimulating trainee participation and the development of novel approaches.

Male-Female Differences in the Effects of Age on Performance Measures Recorded for 23 Hours in Mice.

Functional independence is an important aspect of successful aging and differs with age and by sex in humans. Physical performance often declines earlier than other age-associated functional impairments. Rodent models are used to study pharmacological/toxicological effects of human therapies. However, physical outcomes in mice are usually assessed for short periods, with limited information on the influence of age and sex. Here, we investigated how age and sex affected murine physical performance over 23 hours of continuous observation. Young (3 months) and old (22 months) C57BL/6JArc male and female mice were assessed using the Laboratory Animal Behavior Observation, Registration, and Analysis System. Mice were individually housed for recording of distance travelled, mean gait speed, and durations of different physical activities. Compared to young mice of the same sex, old mice travelled significantly shorter distances with slower gait speeds and shorter durations of locomotion, rearing, climbing, and immobility. Older mice groomed significantly more than young mice. Old females reared more during the light cycle than old males. Young females climbed substantially more than young males. Significant Age * Sex interactions were detected for rearing and climbing, whereby an age-related decline was greater in males than in females. Our results suggest that old age reduces exploratory activities and increases grooming in mice. Age-related declines vary between sexes and tend to be greater in males. This noninvasive assessment can be applied to investigate how different interventions affect rodents of different ages and sexes, through the day-night cycle.

Endovascular Thrombectomy of COVID-19-Related Large Vessel Occlusion: A Systematic Review and Summary of the Literature.

PURPOSE: Despite an overall reduction in the number of stroke cases presenting to hospitals during the COVID-19 pandemic, a remarkably high incidence of acute cerebrovascular disease associated with the infection has been reported. In this systematic review, we assess the neurological outcomes and complications of endovascular thrombectomy (EVT) for large vessel occlusions (LVO) in COVID-19 patients. METHODS: A literature search was performed in PubMed from December 1, 2019 through September 1st, 2020 using different combinations of suitable keywords. Ten studies reporting EVT outcomes and complications were identified. Two studies that included non-LVO pathologies and COVID-19 negative patients with the outcomes analysis were excluded. Patient demographics, comorbidities, anatomic thrombus location, neurological and angiographic outcomes were assessed. RESULTS: A total of 8 studies, in addition to our institutional case series, were ultimately included in this review. The mean age was 62.2 years, of which 67.6% were males. M1 segment involvement was the most commonly reported (53.8%) thrombus location. The mean NIHSS at presentation was 20.4 with no significant change at 24 h. Successful revascularization (TICI ≥ 2b) was achieved in 89%. Early proximal cerebral re-occlusion was reported in 6 patients (11%) and cerebral hemorrhage in 3 patients (4%). In hospital mortality was reported in 15 patients (28.8%). CONCLUSION: Despite angiographically successful EVT of LVOs in the majority of patients, this literature analysis demonstrates overall poor outcomes and high mortality in COVID-19 patients post EVT. An unusual incidence of early intracerebral proximal arterial re-occlusion was notable.

Nationwide mortality trends of delirium in Australia and the United States from 2006 to 2016.

OBJECTIVES: To examine nationwide trends in delirium mortality in Australia and the United States between 2006 and 2016. METHODS: Delirium mortality data for Australian and United States populations were obtained from World Health Organization Mortality Database. Mortality trends were assessed using joinpoint regression. RESULTS: Age-adjusted delirium mortality increased by 16.35%/year and 4.04%/year in Australia and the United States, respectively. Average annual age-adjusted delirium mortality rate (per 1 000 000 population) was 2.90 in Australia, and 1.06 in the United States. Death rates from delirium increased with age. Mortality was consistently higher in men than women, but the rate of annual increase was greater in women. CONCLUSIONS: Our study provided important population-level data on delirium and its outcomes in Australia and the United States. Reported death rates attributed to delirium increased over the 11-year period in both countries and were consistently higher in Australia than the United States. There were distinct age and sex differences in mortality trends.

Polypharmacy Results in Functional Impairment in Mice: Novel Insights Into Age and Sex Interactions.

Males and females may respond differently to medications, yet knowledge about sexual dimorphisms in the effects of polypharmacy remains limited, particularly in aging. This study aimed to assess the effect of high Drug Burden Index (DBI) polypharmacy treatment compared to control on physical function and behavior in young and old, male and female mice. We studied whether age and sex play a role in physical function and behavior following polypharmacy treatment and whether they are paralleled by differences in serum drug levels. Young (2.5 months) and old (21.5 months), C57BL/6 mice were randomized to control or high DBI polypharmacy treatment (simvastatin, metoprolol, oxybutynin, oxycodone, and citalopram; n = 6-8/group) for 4-6 weeks. Compared to control, polypharmacy reduced physical function (grip strength, rotarod latency, gait speed, and total distance), middle zone distance (increased anxiety), and nesting score (reduced activities of daily living) in mice of both ages and sexes (p < .001). Old animals had a greater decline in nesting score (p < .05) and midzone distance (p < .001) than young animals. Grip strength declined more in males than females (p < .05). Drug levels at steady state were not significantly different between polypharmacy-treated animals of both ages and sexes. We observed polypharmacy-induced functional impairment in both age and sex groups, with age and sex interactions in the degree of impairment, which were not explained by serum drug levels. Studies of the pathogenesis of functional impairment from polypharmacy may improve management strategies in both sexes.

Interactions Between the Aging Gut Microbiome and Common Geriatric Giants: Polypharmacy, Frailty, and Dementia.

The gut microbiome has pervasive bidirectional relationships with pharmacotherapy, chronic disease, and physical and cognitive function. We conducted a narrative review of the current literature to examine the relationships between the gut microbiome, medication use, sarcopenia and frailty, and cognitive impairment. Data from in vitro experiments, in vivo experiments in invertebrates and complex organisms, and humans indicate associations between the gut microbiome and geriatric syndromes. Better understanding of the direct and indirect roles of the microbiome may inform future prevention and management of geriatric syndromes.

Quantification of serum levels in mice of seven drugs (and six metabolites) commonly taken by older people with polypharmacy.

Polypharmacy (use of ≥ 5 drugs) is common in older people but has minimal preclinical or clinical evidence of safety or efficacy and is associated with adverse outcomes in older people. Drug-drug interactions are poorly understood beyond drug pairs. An efficient and sensitive method to measure multiple serum drugs and metabolites could inform drug dosing in polypharmacy. Development of a sensitive liquid chromatography - tandem mass spectrometry method to simultaneously measure seven drugs and their respective metabolites in serum in a preclinical model of polypharmacy. This method was validated for optimal recovery, matrix effect, limit of quantification (LOQ), inter- and intra-day variability, and carry over. Serum samples from mice (n = 5-6/group) treated with chronic oral doses of three polypharmacy regimens and five monotherapies were screened for drug and metabolite levels (metoprolol, α-hydroxymetoprolol, O-desmethylmetoprolol, omeprazole, 5-hydroxyomeprazole, omeprazole sulphone, acetaminophen, irbesartan, citalopram, oxybutynin, oxycodone, noroxycodone, oxymorphone and tenivastatin). The LOQ for the compounds ranged from 0.05 to 0.1 ng/mL in serum. Recovery, matrix effect, and inter- and intra-day variability peak response were acceptable. No carry over was observed at the concentrations tested. Analytes were detectable in mice treated with these drugs, and differences in drug levels were observed with different polypharmacy and monotherapy regimens. The method is sensitive and robust to measure parent drugs and metabolites simultaneously in the context of polypharmacy. Polypharmacy appeared to affect drug levels in a preclinical model. This model can be used to understand pharmacokinetics of chronic polypharmacy, which could inform prescribing and improve outcomes for older people.

Chronic Polypharmacy with Increasing Drug Burden Index Exacerbates Frailty and Impairs Physical Function, with Effects Attenuated by Deprescribing, in Aged Mice.

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.

Fall-related mortality trends in Australia and the United Kingdom: Implications for research and practice.

OBJECTIVES: To characterise changes in nationwide fall-related mortality rates in Australia and the United Kingdom (UK) between 2006 and 2016 by age group and sex. STUDY DESIGN: Trend analysis of falls mortality data from World Health Organization (WHO) Mortality Database for the Australian and UK population. MAIN OUTCOME MEASURES: We assessed age-specific, sex-specific and age-adjusted mortality rates. Mortality trends were assessed via the annual percentage change (APC) using joinpoint regression. RESULTS: The annual average age-adjusted falls mortality rate was 38.63 per 1,000,000 population in Australia, and 34.12 per 1,000,000 population in the UK. From 2006 to 2016, age-adjusted mortality rate due to falls increased in Australia and the UK by an average annual rate of 3.77% (95% CI 2.91% to 4.64%; p<0.01) and 2.11% (95% CI 1.43% to 2.80%; p<0.01) respectively. Death rates from falls increased with age. People aged ≥95 years had the highest mortality rate from falls in Australia and the UK. Men had a higher annual average age-adjusted mortality rate from falls than women (1.6 times higher in Australia and 1.7 times higher in the UK). Women had a larger annual percentage increase in falls mortality rate compared to men over the study period. CONCLUSIONS: There was a major increase in reported fall-related deaths in Australia and the UK between 2006 and 2016, especially in the very elderly. Men had a higher mortality rate from falls than women. Factors contributing to the apparent increases in fall-related mortality may include reduced cancer and cardiovascular mortality and better ascertainment of cause of death.

West Nile virus encephalitis: A report of two cases and review of neuroradiological features.

West Nile virus (WNV) is a single-stranded RNA arbovirus of Flavivirus genus that is endemic to the United States and known to cause neuroinvasive disease. Diagnosis is confirmed by the presence of WNV-specific IgM antibodies within serum or cerebrospinal fluid (CSF). Radiologically, it presents as hyperintense T2 signal within deep brain structures (ie, thalami and mid-brain) with or without cerebral peduncle and substantia nigra involvement. On diffusion-weighted imaging, restricted diffusion is reported in basal ganglia and disseminated throughout the white matter. In this report, we describe the imaging findings for 2 cases of WNV from our institution; a 56-year-old female and a 34-year-old female. Increased vigilance for WNV is warranted, particularly in immunosuppressed patients presenting with a clinical picture of viral meningoencephalitis despite initial negative magnetic resonance imaging or CSF analysis. A high suspicion for WNV disease should prompt repeat imaging or laboratory workup.

Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome.

There is an unmet need and urgency to find safe and effective anti-obesity interventions. Our recent study in mice fed on obesogenic diet found that treatment with the alcohol aversive drug disulfiram reduced feeding efficiency and led to a decrease in body weight and an increase in energy expenditure. The intervention with disulfiram improved glucose tolerance and insulin sensitivity, and mitigated metabolic dysfunctions in various organs through poorly defined mechanisms. Here, integrated analysis of transcriptomic and proteomic data from mouse and rat livers unveiled comparable signatures in response to disulfiram, revealing pathways associated with lipid and energy metabolism, redox, and detoxification. In cell culture, disulfiram was found to be a potent activator of autophagy, the malfunctioning of which has negative consequences on metabolic regulation. Thus, repurposing disulfiram may represent a potent strategy to combat obesity.