Search

Preclinical models have been the backbone of translational research for more than a century. Rats and mice are critical models in the preliminary stages of drug testing, both for determining efficacy and ruling out potential human-relevant toxicities. Historically, most preclinical pharmacological studies have used young, relatively healthy, inbred male models in highly controlled environments. In the field of geriatric pharmacology, there is a growing focus on the importance of using more appropriate preclinical models both in the testing of therapeutics commonly used in older populations, and in the evaluation of potential geroprotective drug candidates. Here we provide a commentary on optimizing preclinical models of ageing for translation to clinical trials. We will discuss approaches to modelling clinically relevant contexts such as age, sex, genetic diversity, exposures and environment, as well as measures of clinically relevant outcomes such as frailty and healthspan. We will identify the strengths and limitations of these approaches and areas for improvement. We will also briefly cover new preclinical models that move beyond rodents. We hope this commentary will be a springboard for larger discussions on optimizing preclinical ageing models for testing therapeutics., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Aging is a complex process that involves all tissues in an organism and shows sex dimorphism. While transcriptional changes in aging have been well characterized, the majority of studies have focused on a single sex and sex differences in gene expression in aging are poorly understood. In this study, we explore sex dimorphism in gene expression in aging mice across three tissues., Methods: We collected gastrocnemius muscle, liver and white adipose tissue from young (6 months, n = 14) and old (24 months, n = 14) female and male C57BL/6NIA mice and performed RNA-seq. To investigate sex dimorphism in aging, we considered two levels of comparisons: (a) differentially expressed genes between females and males in the old age group and (b) comparisons between females and males across the aging process. We utilized differential expression analysis and gene feature selection to investigate candidate genes. Gene set enrichment analysis was performed to identify candidate molecular pathways. Furthermore, we performed a co-expression network analysis and chose the gene module(s) associated with aging independent of sex or tissue-type., Results: We identified both tissue-specific and tissue-independent genes associated with sex dimorphism in aged mice. Unique differentially expressed genes between old males and females across tissues were mainly enriched for pathways related to specific tissue function. We found similar results when exploring sex differences in the aging process, with the exception that in the liver genes enriched for lipid metabolism and digestive system were identified in both females and males. Combining enriched pathways across analyses, we identified amino acid metabolism, digestive system, and lipid metabolism as the core mechanisms of sex dimorphism in aging. Although the vast majority of age-related genes were sex and tissue specific, we identified 127 hub genes contributing to aging independent of sex and tissue that were enriched for the immune system and signal transduction., Conclusions: There are clear sex differences in gene expression in aging across liver, muscle and white adipose. Core pathways, including amino acid metabolism, digestive system and lipid metabolism, contribute to sex differences in aging., (© 2024. The Author(s).)

For centuries, aging was considered inevitable and immutable. Geroscience provides the conceptual framework to shift this focus toward a new view that regards aging as an active biological process, and the biological age of an individual as a modifiable entity. Significant steps forward have been made toward the identification of biomarkers for and measures of biological age, yet knowledge gaps in geroscience are still numerous. Animal models of aging are the focus of this perspective, which discusses how experimental design can be optimized to inform and refine the development of translationally relevant measures and biomarkers of biological age. We provide recommendations to the field, including: the design of longitudinal studies in which subjects are deeply phenotyped via repeated multilevel behavioral/social/molecular assays; the need to consider sociobehavioral variables relevant for the species studied; and finally, the importance of assessing age of onset, severity of pathologies, and age-at-death. We highlight approaches to integrate biomarkers and measures of functional impairment using machine learning approaches designed to estimate biological age as well as to predict future health declines and mortality. We expect that advances in animal models of aging will be crucial for the future of translational geroscience but also for the next chapter of medicine., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

On average, aging is associated with unfavorable changes in cellular metabolism, which are the processes involved in the storage and expenditure of energy. However, metabolic dysregulation may not occur to the same extent in all older individuals as people age at different rates. Those who are aging rapidly are at increased risk of adverse health outcomes and are said to be "frail." Here, we explore the links between frailty and metabolism, including metabolic contributors and consequences of frailty. We examine how metabolic diseases may modify the degree of frailty in old age and suggest that frailty may predispose toward metabolic disease. Metabolic interventions that can mitigate the degree of frailty in people are reviewed. New treatment strategies developed in animal models that are poised for translation to humans are also considered. We suggest that maintaining a youthful metabolism into older age may be protective against frailty., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging., Competing Interests: Declaration of interests D.A.S. is a consultant, inventor, board member, and in some cases an investor in Life Biosciences (developing reprogramming medicines), InsideTracker, Zymo, EdenRoc Sciences/Cantata/Dovetail/Metrobiotech, Caudalie, Galilei, Immetas, Animal Biosciences, Tally Health, and more. See https://sinclair.hms.harvard.edu/david-sinclairs-affiliations. E.M.M., M. Blanchette, and M. Bhakta are employees of Catata Bio/Dovetail. Y.C.C., W.G., and X.Y. are employees of Zymo Research. A.J.W. advises Kate Therapeutics and Frequency Therapeutics and is a co-founder, adviser, and equity holder of Elevian, which sponsors Wagers Lab research. L.S. was an employee of Vium. Y.R.L. and L.A.R. are equity owners of Life Biosciences. M.S.B. and D.L.V. advise EdenRoc Sciences. A patent application was filed on the reprogramming methods., (Copyright © 2022 Elsevier Inc. All rights reserved.)

As an organism ages, its health-state is determined by a balance between the processes of damage and repair. Measuring these processes requires longitudinal data. We extract damage and repair transition rates from repeated observations of binary health attributes in mice and humans to explore robustness and resilience, which respectively represent resisting or recovering from damage. We assess differences in robustness and resilience using changes in damage rates and repair rates of binary health attributes. We find a conserved decline with age in robustness and resilience in mice and humans, implying that both contribute to worsening aging health - as assessed by the frailty index (FI). A decline in robustness, however, has a greater effect than a decline in resilience on the accelerated increase of the FI with age, and a greater association with reduced survival. We also find that deficits are damaged and repaired over a wide range of timescales ranging from the shortest measurement scales toward organismal lifetime timescales. We explore the effect of systemic interventions that have been shown to improve health, including the angiotensin-converting enzyme inhibitor enalapril and voluntary exercise for mice. We have also explored the correlations with household wealth for humans. We find that these interventions and factors affect both damage and repair rates, and hence robustness and resilience, in age and sex-dependent manners., Competing Interests: SF, AK, EB, SH, AR No competing interests declared, (© 2022, Farrell et al.)

Calorie restriction (CR) extends lifespan and retards age-related chronic diseases in most species. There is growing evidence that the gut microbiota has a pivotal role in host health and age-related pathological conditions. Yet, it is still unclear how CR and the gut microbiota are related to healthy aging. Here, we report findings from a small longitudinal study of male C57BL/6 mice maintained on either ad libitum or mild (15%) CR diets from 21 months of age and tracked until natural death. We demonstrate that CR results in a significantly reduced rate of increase in the frailty index (FI), a well-established indicator of aging. We observed significant alterations in diversity, as well as compositional patterns of the mouse gut microbiota during the aging process. Interrogating the FI-related microbial features using machine learning techniques, we show that gut microbial signatures from 21-month-old mice can predict the healthy aging of 30-month-old mice with reasonable accuracy. This study deepens our understanding of the links between CR, gut microbiota, and frailty in the aging process of mice.

Frailty can be viewed as a state of physiological decline that increases susceptibility to adverse health outcomes. This loss of physiological reserve means that even small stressors can lead to disability and death in frail individuals. Frailty can be measured with various clinical tools; the two most popular are the frailty index and the frailty phenotype. Clinical studies have used these tools to show that women are frailer than men even though they have longer lifespans. Still, factors responsible for this frailty-mortality paradox are not well understood. This review highlights evidence for male-female differences in frailty from both the clinical literature and in animal models of frailty. We review evidence for higher frailty levels in female animals as seen in many preclinical models. Mechanisms that may contribute to sex differences in frailty are highlighted. In addition, we review work that suggests frailty may play a role in susceptibility to chronic diseases of aging in a sex-specific fashion. Additional mechanistic studies in preclinical models are needed to understand factors involved in male-female differences in frailty in late life., (Copyright © 2021. Published by Elsevier B.V.)

We investigated whether late-life changes in cardiac structure and function were related to high levels of frailty and inflammation in male and female mice. Frailty (frailty index), ventricular structure/function (echocardiography), and serum cytokines (multiplex immunoassay) were measured in 16- and 23-month-old mice. Left ventricular (LV) mass and septal wall thickness increased with age in both sexes. Ejection fraction increased with age in males (60.4 ± 1.4 vs 68.9 ± 1.8%; p < .05) but not females (58.8 ± 2.5 vs 62.6 ± 2.4%). E/A ratios declined with age in males (1.6 ± 0.1 vs 1.3 ± 0.1; p < .05) but not females (1.4 ± 0.1 vs 1.3 ± 0.1) and this was accompanied by increased ventricular collagen levels in males. These changes in ejection fraction (r = 0.52; p = .01), septal wall thickness (r = 0.59; p = .002), E/A ratios (r = -0.49; p = .04), and fibrosis (r = 0.82; p = .002) were closely graded by frailty scores in males. Only septal wall thickness and LV mass increased with frailty in females. Serum cytokines changed modestly with age in both sexes. Nonetheless, in males, E/A ratios, LV mass, LV posterior wall thickness, and septal wall thickness increased as serum cytokines increased (eg, IL-6, IL-3, IL-1α, IL-1β, tumor necrosis factor-α, eotaxin, and macrophage inflammatory protein-1α), while ejection fraction declined with increasing IL-3 and granulocyte-macrophage colony stimulating factor. Cardiac outcomes were not correlated with inflammatory cytokines in females. Thus, changes in cardiac structure and function in late life are closely graded by both frailty and markers of inflammation, but this occurs primarily in males. This suggests poor overall health and inflammation drive maladaptive changes in older male hearts, while older females may be resistant to these adverse effects of frailty., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity 1-3 . Changes to DNA methylation patterns over time form the basis of ageing clocks 4 , but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity 5-7 . Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information-encoded in part by DNA methylation-that can be accessed to improve tissue function and promote regeneration in vivo.

The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict the life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not known. Here, mouse FIs are scored longitudinally until death and machine learning is employed to develop two clocks. A random forest regression is trained on FI components for chronological age to generate the FRIGHT (Frailty Inferred Geriatric Health Timeline) clock, a strong predictor of chronological age. A second model is trained on remaining lifespan to generate the AFRAID (Analysis of Frailty and Death) clock, which accurately predicts life expectancy and the efficacy of a lifespan-extending intervention up to a year in advance. Adoption of these clocks should accelerate the identification of longevity genes and aging interventions.

We investigated effects of age, sex and frailty on contractions, calcium transients and myofilament proteins to determine if maladaptive changes associated with aging were sex-specific and modified by frailty. Ventricular myocytes and myofilaments were isolated from middle-aged (~12 mos) and older (~24 mos) mice. Frailty was assessed with a non-invasive frailty index. Calcium transients declined and slowed with age in both sexes, but contractions were largely unaffected. Actomyosin Mg-ATPase activity increased with age in females but not males; this could maintain contractions with smaller calcium transients in females. Phosphorylation of myosin-binding protein C (MyBP-C), desmin, tropomyosin and myosin light chain-1 (MLC-1) increased with age in males, but only MyBP-C and troponin-T increased in females. Enhanced phosphorylation of MyBP-C and MLC-1 could preserve contractions in aging. Interestingly, the age-related decline in Hill coefficients (r = -0.816; p = 0.002) and increase in phosphorylation of desmin (r = 0.735; p = 0.010), tropomyosin (r = 0.779; p = 0.005) and MLC-1 (r = 0.817; p = 0.022) were graded by the level of frailty in males but not females. In these ways, cardiac remodeling at cellular and subcellular levels is graded by overall health in aging males. Such changes may contribute to heart diseases in frail older males, whereas females may be resistant to these effects of frailty.

Even though they would have great benefit across research and clinical fields, currently there are no accepted biomarkers of frailty. Cross-sectional studies in humans have identified promising candidates including inflammatory markers such as IL-6, immune markers such as WBC count, clinical markers such as albumin, endocrine markers such as vitamin D, oxidative stress markers such as isoprostanes, proteins such as BDNF and epigenetic markers such as DNA methylation, but there are limitations to the current state of the research. Future approaches to the identification of frailty biomarkers should include longitudinal studies, studies using animal models of frailty, studies incorporating novel biomarkers combined into composite panels, and studies investigating sex differences and potential overlap between markers of biological age and frailty., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The aging process results in significant epigenetic changes at all levels of chromatin and DNA organization. These include reduced global heterochromatin, nucleosome remodeling and loss, changes in histone marks, global DNA hypomethylation with CpG island hypermethylation, and the relocalization of chromatin modifying factors. Exactly how and why these changes occur is not fully understood, but evidence that these epigenetic changes affect longevity and may cause aging, is growing. Excitingly, new studies show that age-related epigenetic changes can be reversed with interventions such as cyclic expression of the Yamanaka reprogramming factors. This review presents a summary of epigenetic changes that occur in aging, highlights studies indicating that epigenetic changes may contribute to the aging process and outlines the current state of research into interventions to reprogram age-related epigenetic changes.

The sirtuin family of nicotinamide adenine dinucleotide-dependent deacylases (SIRT1-7) are thought to be responsible, in large part, for the cardiometabolic benefits of lean diets and exercise and when upregulated can delay key aspects of aging. SIRT1, for example, protects against a decline in vascular endothelial function, metabolic syndrome, ischemia-reperfusion injury, obesity, and cardiomyopathy, and SIRT3 is protective against dyslipidemia and ischemia-reperfusion injury. With increasing age, however, nicotinamide adenine dinucleotide levels and sirtuin activity steadily decrease, and the decline is further exacerbated by obesity and sedentary lifestyles. Activation of sirtuins or nicotinamide adenine dinucleotide repletion induces angiogenesis, insulin sensitivity, and other health benefits in a wide range of age-related cardiovascular and metabolic disease models. Human clinical trials testing agents that activate SIRT1 or boost nicotinamide adenine dinucleotide levels are in progress and show promise in their ability to improve the health of cardiovascular and metabolic disease patients.

Cardiovascular diseases increase dramatically with age in both men and women. While it is clear that advanced age allows more time for individuals to be exposed to risk factors in general, there is strong evidence that age itself is a major independent risk factor for cardiovascular disease. Indeed, there are distinct age-dependent cellular, structural, and functional changes in both the heart and blood vessels, even in individuals with no clinical evidence of cardiovascular disease. Studies in older humans and in animal models of aging indicate that this age-related remodeling is maladaptive. An emerging view is that the heart and blood vessels accumulate cellular and subcellular deficits with age and these deficits increase susceptibility to disease in older individuals. Aspects of this age-dependent remodeling of the heart and blood vessels differ between the sexes. There is also new evidence that these maladaptive changes are more prominent in older animals and humans with a high degree of frailty. These observations may help explain why men and women are susceptible to different cardiovascular diseases as they age and why frail older adults are most often affected by these diseases.

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 Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America.)

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 Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Key Points: 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., Abstract: 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 (≈7 months) and aged (≈27 months) 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 Ca 2+ transients. These changes were not due to reduced sarcoplasmic reticulum stores, but were graded by smaller Ca 2+ 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., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

The incidence of cardiovascular disease is rising as the population ages. This has led to an increase in the need to perform cardiac surgery in older patients. However, aged hearts are particularly susceptible to reperfusion injury following periods of myocardial ischaemia that occur during cardiac surgery. Indeed, older adults experience myocardial dysfunction and reduced survival post-surgery compared to younger people and certain groups, including older women and frail older adults, are at particular risk. This highlights the need to design cardioprotective strategies specifically for the ageing heart. Cardioprotection during surgery is often accomplished by perfusing the heart with chemical arresting agents, known as cardioplegic solutions. New protective strategies have been developed and tested in animal models, where cardioplegic solutions have been modified by changing their temperature, chemical components and/or the frequency of delivery. In addition, drugs designed to activate cardioprotective mechanisms or to inhibit mechanisms involved in injury have been added to improve the efficacy of these solutions. However, most experimental studies have developed and optimized cardioplegic solutions in hearts from younger male animals. This review discusses pre-clinical models used to optimize cardioplegic solutions, with an emphasis on the few studies that have used hearts from older animals. Pharmacologic agents that have been shown to enhance the benefits of cardioplegia in younger hearts and could, in theory, protect vulnerable older hearts are also considered. We emphasize the need to conduct studies in frail older animals of both sexes to facilitate translation of laboratory-based observations to the clinic., (© 2016 John Wiley & Sons Australia, Ltd.)

We aimed to develop a mouse model of polypharmacy, primarily to establish whether short-term exposure to polypharmacy causes adverse geriatric outcomes. We also investigated whether old age increased susceptibility to any adverse geriatric outcomes of polypharmacy. Young (n= 10) and old (n= 21) male C57BL/6 mice were administered control diet or polypharmacy diet containing therapeutic doses of five commonly used medicines (simvastatin, metoprolol, omeprazole, acetaminophen, and citalopram). Mice were assessed before and after the 2- to 4-week intervention. Over the intervention period, we observed no mortality and no change in food intake, body weight, or serum biochemistry in any age or treatment group. In old mice, polypharmacy caused significant declines in locomotor activity (pre minus postintervention values in control 2 ± 13 counts, polypharmacy 32 ± 7 counts,p< .05) and front paw wire holding impulse (control -2.45 ± 1.02 N s, polypharmacy +1.99 ± 1.19 N s,p< .05), loss of improvement in rotarod latency (control -59 ± 11 s, polypharmacy -1.7 ± 17 s,p< .05), and lowered blood pressure (control -0.2 ± 3 mmHg, polypharmacy 11 ± 4 mmHg,p< .05). In young mice, changes in outcomes over the intervention period did not differ between control and polypharmacy groups. This novel model of polypharmacy is feasible. Even short-term polypharmacy impairs mobility, balance, and strength in old male mice., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This article investigates the effect on the mouse frailty index (FI), of factors known to influence lifespan and healthspan in mice: strain (short-lived DBA/2J mice vs long-lived C57BL/6J mice), calorie restriction (CR), and resveratrol treatment. The mouse FI, based on deficit accumulation, was recently validated in C57BL/6J mice by Whitehead JC, Hildebrand BA, Sun M, et al. (A clinical frailty index in aging mice: comparisons with frailty index data in humans. J Gerontol A Biol Sci Med Sci. 2014;69:621-632) and shares many characteristics of the human FI. FI scores were measured in male and female aged (18 months) ad-libitum fed and CR DBA/2J and C57BL/6J mice, as well as male aged (24 months) C57BL/6J mice ad-libitum fed with or without resveratrol (100 mg/kg/day) in the diet for 6 months. Mean scores of two raters were used, and the raters had excellent inter-rater reliability (ICC = 0.88, 95% CI [0.80, 0.92]). Furthermore, the interventions of CR and resveratrol were associated with a significant reduction in FI scores in C57BL/6J mice, compared to age-matched controls. The short-lived DBA/2J mice also had slightly higher FI scores than the C57BL/6J mice, for the male calorie-restricted groups (DBA/2J FI = 0.16±0.03, C57BL/6J FI = 0.11±0.03, p = .01). This study uses the mouse FI developed by Whitehead JC, Hildebrand BA, Sun M, et al. (A clinical frailty index in aging mice: comparisons with frailty index data in humans. J Gerontol A Biol Sci Med Sci. 2014;69:621-632) in a different mouse colony and shows that this tool can be applied to quantify the effect of dietary and pharmaceutical interventions on frailty., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Repetition priming refers to a form of implicit memory in which prior exposure to a stimulus facilitates the subsequent processing of the same or a related stimulus. One frequently used repetition priming task is word-stem completion priming. In this task, participants complete a series of beginning word stems with the first word that comes to mind after having viewed, in an unrelated context, words that can complete some of the stems. Patients with Alzheimer's disease (AD) exhibit a significant deficit in word-stem completion priming, but the neural mechanisms underlying this deficit have yet to be identified. The present study examined the possibility that the word-stem completion priming deficit in AD is due to disruption of ascending neuromodulatory systems that mediate cortical arousal by comparing word-stem completion priming and behavioral measures of spatial orienting and phasic alerting. Results showed that in healthy elderly controls higher levels of phasic alerting were associated with a sharpening of the temporal dynamics of priming across two delay intervals: those with higher levels of alerting showed more immediate priming but less delayed priming than those with lesser levels of alerting. In patients with AD, priming was impaired despite intact levels of phasic alerting and spatial orienting, and group status rather than individual levels of alerting or orienting predicted the magnitude of their stem-completion priming. Furthermore, the change in priming across delays they displayed was not related to level of alerting or orienting. These findings support the role of the noradrenergic projection system in modulating the level of steady-state cortical activation (or "cortical tonus") underlying both phasic alerting and the temporal dynamics of repetition priming. However, impaired priming in patients with AD does not appear to be due to disruption of this neuromodulatory system., (Copyright © 2015 Elsevier Ltd. All rights reserved.)