Frailty In Mice Research Articles

Sex-specific components of frailty in C57BL/6 mice.

Many age-related biochemical, physiological and behavioral changes are known to be sex-specific. However, how sex influences frailty status and mortality risk in frail rodents has yet to be established. The purpose of this study was therefore to characterize sex differences in frail mice across the lifespan. Male (n=29) and female (n=27) mice starting at 17 months of age were assessed using a frailty phenotype adjusted according to sex, which included body weight, walking speed, strength, endurance and physical activity. Regardless of sex, frail mice were phenotypically dysfunctional compared to age-matched non-frail mice, while non-frail females generally possessed a higher body fat percentage and were more physically active than non-frail males (p≤0.05). The prevalence of frailty was greater in female mice at 26 months of age (p=0.05), but if normalized to mean lifespan, no sex differences remained. No differences were detected in the rate of death or mean lifespan between frail male and female mice (p≥0.12). In closing, these data indicate that sexual differences exist in aging C57BL/6 mice and if the frailty criteria are adjusted according to sex, the prevalence of frailty increases across age with frail mice dying early in life, regardless of sex.

Identifying Characteristics of Frailty in Female Mice Using a Phenotype Assessment Tool.

Preclinical studies are important in identifying the underlying mechanisms contributing to frailty. Frailty studies have mainly focused on male rodents with little directed at female rodents. Therefore, the purposes of this study were to identify the onset and prevalence of frailty across the life span in female mice, and to determine if frailty predicts mortality. Female C57BL/6 (n = 27) mice starting at 17 months of age were assessed across the life span using a frailty phenotype, which included body weight, walking speed, strength, endurance, and physical activity. The onset of frailty occurred at approximately 17 months (1/27 mice), with the prevalence of frailty increasing thereafter. At 17 months, 11.1% of the mice were pre-frail and by 26 months peaked at 36.9%. The percentage of frail mice progressively increased up to 66.7% at 32 months. Non-frail mice lived to 29 months whereas frail/pre-frail mice lived only to 26 months (p = .04). In closing, using a mouse frailty phenotype, we are able to identify that the prevalence of frailty in female mice increases across the life span and accurately predicts mortality. Together, this frailty phenotype has the potential to yield information about the underlying mechanisms contributing to frailty.

Sublethal whole-body irradiation causes progressive premature frailty in mice

There is an unmet need to develop and validate therapies that can treat or at least prevent premature therapy-induced frailty, multi-morbidity and mortality in long-term tumour survivors. In an approach to develop a first mouse model for therapy-induced long-term frailty, we irradiated male C57Bl/6 mice at 5–6 months of age sub-lethally with 3 × 3 Gy (whole body) and assessed subsequent frailty for up to 6 months using a Rockwood-type frailty index (FI). Frailty scorers were trained to obtain excellent inter- and intra-observer reproducibility. Irradiated mice developed progressive frailty approximately twice as fast as controls. This was premature frailty; it was phenotypically identical to that in non-irradiated mice at higher age. As expected, frailty was associated with decreased cognition and predicted mortality. In irradiated mice, frailty and neuromuscular performance, measured by Rotarod and Hanging Wire tests, were not associated with each other, probably because of long-term decreased body weights after irradiation. We conclude that progressive frailty following sub-lethal irradiation comprises a sensitive and easy to use test bed for interventions to stop premature ageing in long-term tumour survivors.

Hericium erinaceus Improves Recognition Memory and Induces Hippocampal and Cerebellar Neurogenesis in Frail Mice during Aging.

Frailty is a geriatric syndrome associated with both locomotor and cognitive decline, implicated in both poor quality of life and negative health outcomes. One central question surrounding frailty is whether phenotypic frailty is associated with the cognitive impairment during aging. Using spontaneous behavioral tests and by studying the dynamic change during aging, we demonstrated that the two form of vulnerability, locomotor and recognition memory decline, develop in parallel and therefore, integration of the motoric and cognitive evaluations are imperative. We developed an integrated frailty index based on both phenotypic and recognition memory performances. Hericium erinaceus (H. erinaceus) is a medicinal mushroom that improves recognition memory in mice. By using HPLC-UV-ESI/MS analyses we obtained standardized amounts of erinacine A and hericenones C and D in H. erinaceus extracts, that were tested in our animal model of physiological aging. Two-month oral supplementation with H. erinaceus reversed the age-decline of recognition memory. Proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) immunohistochemistry in the hippocampus and cerebellum in treated mice supported a positive effect of an H. erinaceus on neurogenesis in frail mice.

Assessing onset, prevalence and survival in mice using a frailty phenotype.

Little is known whether frailty assessments in mice are capable of distinguishing important characteristics of the frailty syndrome. The goals of this study were to identify the onset and the prevalence of frailty across the lifespan and to determine if a frailty phenotype predicts mortality. Body weight, walking speed, strength, endurance and physical activity were assessed in male C57BL/6 mice every three months starting at 14 months of age. Mice that fell in the bottom 20% for walking speed, strength, endurance and physical activity, and in the top 20% for body weight were considered to have a positive frailty marker. The onset of frailty occurred at 17 months, and represented only 3.5% of the mouse cohort. The percentage of frail mice increased with age until basically every mouse was identified as frail. Frail, pre-frail, and non-frail mice had mean survival ages of 27, 29 and 34 months, respectively. In closing, frail mice lack resilience; in that, multiple tissue/organ systems may deteriorate at an accelerated rate and ultimately lead to early mortality when compared to non-frail mice. Identifying the onset and prevalence of frailty, in addition to predicting mortality, has potential to yield information about several aging processes.

A Murine Frailty Index Based on Clinical and Laboratory Measurements: Links Between Frailty and Pro-inflammatory Cytokines Differ in a Sex-Specific Manner.

A frailty index (FI) based on clinical deficit accumulation (FI-Clinical) quantifies frailty in aging mice. We aimed to develop a laboratory test-based murine FI tool (FI-Lab) and to investigate the effects of age and sex on FI-Lab scores, FI-Clinical scores, and the combination (FI-Combined), as well as to explore links between frailty and inflammation. Studies used older (17 and 23 months) C57BL/6 mice of both sexes. We developed an FI-Lab (blood pressure, blood chemistry, echocardiography) based on deviation from reference values in younger adults (12 months), which showed similar characteristics to a human FI-Lab tool. Interestingly, while FI-Clinical scores were higher in females, the opposite was true for FI-Lab scores and there was no sex difference in FI-Combined scores. All three FI tools revealed a positive correlation between pro-inflammatory cytokine levels and frailty in aging mice that differed between the sexes. Elevated levels of the pro-inflammatory cytokines interleukin (IL)-6, IL-9, and interferon-γ were associated with higher FI scores in aging females, while levels of IL-12p40 rose as FI scores increased in older males. Thus, an FI tool based on common laboratory tests can quantify frailty in mice; the positive correlation between inflammation and frailty scores in naturally aging mice differs between the sexes.

Identifying the Onset of Frailty

PURPOSE: Frailty is a clinical syndrome associated with adverse health outcomes in older adults. Currently, there is a great need to identify interventions to prevent or delay the onset as well as decrease the burden of frailty symptoms. Identifying the onset of frailty is one of the first steps in developing effective interventions. Therefore, the purpose of this study was to determine the onset of frailty using the mouse frailty index. METHODS: Male C57BL/6J (n=32) were purchased at 12 months of age. At 14 months of age, the mice were subjected to a frailty assessment that included 5 criteria: loss of body weight, weakness (grip strength), slow walking speed (Rota-rod), low activity level (voluntary wheel running) and poor endurance (treadmill test). Mice repeated these tests every 3 months throughout their lifespan. The designated cutoff point for each frailty criterion was determined from data collected at 14 months of age and was set at 1.5 SD below the mean. If a mouse had three of the criteria scores below the cutoff points, the mouse was identified as frail, while a mouse with two criteria scores was identified as mildly frail. RESULTS: Prevalence of frailty increased across the lifespan of the mice, with 75% of the 35 month old mice identified as frail. The survival rate at 35 months of age was 25% of the original cohort. The onset of frailty occurred at 23 months of age (88% survival) while mice 17 months of age (94% survival) were considered mildly frail. Mildly frail mice fell below the cutoff points for endurance and walking speed, whereas the frail mice fell below the cutoff points for endurance, walking speed, and activity levels. Although endurance, walking speed, and activity levels were the criterion identified in the frail mice, all criteria included in the frailty assessment decreased across the lifespan of mice. Reductions were observed in body weight (5.3%), strength (18.9%) endurance (51.1%), walking speed (31.4%), and activity levels (89.9%). A progression from mildly frail to frail to mortality was observed; in that, mildly frail mice at 17 months of age were frail by 23 months and died at 26 months. CONCLUSIONS: Taken together, the onset of frailty occurs early in the lifespan and is associated with negative outcomes in mice. It provides the framework to develop interventions for preventing or delaying the frailty.

Frailty Quantified by the "Valencia Score" as a Potential Predictor of Lifespan in Mice.

The development of frailty scores suitable for mice and which resemble those used in the clinical scenario is of great importance to understand human frailty. The aim of the study was to determine an individual frailty score for each mouse at different ages and analyze the association between the frailty score and its lifespan. For this purpose, the "Valencia Score" for frailty was used. Thus, a longitudinal study in mice was performed analyzing weight loss, running time and speed, grip strength and motor coordination at the late-adult, mature and old ages (40, 56 and 80 weeks old, respectively). These parameters are equivalent to unintentional weight loss, poor endurance, slowness, weakness, and low activity level, respectively, in humans. A cut-off point was used to identify frail mice for each criterion. All the measurements were also performed on chronologically adult prematurely aging mice. The results show that by using the "Valencia Score" for frailty a prematurely aged phenotype can be identified even during the adulthood of animals. This opens up the possibility of carrying out preventive long-term interventions. Moreover, the individual frailty score of a given mouse at the late-adult, mature and old ages is shown to be a relevant predictor of its lifespan.

Aged interleukin-10tm1Cgn chronically inflamed mice have substantially reduced fat mass, metabolic rate, and adipokines.

Interleukin 10tm1Cgn (IL 10tm) mice have been utilized as a model of chronic inflammation and declining health span because of their propensity to develop chronic activation in NFkB pathways, skeletal muscle and cardiac changes, and mitochondrial dysfunction. We hypothesized that older IL 10tm frail mice would have alterations similar to frail, older humans in measured parameters of glucose metabolism, oxygen consumption (VO2), respiratory quotient (RQ), spontaneous locomotor activity, body composition and plasma adipokine levels. To test this hypothesis, we investigated these metabolic parameters in cohorts of 3, 10, and 20 month old IL 10tm female mice and age and gender matched C57Bl/6 mice. Insulin sensitivity, glucose homeostasis, locomotor activity and RQ were not significantly altered between the two strains of mice. Interestingly, old IL 10tm mice had significantly decreased VO2 when normalized by lean mass, but not when normalized by fat mass or the lean/fat mass ratio. NMR based body composition analysis and dissection weights show that fat mass is decreased with age in IL 10tm mice compared to controls. Further, plasma adiponectin and leptin were also decreased in IL 10tm.These findings suggest that frailty observed in this mouse model of chronic inflammation may in part be driven by alterations in fat mass, hormone secretion and energy metabolism.

Influence of an ACE inhibitor on frailty and cardiac function in old male C57BL/6 mice

Background: Frailty is the accumulation of health deficits over the lifespan. Frailty results in increased risk of adverse outcomes including poor cardiovascular outcomes. Angiotensin converting enzyme (ACE) inhibitors improve exercise capacity in older adults without cardiovascular disease, and could be a potential frailty intervention. The aim of this study was to investigate whether chronic treatment with the ACE inhibitor enalapril would attenuate frailty in mice, and whether this occurs through changes to cardiac function. Methods: Male C57BL/6 mice (17 months) were fed enalapril containing chow (40 mg/kg/day; n=25) or control feed (n=13). After 6 weeks blood pressure (BP) was measured with a tail-cuff. Once the mice were 24 months old (7 months treatment), frailty was quantified with a validated mouse frailty index and in vivo cardiac function was measured using echocardiography. Results: Frailty index scores were significantly lower in the enalapril group than the control group after 7 months (0.24 ± 0.01 vs 0.29 ± 0.01, p<0.001). Enalapril treatment also resulted in lower systolic BP (85.0 ± 10.5 vs 98.1 ± 12.3 mmHg, p<0.01), with a trend towards decreased diastolic BP (65.4 ± 4.0 vs 75.8 ± 3.9 mmHg, p=0.08). Echocardiography showed changes to the left ventricle (LV) of the enalapril treated mice compared to control, including a thinner LV anterior wall in systole (1.38 ± 0.08 vs 1.60 ± 0.05 mm, p<0.05), smaller LV mass (127.2 ± 9.6 vs 180.7 ± 14.4 mg, p<0.01) and reduced stroke volume (36.5 ± 2.4 vs 48.5 ± 3.6 μl, p<0.01) and cardiac output (18.3 ± 1.2 vs 23.2 ± 1.7 ml/min, p<0.05). Conclusion: Enalapril treatment attenuated frailty in old male mice. As expected it also resulted in reduced blood pressure. Cardiac mechanisms contributing to the attenuation of frailty may include changes to the structure and function of the heart.

The impact of age and frailty on ventricular structure and function in C57BL/6

Background: On average, cardiac hypertrophy and contractile dysfunction increase with age. Still, individuals age at different rates and their health status varies from fit to frail. We investigated the influence of frailty on age-dependent ventricular remodeling. Methods: Frailty was quantified as deficit accumulation in adult (≈7 mos) and aged (≈27 mos) C57BL/6 mice by adapting a validated frailty index (FI) tool. Hypertrophy and contractile function were evaluated in Langendorff-perfused hearts; cellular correlates/mechanisms were investigated in ventricular myocytes. Results: FI scores increased with age. Mean cardiac hypertrophy increased with age, but values in the adult and aged groups overlapped. When plotted as a function of frailty, hypertrophy was graded by FI score (r=0.67-0.55, p<0.0003). Myocyte area also correlated positively with FI (r=0.34; p=0.03). Left ventricular developed pressure (LVDP) plus rates of pressure development (+dP/dt) and decay (-dP/dt) declined with age and this was graded by frailty (r=-0.51, p=0.0007; r=-0.48, p=0.002; r=-0.56, p=0.0002 for LVDP, +dP/dt and -dP/dt). Smaller, slower contractions graded by FI score were also seen in ventricular myocytes. Contractile dysfunction in cardiomyocytes isolated from frail mice was attributable to parallel changes in underlying Ca2+ transients. These changes were not due to reduced sarcoplasmic reticulum stores, but were graded by smaller Ca2+ currents (r=-0.40, p=0.008), lower gain (r=-0.37, p=0.02) and reduced expression of Cav1.2 protein (r=-0.68, p=0.003). Conclusions: These results show that cardiac hypertrophy and contractile dysfunction in naturally-ageing mice are graded by overall health and suggest that frailty, in addition to chronological age, can help explain heterogeneity in cardiac ageing. This model system can ultimately be used to test interventions designed to improve cardiovascular outcomes in frail older adults.

A Comparison of Two Mouse Frailty Assessment Tools.

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 impact of age and frailty on ventricular structure and function in C57BL/6J mice.

Heart size increases with age (called hypertrophy), and its ability to contract declines. However, these reflect average changes that may not be present, or present to the same extent, in all older individuals. That aging happens at different rates is well accepted clinically. People who are aging rapidly are frail and frailty is measured with a 'frailty index'. We quantified frailty with a validated mouse frailty index tool and evaluated the impacts of age and frailty on cardiac hypertrophy and contractile dysfunction. Hypertrophy increased with age, while contractions, calcium currents and calcium transients declined; these changes were graded by frailty scores. Overall health status, quantified as frailty, may promote maladaptive changes associated with cardiac aging and facilitate the development of diseases such as heart failure. To understand age-related changes in heart structure and function, it is essential to know both chronological age and the health status of the animal. On average, cardiac hypertrophy and contractile dysfunction increase with age. Still, individuals age at different rates and their health status varies from fit to frail. We investigated the influence of frailty on age-dependent ventricular remodelling. Frailty was quantified as deficit accumulation in adult (≈7months) and aged (≈27months) C57BL/6J mice by adapting a validated frailty index (FI) tool. Hypertrophy and contractile function were evaluated in Langendorff-perfused hearts; cellular correlates/mechanisms were investigated in ventricular myocytes. FI scores increased with age. Mean cardiac hypertrophy increased with age, but values in the adult and aged groups overlapped. When plotted as a function of frailty, hypertrophy was graded by FI score (r=0.67-0.55, P<0.0003). Myocyte area also correlated positively with FI (r=0.34, P=0.03). Left ventricular developed pressure (LVDP) plus rates of pressure development (+dP/dt) and decay (-dP/dt) declined with age and this was graded by frailty (r=-0.51, P=0.0007; r=-0.48, P=0.002; r=-0.56, P=0.0002 for LVDP, +dP/dt and -dP/dt). Smaller, slower contractions graded by FI score were also seen in ventricular myocytes. Contractile dysfunction in cardiomyocytes isolated from frail mice was attributable to parallel changes in underlying Ca2+ transients. These changes were not due to reduced sarcoplasmic reticulum stores, but were graded by smaller Ca2+ currents (r=-0.40, P=0.008), lower gain (r=-0.37, P=0.02) and reduced expression of Cav1.2 protein (r=-0.68, P=0.003). These results show that cardiac hypertrophy and contractile dysfunction in naturally aging mice are graded by overall health and suggest that frailty, in addition to chronological age, can help explain heterogeneity in cardiac aging.

A new mouse model of frailty: the Cu/Zn superoxide dismutase knockout mouse

Frailty is a geriatric syndrome that is an important public health problem for the older adults living in the USA. Although several methods have been developed to measure frailty in humans, we have very little understanding of its etiology. Because the molecular basis of frailty is poorly understood, mouse models would be of great value in determining which pathways contribute to the development of frailty. More importantly, mouse models would be critical in testing potential therapies to treat and possibly prevent frailty. In this article, we present data showing that Sod1KO mice, which lack the antioxidant enzyme, Cu/Zn superoxide dismutase, are an excellent model of frailty, and we compare the Sod1KO mice to the only other mouse model of frailty, mice with the deletion of the IL-10 gene. Sod1KO mice exhibit four characteristics that have been used to define human frailty: weight loss, weakness, low physical activity, and exhaustion. In addition, Sod1KO mice show increased inflammation and sarcopenia, which are strongly associated with human frailty. The Sod1KO mice also show alterations in pathways that have been proposed to play a role in the etiology of frailty: oxidative stress, mitochondrial dysfunction, and cell senescence. Using Sod1KO mice, we show that dietary restriction can delay/prevent characteristics of frailty in mice.

Atrial structure, function and arrhythmogenesis in aged and frail mice

Atrial fibrillation (AF) is prevalent in aging populations; however not all individuals age at the same rate. Instead, individuals of the same chronological age can vary in health status from fit to frail. Our objective was to determine the impacts of age and frailty on atrial function and arrhythmogenesis in mice using a frailty index (FI). Aged mice were more frail and demonstrated longer lasting AF compared to young mice. Consistent with this, aged mice showed longer P wave duration and PR intervals; however, both parameters showed substantial variability suggesting differences in health status among mice of similar chronological age. In agreement with this, P wave duration and PR interval were highly correlated with FI score. High resolution optical mapping of the atria demonstrated reduced conduction velocity and action potential duration in aged hearts that were also graded by FI score. Furthermore, aged mice had increased interstitial fibrosis along with changes in regulators of extracellular matrix remodelling, which also correlated with frailty. These experiments demonstrate that aging results in changes in atrial structure and function that create a substrate for atrial arrhythmias. Importantly, these changes were heterogeneous due to differences in health status, which could be identified using an FI.

Development of a Rat Clinical Frailty Index.

Rats are a commonly used model for aging studies, and a frailty assessment tool for rats would be of considerable value. There has been a recent focus on the development of preclinical models of frailty in mice. A mouse clinical frailty index (FI) was developed based on clinical frailty assessment tools. This FI measures the accumulation of clinically evident health-related deficits in mice. This paper aimed to develop a rat clinical FI. Male Fischer 344 rats were aged from 6 to 9 months (n = 12), and from 13 to 21 months (n = 41). A FI comprised of 27 health-related deficits was developed from a review of the literature and consultation with a veterinarian. Deficits were scored 0 if absent, 0.5 if mild, or 1 if severe. A FI score was determined for each rat every 3–4 months, and for the older group mortality was assessed up to 21 months. Mean FI scores significantly increased at each time point for the older rats. A high FI score measured at both 17 months of age and terminally was also associated with decreased probability of survival as assessed with Kaplan–Meier curves. The rat clinical FI has significant value for use in aging and interventional studies.

The impacts of age and frailty on heart rate and sinoatrial node function.

Sinoatrial node (SAN) function declines with age; however, not all individuals age at the same rate and health status can vary from fit to frail. Frailty was quantified in young and aged mice using a non-invasive frailty index so that the impacts of age and frailty on heart rate and SAN function could be assessed. SAN function was impaired in aged mice due to alterations in electrical conduction, changes in SAN action potential morphology and fibrosis in the SAN. Changes in SAN function, electrical conduction, action potential morphology and fibrosis were correlated with, and graded by, frailty. This study shows that mice of the same chronological age have quantifiable differences in health status that impact heart rate and SAN function and that these differences in health status can be identified using our frailty index. Sinoatrial node (SAN) dysfunction increases with age, although not all older adults are affected in the same way. This is because people age at different rates and individuals of the same chronological age vary in health status from very fit to very frail. Our objective was to determine the impacts of age and frailty on heart rate (HR) and SAN function using a new model of frailty in ageing mice. Frailty, which was quantified in young and aged mice using a frailty index (FI), was greater in aged vs. young mice. Intracardiac electrophysiology demonstrated that HR was reduced whereas SAN recovery time (SNRT) was prolonged in aged mice; however, both parameters showed heteroscedasticity suggesting differences in health status among mice of similar chronological age. Consistent with this, HR and corrected SNRT were correlated with, and graded by, FI score. Optical mapping of the SAN demonstrated that conduction velocity (CV) was reduced in aged hearts in association with reductions in diastolic depolarization (DD) slope and action potential (AP) duration. In agreement with in vivo results, SAN CV, DD slope and AP durations all correlated with FI score. Finally, SAN dysfunction in aged mice was associated with increased interstitial fibrosis and alterations in expression of matrix metalloproteinases, which also correlated with frailty. These findings demonstrate that age-related SAN dysfunction occurs in association with electrical and structural remodelling and that frailty is a critical determinant of health status of similarly aged animals that correlates with changes in HR and SAN function.

TGFβ Superfamily Members Mediate Androgen Deprivation Therapy-Induced Obese Frailty in Male Mice

First line treatment for recurrent and metastatic prostate cancer is androgen deprivation therapy (ADT). Use of ADT has been increasing in frequency and duration, such that side effects increasingly impact patient quality of life. One of the most significant side effects of ADT is sarcopenia, which leads to a loss of skeletal muscle mass and function, resulting in a clinical disability syndrome known as obese frailty. Using aged mice, we developed a mouse model of ADT-induced sarcopenia that closely resembles the phenotype seen in patients, including loss of skeletal muscle strength, reduced lean muscle mass, and increased adipose tissue. Sarcopenia onset occurred about 6 weeks after castration and was blocked by a soluble receptor (ActRIIB-Fc) that binds multiple TGFβ superfamily members, including myostatin, growth differentiation factor 11, activin A, activin B, and activin AB. Analysis of ligand expression in both gastrocnemius and triceps brachii muscles demonstrates that each of these proteins is induced in response to ADT, in 1 of 3 temporal patterns. Specifically, activin A and activin AB levels increase and decline before onset of strength loss at 6 weeks after castration, and myostatin levels increase coincident with the onset of strength loss and then decline. In contrast, activin B and growth differentiation factor 11 levels increase after the onset of strength loss, 8-10 weeks after castration. The observed patterns of ligand induction may represent differential contributions to the development and/or maintenance of sarcopenia. We hypothesize that some or all of these ligands are targets for therapy to ameliorate ADT-induced sarcopenia in prostate cancer patients.

Commentary: Age-related neurodegenerative disease research needs aging models.

Commentary: Age-related neurodegenerative disease research needs aging models.

Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type

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 (300mg/kg via oral gavage), chronic (100mg/kg/day in diet for six weeks) or sub-acute (250mg/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.