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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.

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.

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.

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.Trend analysis of falls mortality data from World Health Organization (WHO) Mortality Database for the Australian and UK population.We assessed age-specific, sex-specific and age-adjusted mortality rates. Mortality trends were assessed via the annual percentage change (APC) using joinpoint regression.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%; p0.01) and 2.11% (95% CI 1.43% to 2.80%; p0.01) 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.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.

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.

Surf tourism is the principal development driver in many coastal communities around the world. Surf tourism development brings economic opportunities to residents in coastal destinations, but has also been criticized for associations with gentrification, pollution, and inequity. While many have speculated that surfers represent a crisis-resistant tourist segment, this had not yet been empirically demonstrated, nor had the sustainability implications of their travel during crises been explored. Building on ethnographic observations and two interview phases with 25 resident surfers in Bocas del Toro, Panama, this is the first study to do both. The findings reveal that the pandemic exacerbated existing sustainability challenges by accelerating development near surf-breaks, fomenting tensions within the surf community (related to surf tourism business operations and the distribution of benefits) and facilitating residents to surf more frequently—exacerbating surf-resource crowding. Evidence also revealed, however, a potential shift in surfers’ collective consciousness in the context of the pandemic, which reduced conflicts between visiting and resident surfers. This paper exposes the urgent need for stakeholders in surf communities, and particularly surf tourism business owners, to cooperate in order to preserve surf experiences that are vital to resident mental/physical health and well-being, as well as the attractiveness as a surf tourism destination.

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.

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.

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 (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.

Obesity is a top public health concern, and a molecule that safely treats obesity is urgently needed. Disulfiram (known commercially as Antabuse), an FDA-approved treatment for chronic alcohol addiction, exhibits anti-inflammatory properties and helps protect against certain types of cancer. Here, we show that in mice disulfiram treatment prevented body weight gain and abrogated the adverse impact of an obesogenic diet on insulin responsiveness while mitigating liver steatosis and pancreatic islet hypertrophy. Additionally, disulfiram treatment reversed established diet-induced obesity and metabolic dysfunctions in middle-aged mice. Reductions in feeding efficiency and increases in energy expenditure were associated with body weight regulation in response to long-term disulfiram treatment. Loss of fat tissue and an increase in liver fenestrations were also observed in rats on disulfiram. Given the potent anti-obesogenic effects in rodents, repurposing disulfiram in the clinic could represent a new strategy to treat obesity and its metabolic comorbidities.

The mouse clinical frailty index and the mouse frailty phenotype assessment are two recently developed tools used to assess frailty in mice. The objectives of this study were to investigate whether the same mice are identified as frail with both tools and to examine the association of each of the assessment tools with age and frailty-related outcomes. Frailty was measured using both tools in old (~24 months; n = 36) C57BL/6 male mice. After 2 weeks, blood pressure and heart rate were measured and serum samples were collected for analysis of alanine aminotransferase, creatinine, and albumin levels. The mouse frailty phenotype assessment identified no mice as frail but modification of the assessment tool identified six mice as frail. The mouse clinical frailty index identified 16 mice as frail and the agreement between the two scales was 50.0%. Increasing clinical frailty index scores were correlated with low serum alanine aminotransferase, as well as decreased heart rate, and reduced heart rate variance. We conclude that, consistent with equivalent frailty assessment scales in humans, both tools have value but do not necessarily identify the same mice as frail.

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.

Ageing, polypharmacy (≥ 5 different drugs) and increasing DBI (anticholinergic/sedative medication exposure) are associated with falls and impaired physical function. Preclinical ageing models can assess underlying mechanistic changes. We investigated whether chronic therapeutic drugs (polypharmacy or monotherapy), with increasing DBI and/or ceasation (deprescribing), affected physical function and/or muscle histology in mice. 12-month-old male C57BL/6 mice received either control diet or study drug(s). Polypharmacy diets consisted of Zero DBI (metoprolol, simvastatin, omeprazole, paracetamol, irbesartan), Low DBI (metoprolol, simvastatin, omeprazole, paracetamol, citalopram) and High DBI (metoprolol, simvastatin, citalopram, oxycodone, oxybutynin). Individual drugs (High DBI regimen) were tested as monotherapy. At 21-months, animals were randomised to continue treatment or gradual withdrawal. Rotarod performance was assessed at 12-24-months, and balance beam (6mm) at 24-months. Gastrocnemius muscle samples were collected at 27-months. Rotarod results indicate significant reduced endurance for citalopram mice (n=15–36) compared to control (n=24–29; p

The ethical, logistical, and biological complications of working with an older population of people inherently limits clinical studies of frailty. The recent development of animal models of frailty, and tools for assessing frailty in animal models provides an invaluable opportunity for frailty research. This review summarizes currently published animal models of frailty including the interleukin-10 knock-out mouse, the mouse frailty phenotype assessment tool, and the mouse clinical frailty index. It discusses both current and potential roles of these models in research into mechanisms of frailty, interventions to prevent/delay frailty, and the effect of frailty on outcomes. Finally, this review discusses some of the challenges and opportunities of translating research findings from animals to humans.

Summary While 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.

Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute over-exposures. The risk of hepatotoxicity from non-acute paracetamol exposures is less extensively studied, and this is the exposure most common in older adults. Evidence on the effectiveness of N-acetyl cysteine (NAC) for non-acute paracetamol exposures, in any age group, is lacking. This study aimed to examine the effect of long-term exposure to therapeutic doses of paracetamol and sub-acute paracetamol over-exposure, in young and old mice, and to investigate whether NAC was effective at preventing paracetamol hepatotoxicity induced by these exposures. Young and old male C57BL/6 mice were fed a paracetamol-containing (1.33g/kg food) or control diet for 6 weeks. Mice were then dosed orally 8 times over 3 days with additional paracetamol (250mg/kg) or saline, followed by either one or two doses of oral NAC (1200mg/kg) or saline. Chronic low-dose paracetamol exposure did not cause hepatotoxicity in young or old mice, measured by serum alanine aminotransferase (ALT) elevation, and confirmed by histology and a DNA fragmentation assay. Sub-acute paracetamol exposure caused significant hepatotoxicity in young and old mice, measured by biochemistry (ALT) and histology. Neither a single nor double dose of NAC protected against this toxicity from sub-acute paracetamol in young or old mice. This finding has important clinical implications for treating toxicity due to different paracetamol exposure types in patients of all ages, and implies a need to develop new treatments for sub-acute paracetamol toxicity.

Polypharmacy (use of ≥ 5 medications) and Drug Burden Index (DBI: measures cumulative exposure to anticholinergic and sedative drugs) impair function in older adults. Preclinical studies can provide a mechanistic understanding. We aim to evaluate the effect of chronic polypharmacy, medications with increasing DBI and deprescribing (cessation of medications) on cardiac function and histology in aged mice. Twelve-month-old male C57BL/6 mice received control feed or feeds/water containing therapeutic doses of drugs in regimens of polypharmacy with Zero DBI (simvastatin, metoprolol, omeprazole, paracetamol, irbesartan), Low DBI (simvastatin, metoprolol, omeprazole, paracetamol, citalopram), High DBI (simvastatin, metoprolol, oxybutynin, oxycodone, citalopram) or monotherapy with each of the five drugs from the High DBI diet. At 21 months, animals were re-randomised to continue treatment or be deprescribed. Blood pressure (BP) and rotarod performance (endurance) were assessed every 3 months and hearts were collected at 27 months. Compared to control, we observed a significant decrease in systolic and diastolic BP in Zero DBI, Low DBI, metoprolol and simvastatin treated mice and not in High DBI treated mice at 21 months (p

Polypharmacy (use of ≥ 5 drugs) and increasing DBI (measure of total exposure to anticholinergic and sedative drugs) is associated with impaired physical function in observational studies of older adults. We aim to determine the effect of polypharmacy, DBI and deprescribing (withdrawing drugs) on functional outcomes in aged mice. From 12 to 21 months of age male C57BL/6 mice were fed control or treatment containing therapeutic doses of five drugs with Zero DBI (simvastatin, metoprolol, omeprazole, paracetamol, irbesartan), Low DBI (simvastatin, metoprolol, omeprazole, paracetamol, citalopram), High DBI (simvastatin, metoprolol, oxybutynin, oxycodone, citalopram), or single drug (simvastatin, metoprolol, oxybutynin, oxycodone or citalopram) (n=40/ group). At 21 months, animals either continued treatment or were deprescribed (n=20/ group). Functional tests were conducted at 12, 15, 18, 21 and 24 months. From 12–24 months, compared to control diet, locomotor activity (open field) and nest making declined following Low DBI, High DBI and citalopram treatment, frailty index score increased following High and citalopram treatment, and grip strength (wire hang) decreased following Low DBI and citalopram treatment (p

Opioids have been administered intrathecally with subarachnoid block for postoperative pain relief in parturients undergoing elective cesarean deliveries. This case report presents the uncommon occurrence of intrathecal opioid-induced hypothermia in the latent phase of recovery following elective cesarean delivery. There are few case reports on the occurrence of latent-phase postanesthesia care hypothermia in patients receiving subarachnoid block with morphine sulfate injection (Duramorph). Hypothermia can occur postoperatively for many reasons and can be life-threatening. In this case, hypothermia developed and progressed throughout the postoperative period. The causes of hypothermia were evaluated and treated without success initially. Thyroid dysfunction and alternative differential diagnoses were ruled out. Further assessment determined that the morphine injection might have been a contributing factor. Naloxone at 40-μg increments was administered intravenously and corrected the hypothermia. Awareness of hypothermia postoperatively with associated morphine administration through subarachnoid block must be ruled out in cases of progressing hypothermia.

Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice.

Increasing DBI (measure of patient’s total exposure to anticholinergics and sedatives) is associated with impaired physical function in observational studies of older adults. We aim to determine the effect of polypharmacy (use of ≥ 5 drugs) and increasing DBI on functional outcomes in aged mice. From 12 to 21 months of age male C57BL/6 mice are fed control diet or treated feed/water containing therapeutic doses of five drugs with Zero DBI (simvastatin, metoprolol, omeprazole, paracetamol, irbesartan), Low DBI (simvastatin, metoprolol, omeprazole, paracetamol, citalopram), High DBI (simvastatin, metoprolol, oxybutynin, oxycodone, citalopram), or single drug (simvastatin, metoprolol, oxybutynin, oxycodone or citalopram). A panel of functional tests was performed every 3 months. Results to date at 15 months of age, compared to control diet, have found that openfield locomotor activity and midzone entries significantly declined in Low DBI, High DBI and citalopram groups (n=10–13, p

We developed a translational model to evaluate whether polypharmacy (use of ≥5 different medicines) causes adverse geriatric outcomes and whether these are reversible with deprescribing (withdrawal of medicines). Old (23–24 months) male C57BL/6 mice received control diet (no drugs) for eleven weeks, or diet containing therapeutic doses of five commonly used drugs (simvastatin, metoprolol, omeprazole, paracetamol, citalopram) for four weeks, which were gradually withdrawn over the next six weeks. Physical performance was assessed at baseline, four and eleven weeks and transformed into Frailty Intervention Assessment Values (FIAV): sum of standardised values for locomotor activity, rotarod performance and front paw hang. After four weeks, FIAV was unchanged in controls and declined with polypharmacy (p

Isoniazid is the first-line treatment for tuberculosis; however, its use is limited by hepatotoxicity. Age-related differences in isoniazid pharmacokinetics and hepatotoxicity are uncertain. We aimed to investigate these in young (3 ± 0 months, n = 26) and old (23.0 ± 0.2 months, n = 27) male Fischer 344 rats following a low- or high-dose toxic regimen of isoniazid or vehicle (4 doses/day over 2 days; low: 100, 75, 75, 75 mg/kg; high: 150, 105, 105, 105 mg/kg i.p. every 3 h). Fifteen hours after the last dose, animals were euthanized and sera and livers were prepared for analysis. Isoniazid treatment increased serum hepatotoxicity markers (alanine and aspartate transaminase) in young animals but not in old animals, and only reached significance with the high dose in young animals. Isoniazid treatment caused a trend towards an increase in necrosis in young animals with both doses. In contrast, microvesicular steatosis was increased in old isoniazid-treated animals, reaching significance only with the low dose (steatosis prevalence in old: vehicle 1/9, isoniazid 4/5; P < 0.05). Among isoniazid-treated animals, concentrations of toxic intermediates acetylhydrazine and hydrazine were higher in old than young animals (P < 0.05). With both doses, hepatic cytochrome P450 2E1 activity was higher in young animals compared with old (P < 0.05). There were no other age effects seen on any of the other measured enzymes involved in isoniazid metabolism (N-acetyl transferase, amidase, glutathione-S-transferase). These results show age-related changes in isoniazid pharmacokinetics may contribute towards differential patterns of toxicity and confirm that standard hepatotoxicity markers do not detect isoniazid-induced microvesicular steatosis.

Elders are thought to be at increased risk of drug induced liver injury (DILI), however there is little empirical evidence to prove it. We aimed to determine the effect of ageing on DILI in male Fischer 344 rats. Young and old rats were treated via intraperitoneal injection with toxic regimens of either acetaminophen (single dose of 800mg/kg) or isoniazid (4 doses daily; low dose regimen: 100, 70, 70, 70mg/kg or high dose regimen: 150, 105, 105, 105mg/kg (3 hours apart) over 2 days) or vehicle controls. After euthanasia, sera and livers were collected for testing. With acetaminophen treatment, higher serum drug levels were observed in old than in young animals, but conversely serum hepatotoxicity markers were elevated in young animals but not old. Hepatic DNA fragmentation was increased in old animals treated with acetaminophen when compared to all other groups. Similarly, with isoniazid treatment, higher levels of hepatotoxic metabolites were observed in old than in young animals, and serum hepatotoxicity markers were elevated in young animals but not in old. Compared to age-matched controls, with isoniazid treatment there was a trend towards increased necrosis in young rats and increased hepatic microvesicular steatosis in old. Toxic isoniazid insults did not cause hepatic DNA fragmentation. In both studies, the activity of hepatic CYP2E1, which generates toxic intermediates from acetaminophen and isoniazid, was significantly reduced in old animals compared to young. Old age affects the pattern and risk of DILI from acetaminophen and isoniazid differently and age-related changes in metabolism probably contribute.

Apoptosis is increased in the liver in old age and is a common pathological feature of liver disease. The mitochondria play a key role in regulating apoptosis via the intrinsic death pathway. As the effect of aging on this pathway is unclear, we aimed to characterize the impact of aging on the hepatic intrinsic death pathway and apoptosis. Livers from young adult (6.6 ± 0.3 months, n = 9) and old (25.4 ± 0.7 months, n = 9) male Fischer 344 rats were extracted for cellular fractionation and immunobloting. In old age there were lower mitochondrial protein levels of pro-apoptotic BAK, BID, tBID and VDAC1 (p < 0.05) and of anti-apoptotic Bcl-2. Compared to young, old rats had lower cytosolic protein levels of pro-apoptotic BAX, BAK, BID, tBID and anti-apoptotic Bcl-xL (p < 0.05). BAK, Bcl-2 and Bcl-xL were found in the cytosol. Furthermore with old age, cytosolic protein levels of cytochrome C, AIF and cleaved caspase-9 did not change but activation of caspase-3, -6 and -7 increased (p < 0.05) and DNA fragmentation trended to increase. Our results suggest an age-related decline in the levels of a number of proteins involved in the intrinsic death pathway, an uncoupling of intermediate apoptosis signaling and increased cellular apoptosis in the liver in old age.

Background Discussions about advance directives should be offered to all nursing home residents. Managed Medicare programs for nursing home residents allow for the development of performance improvement initiatives to ensure that these discussions occur and are documented. Purpose To assess the effectiveness of an intervention to increase discussion and documentation of advance directives for enrollees in a managed Medicare program for nursing home residents, and to evaluate whether this intervention affected preferences for cardiopulmonary resuscitation (CPR) and hospitalization among enrollees. Subjects Participants were 4,248 enrollees in a managed Medicare program in 1996, and 6,598 enrollees in 1997, in Georgia, Maryland, Massachusetts, Minnesota, Arizona, and Florida. Design Descriptive study of a quality improvement initiative. Methods A chart review was conducted in the fall of 1996 to determine the prevalence of documented advance directive discussions among all enrollees, and the preferences regarding CPR and hospitalization. Because the discussion rates varied across sites, and were lower than expected, each site developed strategies to improve advance directive discussion and documentation. One year later, a similar survey was conducted to determine the efficacy of the interventions, as well as to assess the impact, if any, on rates of desire for CPR and hospitalization. Results Documented discussions of advance directives increased across the six sites from 73% to 85% (P Conclusions In a managed care program, documentation of advance directive discussions can be increased with focused efforts. Overall, most enrollees did not desire CPR, but a majority desired hospitalization. Despite the similarity of interventions and program philosophy across sites, significant geographic variations in desire for CPR and hospitalization remained.

Dear Editor, We read with great interest the article “Reliability of a Frailty Index Based on the Clinical Assessment of Health Deficits in Male C57BL/6J Mice” recently published online in the Journal of Gerontology Biological Sciences (1). Feridooni and colleagues investigated the reliability of a recently developed mouse clinical frailty index between two raters, in three separate groups of male C57BL/6 mice aged 0.9–1.2 years, with discussion and refinement of index descriptors between assessment of each group. They found high overall inter-rater reliability, and that measures of reliability increased sequentially over the three groups. Our assessment of the mouse clinical frailty index in one published (2) and two unpublished studies of male C57BL/6 mice shed further light on factors that impact on its inter-rater reliability. Our studies clarify that practice and experience with assessment of the mouse clinical frailty index, without discussion or refinement, does not improve inter-rater reliability. We have completed two projects assessing the frailty index of old (Project 1 n = 55, 26.1±0.5 months; Project 2 n = 17, 23.9±0.2 months) mice before and after 4–6 weeks of a dietary/pharmaceutical intervention. Each project used two raters for the frailty index, who did not discuss or compare their scoring until the completion of the projects. The inter-rater reliability between the two raters for both of these projects did not improve with practice or experience (Project 1 Pre ICC=0.522[CI 0.181–0.721], p = .00; r 2 = .361, p = .00; Post ICC = 0.488[CI 0.244–0.652], p = .01; r 2 = .328, p = .00; Project 2 Pre ICC = 0.705[CI 0.186–0.893], p = .01; r 2 = .562, p = .02; Post ICC = 0.561[CI 0.122–0.781], p = .01; r 2 = .391, p = .02). These results fall within the range of reliability statistics observed by Feridooni and colleagues (1), using different raters in different research groups and countries. Another factor that we have identified as affecting the inter-rater reliability when assessing the mouse clinical frailty index is the professional background and baseline animal training of the raters. In order to explore this, we had four raters assess the clinical frailty index of a cohort of old (n = 74, 19.0±1.0 months) mice, with no discussion or training period. Two raters were animal technicians with 5–10 years of experience and training in animal handling, and two raters were research scientists with minimal animal handling training, and 3–6 years of animal research experience. Interestingly, the inter-rater reliability between the technicians and researchers was poor (ICC = 0.201–0.489, p < .05; r 2 = −0.028 to 0.33, p < .05), despite moderate inter-rater reliability between the technicians (ICC = 0.605[CI 0.344–0.762], p = .00; r 2 = .454, p = .00) and excellent inter-rater reliability between the scientists (ICC=0.88[95%CI 0.80–0.92] p = 0.00; r 2 = .817, p = .00). Furthermore, it does appear to be the background, rather than the years of experience that are important, as the inter-rater reliabilities in our pre and post intervention studies (data above), which were all performed by scientists, were moderate to high despite the raters including PhD students and a senior postdoc/laboratory manager. This suggests that the selection of raters for the mouse clinical frailty index must be done carefully, and preference given to raters with the same training/background, but not necessarily experience level, if comparisons are to be made between and across mouse groups and studies.

We investigated the effect of aging on hepatic pharmacokinetics and the degree of hepatotoxicity following a toxic dose of acetaminophen. Young and old male Fischer 344 rats were treated with 800 mg/kg acetaminophen (young n = 8, old n = 5) or saline (young n = 9, old n = 9). Serum measurements showed old rats treated with acetaminophen had significantly lower serum alanine aminotransferase and higher acetaminophen and acetaminophen glucuronide levels and creatinine, compared with acetaminophen treated young rats (p < .05). Immunoblotting and activity assays showed old saline-treated rats had twofold lower cytochrome P450 2E1 activity and threefold higher NAD(P)H quinone oxireductase 1 protein expression and activity than young saline-treated rats (p < .05), although Nrf2, glutathione cysteine ligase-modulatory subunit, glutathione cysteine ligase-catalytic subunit, and cytochrome P450 2E1 protein expressions were unchanged. Primary hepatocytes isolated from young rats treated with 10 mM acetaminophen had lower survival than those from old rats (52.4% ± 5.8%, young; 83.6% ± 1.7%, old, p < .05). The pharmacokinetic changes described may decrease susceptibility to acetaminophen-induced hepatotoxicity but may increase risk of nephrotoxicity in old age.

This study compared serum pyridine levels (NAD(+)/NADH) in trained (n = 6) and untrained (n = 7) subjects after continuous progressive exercise at 50%, 70% then 95% of physical work capacity until fatigue (TTF) after consuming a placebo or antioxidant (AO) cocktail (Lactaway(©)). An increase of 17% in TTF was observed in AO as compared to placebo (p = 0.032). This was accompanied by a significant increase in serum NAD(+) levels (p = 0.037) in the AO supplemented group post exercise. The increases in NAD(+) and improved endurance reflect lower oxidative stress-induced suppression of aerobic respiration.

Serotonin (5-HT) is released from the enterochromaffin cells and plays an important role in regulating intestinal function. Although the release of 5-HT is well documented, the contribution of the serotonin reuptake transporter (SERT) to the levels and actions of 5-HT in the intestine is unclear. This study aimed to demonstrate real-time SERT activity in ileal mucosa and to assess the effects of SERT inhibition using fluoxetine. Electrochemical recordings were made from the mucosa in full-thickness preparations of rat ileum using a carbon fiber electrode to measure 5-HT oxidation current and a force transducer to record circular muscle (CM) tension. Compression of the mucosa stimulated a peak 5-HT release of 12 ± 6 μM, which decayed to 7 ± 4 μM. Blockade of SERT with fluoxetine (1 μM) increased the peak compression-evoked release to 19 ± 9 μM, and the background levels of 5-HT increased to 11 ± 7 μM ( P < 0.05, n = 7). When 5-HT was exogenously applied to the mucosa, fluoxetine caused a significant increase in the time to 50% and 80% decay of the oxidation current. Fluoxetine also increased the spontaneous CM motility ( P < 0.05; n = 7) but did not increase the CM contraction-evoked 5-HT release ( P > 0.05, n = 5). In conclusion, this is the first characterization of the real-time uptake of 5-HT into the rat intestine. These data suggest that SERT plays an important role in the modulation of 5-HT concentrations that reach intestinal 5-HT receptors.

Background A spectrum of histopathological changes have been described in isoniazid hepatotoxicity. The cause of increased isoniazid hepatotoxicity in old age is uncertain. Aims To investigate the influence of age on histological and biochemical outcomes following a toxic regimen of isoniazid in male Fischer 344 rats. Methods Young (6 months) and old (24 months) rats were fasted for 16 hours followed by a toxic regimen of isoniazid or saline vehicle (4 doses/day: 100, 75, 75, 75 mg/kg i.p. every 3 hours over 2 days). Fifteen hours after the last dose livers were prepared for histology and sera were collected for biochemical analysis. Results Without reaching significance, the prevalence of necrosis was higher in young than old isoniazid treated animals (young 5/7, old 1/5; p p p > 0.05) Again relative to saline, serum hepatotoxicity markers ALT and AST in isoniazid treated animals were unchanged or higher in young but unchanged or lower in old animals ( p p Conclusion Different patterns of injury to toxic doses of isoniazid were observed with age, with young rats showing a necroinflammatory pattern of injury, and old rats showing steatosis and higher levels of toxic intermediates.