David G Le Couteur’s research while affiliated with Concord Hospital and other places

Background Optimal heart failure (HF) pharmacotherapy (guideline‐directed medical therapy and diuretics) in older people with frailty is uncertain due to limited evidence. Aims To evaluate utilisation of HF pharmacotherapy and prevalence of polypharmacy, adverse drug events (ADEs), falls, delirium, renal impairment and duration of hospitalisation in older inpatients, according to frailty. Methods A retrospective cross‐sectional study of the TO HOME cohort of 2000 inpatients ≥75 years admitted for ≥48 h to rehabilitation, geriatric or general medicine from 1 July 2016 to 30 June 2017 across six hospitals in Sydney, Australia. Data were collected from electronic medical records. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification identified HF diagnosis, ADEs and frailty using hospital frailty risk score. Outcomes included utilisation of HF pharmacotherapy; polypharmacy; ADEs, falls, delirium, renal and impairment; and duration of hospitalisation. Results Among 439 (22.0% of TO HOME cohort) patients with undifferentiated HF, 284 (69.5%) had intermediate or high risk of frailty, and 412 (94%) took ≥1 HF pharmacotherapy, with 357 (81.3%) patients on loop diuretics. Patients with high frailty risk frequently continued beta‐blockers (70%) and discontinued renin‐angiotensin system inhibitors (57%). Most patients experienced polypharmacy ( n = 426, 97.0%). Renal impairment prevalence was 67%–76% across frailty groups. Increasing frailty risk (low, intermediate and high) was associated with increasing prevalence of ADEs (31%, 56% and 84%), falls (12%, 25% and 46%) and delirium (8%, 27% and 49%) and longer hospitalisation. Conclusions Frailty, HF‐pharmacotherapy changes in hospital and ADEs were common among older inpatients with HF. The association of adverse outcomes according to frailty needs further investigation. Poor documentation of HF phenotype may be a barrier to medication optimisation in older inpatients.

Rodents have been the primary model for mammalian nutritional physiology for decades. Despite an extensive body of literature, controversies remain around the effects of specific nutrients and total energy intake on several aspects of nutritional biology, even in this well-studied model. One approach that is helping to bring clarity to the field is the geometric framework for nutrition (GFN). The GFN is a multidimensional paradigm that can be used to conceptualize nutrition and nutritional effects, design experiments, and interpret results. To date, more than 30 publications have applied the GFN to data from rodent models of nutrition. Here we review the major conclusions from these studies. We pay particular attention to the effects of macronutrients on satiety, glucose metabolism, lifespan and the biology of aging, reproductive function, immune function, and the microbiome. We finish by highlighting several knowledge gaps that became evident upon reviewing this literature.

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.

Atherogenesis is associated with elevated plasma levels of oxidized low-density lipoproteins (oxLDL). In vivo, oxLDL causes liver endothelial swelling, and disrupts liver sinusoidal endothelial cell (LSECs) fenestrations. We mapped the nanoscale kinetics of these changes in vitro in isolated rat LSECs challenged with oxLDL and monitored viability with endocytosis and cytotoxicity assays. OxLDL disrupted LSEC ultrastructure – increasing oxLDL concentrations and oxidation levels caused sieve plate loss, fenestration fusion, and gap formation. Importantly, these effects were not uniform across all LSECs. LSECs retained the ability to endocytose ligands irrespective of the presence of oxLDL. However, increasing oxidation levels and concentrations of oxLDL inhibited LSEC mediated degradation of endocytosed ligands. Viability was unaffected by any oxLDL challenge. In conclusion, oxLDL disrupts LSEC ultrastructural morphology in vitro but LSECs remain viable and mostly maintain the scavenging function during oxLDL challenge.

Plant‐based diets reduces the risk of chronic conditions. The interaction between protein source and other macronutrients—fat (F) and carbohydrate (C)—has yet to be investigated. The aim was to assess the main and interactive effects of protein‐source (plant vs. animal) and F:C (high or low) and the transition from an Australian diet to a whole food diet on various health markers in older individuals. This single‐blinded, parallel, randomised experimental trial used a 2 × 2 factorial design to compare pro‐vegetarian (70:30 plant to animal) versus omnivorous (50:50 plant to animal) diets at 14% protein and varying fat‐to‐carbohydrate ratios (high fat ~40% vs. low fat ~30%) over 4 weeks. Study foods were provided, alcohol consumption was discouraged, and dietary intake was determined through food records. Analysis included both RCT and observational data. Changes in appetite, palatability of diets, and dietary intake were assessed. Body composition, muscle strength, function, gut microbiome, and cardiometabolic health parameters were measured. Data from 113 (of the 128 randomised) individuals aged 65–75 years were analysed. Pro‐vegetarian diets reduced diastolic blood pressure, total cholesterol and glucose levels. Moreover, the overall sample exhibited increased short‐chain fatty acids and FGF21 levels, as well as improvements in body composition, function, and cardio‐metabolic parameters irrespective of dietary treatment. Transitioning to a diet rich in fruit, vegetables, fibre, and moderate protein was associated with improved health markers in older age, with added benefits from pro‐vegetarian diets. Further research on long‐term effects is needed.

The clearance of peripheral beta amyloid (Aβ) is a potential target for the treatment of Alzheimer’s disease (AD). The liver has been implicated in the elimination of Aβ from the peripheral circulation. Here, the single-pass uptake of Aβ40 in perfused livers from young and old rats (6 to 10 rats per group) was investigated with the multiple indicator dilution technique. Aβ40 had volumes of distribution between those of the vascular marker Evans Blue and the extracellular marker sucrose. The hepatic extraction of Aβ40 was negligible, explained in part by the small permeability surface area products consistent with a high endothelial barrier to liver uptake. There were no substantial effects of age on any of these results. In vitro experiments with isolated hepatocytes and liver sinusoidal endothelial cells showed only very small amounts of Aβ uptake consistent with low intrinsic clearance. These results indicate that the hepatic clearance of Aβ is capacity-limited, explained by the low-permeability surface area products and hepatocyte uptake. However, this does not preclude an effect of aging in longer-term in vivo studies where age-related changes in liver blood flow and protein binding influence liver clearance.

Poor nutrition is a risk factor for dental decay in younger people. However, except for sugar it is unclear if this is true in older age groups. The aim of this study was to analyze the possible associations between overall dietary intake of nutrients and diet quality and presence of dental decay in community dwelling older men. A cross-sectional analysis of a longitudinal study with a standardized validated diet history assessment and comprehensive oral health examination in 520 community dwelling men (mean age: 84 years) participating in the Concord Health and Ageing in Men Project. Nutrient Reference Values (NRVs) were used to determine if individual micronutrients and macronutrients were meeting recommendations. Acceptable Macronutrient Distribution Ranges (AMDR) were attained for fat and carbohydrate intakes and were incorporated into a dichotomous variable to determine if the participants were consuming a high fat and low carbohydrate diet. Diagnosis of coronal caries was based on visual criteria and inspection and was completed on each of the five coronal surfaces. Root surface caries was textual changes across four root surfaces. This diagnosis was used to categorize participants by presence and severity of coronal and root caries. Adjusted logistic regression showed not meeting the recommended intakes for thiamin (odds ratio (OR): 2.32 95% confidence interval (CI) 1.15 - 4.67), and zinc (OR: 3.33, 95% CI 1.71 – 6.48) were associated with presence of severe root decay. Adjusted analysis also showed that participants who were outside the recommended AMDR for fat (OR: 0.61, 95% CI 0.38 – 0.98), and those who consumed a high fat and low carbohydrate diet (OR: 0.56, 95% CI 0.35 – 0.91) were less likely to have coronal tooth decay. Our study shows associations between micronutrients and macronutrients and coronal and root surface decay. Although this study cannot prescribe causality or be generalized to all older adults, diet has a possible association with dental decay in older men.

The International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee aims to improve the use of drugs in older adults and develop new therapeutic approaches for the syndromes and diseases of old age through advocacy, education, and research. In the present paper, we propose strategies relevant to drug development and evaluation, spanning preclinical and the full range of clinical studies. Drugs for older adults need to consider not only age, but also other characteristics common in geriatric patients, such as multimorbidity, polyphar-macy, falls, cognitive impairment, and frailty. The IUPHAR Geriatric Committee's position statement on 'Measurement of Frailty in Drug Development and Evaluation' is included, highlighting 12 key principles that cover the spectrum of translational research. We propose that where older adults are likely to be major users of a drug, that frailty is measured at baseline and as an outcome. Preclinical models that replicate the age, frailty, duration of exposure, comorbidities, and co-medications of the proposed patients may improve translation. We highlight the potential application of recent technologies, such as physiologically based pharmacokinetic-pharmacodynamic modeling informed by frailty biology, and Artificial Intelligence, to inform personalized medicine for older patients. Considerations for the rapidly aging populations in low- and middle-income countries related to health-care and clinical trials are outlined. Involving older adults, their caregivers and health-care providers in all phases of research should improve drug development, evaluation, and outcomes for older adults internationally.

Our objective was to evaluate the association of antioxidant intake and the inflammatory potential of the diet with functional decline in older men. A diet history questionnaire was used to collect dietary intake data from men aged ≥ 75 years ( n = 794) participating in the Concord Health and Aging in Men Project cohort study. Intake of vitamins A, C, E, and zinc were compared to the Australian Nutrient Reference Values to determine adequacy. The Energy-adjusted Dietary Inflammatory Index (E-DII TM ) was used to assess the inflammatory potential of the diet. Physical performance data was collected via handgrip strength and walking speed tests, and Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) questionnaires, at baseline and 3-year follow-up ( n = 616). Logistic regression analysis was used to identify associations between diet and incident poor physical function and disability. Both poor antioxidant intake and high E-DII scores at baseline were significantly associated with poor grip strength and ADL disability at 3-year follow-up. No significant associations with walking speed or IADL disability were observed. Individual micronutrient analysis revealed a significant association between the lowest two quartiles of vitamin C intake and poor grip strength. The lowest quartiles of intake for vitamins A, C, E, and zinc were significantly associated with incident ADL disability. The study observed that poor antioxidant and anti-inflammatory food intake were associated with odds of developing disability and declining muscle strength in older men. Further interventional research is necessary to clarify the causality of these associations.