Age-related Deficits Research Articles

Binge ethanol exposure in advanced age elevates neuroinflammation and early indicators of neurodegeneration and cognitive impairment in female mice

Binge drinking is rising among aged adults (>65 years of age), however the contribution of alcohol misuse to neurodegenerative disease development is not well understood. Both advanced age and repeated binge ethanol exposure increase neuroinflammation, which is an important component of neurodegeneration and cognitive dysfunction. Surprisingly, the distinct effects of binge ethanol exposure on neuroinflammation and associated degeneration in the aged brain have not been well characterized. Here, we establish a model of intermittent binge ethanol exposure in young and aged female mice to investigate the effects of advanced age and binge ethanol on these outcomes. Following intermittent binge ethanol exposure, expression of pro-inflammatory mediators (tnf-α, il-1β, ccl2) was distinctly increased in isolated hippocampal tissue by the combination of advanced age and ethanol. Binge ethanol exposure also increased measures of senescence, the nod like receptor pyrin domain containing 3 (NLRP3) inflammasome, and microglia reactivity in the brains of aged mice compared to young. Binge ethanol exposure also promoted neuropathology in the hippocampus of aged mice, including tau hyperphosphorylation and neuronal death. We further identified advanced age-related deficits in contextual memory that were further negatively impacted by ethanol exposure. These data suggest binge drinking superimposed with advanced age promotes early markers of neurodegenerative disease development and cognitive decline, which may be driven by heightened neuroinflammatory responses to ethanol. Taken together, we propose this novel exposure model of intermittent binge ethanol can be used to identify therapeutic targets to prevent advanced age- and ethanol-related neurodegeneration.

ASSOCIATIVE AND EXECUTIVE INFLUENCES ON MEMORY FOR EVENTS AS REVEALED BY AGING AND DISTRACTION

Abstract Diagnostic tests of memory functioning typically employ verbal material, potentially encouraging mnemonic strategies ranging from rehearsal to visual imagery. Poor performance could thus reflect either impairments in basic associative mechanisms or impairments in executive functions underlying strategy deployment. Kersten et al. (2018) developed a more ecologically valid test of episodic memory, the Person-Action Conjunction (PAC) Test, involving memory for who did what in events. They found that when many different actors performed the actions, memory for who performed each action was related to tests of associative functioning, whereas when only two actors performed all the actions, memory performance was related to executive functioning. The present research tested the ensuing prediction that manipulating the availability of executive resources through distraction should only impact performance when a small number of actors perform the actions. The PAC Test was administered to 207 young adults (M age = 20.39) and 163 healthy older adults (M age = 70.80), either with no distraction or while performing a tone counting distractor task. Young adults performed better than older adults at remembering who did what, consistent with an age-related associative deficit. When two actors performed all the actions, distraction impacted both age groups’ memory for which actor performed each action. When many different actors performed the actions, distraction had no specific impact on memory for who did what. Implications will be discussed for the development of diagnostic tests to differentiate impairments in basic memory mechanisms (e.g., early-stage Alzheimer’s disease) from impairments of executive functioning (e.g., vascular dementia).

A PILOT STUDY OF EPIGENETIC AGING IN THE CONTEXT OF AN INTENSIVE LIFESTYLE INTERVENTION: THE LOOK AHEAD STUDY

Abstract Type 2 diabetes and obesity increase the rate of accumulation of age-related health deficits and accelerate biological aging. An intervention promoting weight loss among adults with these conditions, the Action for Health in Diabetes (Look AHEAD) Intensive Lifestyle Intervention (ILI), attenuated health deficit accumulation measured by a frailty index, through a variety of diet and exercise strategies and optional weight loss medications to achieve and maintain ≥7% weight loss. To better understand the long-term effects of the Look AHEAD ILI on aging biology, we leveraged biospecimens from 62 women aged 60-71 years who participated in the Look AHEAD randomized clinical trial of ILI (n=32) and diabetes support and education (control condition, n=30), and tested for associations of ILI vs control condition on the rate of epigenetic aging. Five DNA methylation-based aging measures were generated from blood collected at baseline and 14 years later. Unexpectedly, the intervention was associated with a long-term increase in AgeAccelPheno compared to the control condition (t-test, p< 0.05). ILI was not associated with a change in other epigenetic measures over 14 years (AgeAccelHannum, AgeAccelHorvath, AgeAccelGrim and DunedinPACE), or a change in a frailty index reflecting accumulation of 38 health deficits. Overall, the average change in frailty index was higher among participants with advanced epigenetic age at baseline (AgeAccelHannum>0 and AgeAccelGrim>0,p < 0.05), suggesting that epigenetic aging markers may be useful predictors of frailty risk. Well-powered studies are needed to better understand the long-term impact of intensive lifestyle interventions on epigenetic aging in adults with diabetes and obesity.

How do neurons age? A focused review on the aging of the microtubular cytoskeleton.

Aging is the leading risk factor for Alzheimer's disease and other neurodegenerative diseases. We now understand that a breakdown in the neuronal cytoskeleton, mainly underpinned by protein modifications leading to the destabilization of microtubules, is central to the pathogenesis of Alzheimer's disease. This is accompanied by morphological defects across the somatodendritic compartment, axon, and synapse. However, knowledge of what occurs to the microtubule cytoskeleton and morphology of the neuron during physiological aging is comparatively poor. Several recent studies have suggested that there is an age-related increase in the phosphorylation of the key microtubule stabilizing protein tau, a modification, which is known to destabilize the cytoskeleton in Alzheimer's disease. This indicates that the cytoskeleton and potentially other neuronal structures reliant on the cytoskeleton become functionally compromised during normal physiological aging. The current literature shows age-related reductions in synaptic spine density and shifts in synaptic spine conformation which might explain age-related synaptic functional deficits. However, knowledge of what occurs to the microtubular and actin cytoskeleton, with increasing age is extremely limited. When considering the somatodendritic compartment, a regression in dendrites and loss of dendritic length and volume is reported whilst a reduction in soma volume/size is often seen. However, research into cytoskeletal change is limited to a handful of studies demonstrating reductions in and mislocalizations of microtubule-associated proteins with just one study directly exploring the integrity of the microtubules. In the axon, an increase in axonal diameter and age-related appearance of swellings is reported but like the dendrites, just one study investigates the microtubules directly with others reporting loss or mislocalization of microtubule-associated proteins. Though these are the general trends reported, there are clear disparities between model organisms and brain regions that are worthy of further investigation. Additionally, longitudinal studies of neuronal/cytoskeletal aging should also investigate whether these age-related changes contribute not just to vulnerability to disease but also to the decline in nervous system function and behavioral output that all organisms experience. This will highlight the utility, if any, of cytoskeletal fortification for the promotion of healthy neuronal aging and potential protection against age-related neurodegenerative disease. This review seeks to summarize what is currently known about the physiological aging of the neuron and microtubular cytoskeleton in the hope of uncovering mechanisms underpinning age-related risk to disease.

Exercise-induced neuroplasticity in autonomic nuclei restores the cardiac vagal tone and baroreflex dysfunction in aged hypertensive rats.

Aging is accompanied by considerable deterioration of homeostatic systems, such as autonomic imbalance characterized by heightened sympathetic activity, lower parasympathetic tone, and depressed heart rate (HR) variability, which are aggravated by hypertension. Here, we hypothesized that these age-related deficits in aged hypertensive rats can be ameliorated by exercise training, with benefits to the cardiovascular system. Therefore, male 22-mo-old spontaneously hypertensive rats (SHRs) and age-matched Wistar Kyoto (WKY) submitted to moderate-intensity exercise training (T) or kept sedentary (S) for 8 wk were evaluated for hemodynamic/autonomic parameters, baroreflex sensitivity, cardiac sympathetic/parasympathetic tone and analysis of dopamine β-hydroxylase (DBH+) and oxytocin (OT+) pathways of autonomic brain nuclei. Aged SHR-S versus WKY-S exhibited elevated mean arterial pressure (MAP: +51%) and HR (+20%), augmented pressure/HR variability, no cardiac vagal tone, and depressed reflex control of the heart (HR range, -28%; gain, -49%). SHR-T exhibited a lower resting HR, a partial reduction in the MAP (-14%), in the pressure/HR variabilities, and restored parasympathetic modulation, with improvement of baroreceptor reflex control when compared with SHR-S. Exercise training increased the ascending DBH+ projections conveying peripheral information to the paraventricular nucleus of hypothalamus (PVN), augmented the expression of OT+ neurons, and reduced the density of DBH+ neurons in the rostral ventrolateral medulla (RVLM) of SHR-T. Data indicate that exercise training induces beneficial neuroplasticity in brain autonomic circuitry, and it is highly effective to restore the parasympathetic tone, and attenuation of age-related autonomic imbalance and baroreflex dysfunction, thus conferring long-term benefits for cardiovascular control in aged hypertensive individuals.NEW & NOTEWORTHY Exercise training reduces high blood pressure and cardiovascular autonomic modulation in aged hypertensive rats. The dysfunction in the baroreflex sensitivity and impaired parasympathetic tone to the heart of aged hypertensive rats are restored by exercise training. Exercise induces beneficial neuroplasticity in the brain nuclei involved with autonomic control of cardiovascular function of aged hypertensive rats.

Comparison of Frailty and Chronological Age as Determinants of the Murine Gut Microbiota in an Alzheimer's Disease Mouse Model.

The ageing of an organism is associated with certain features of functional decline that can be assessed at the cellular level (e.g., reduced telomere length, loss of proteostasis, etc.), but also at the organismic level. Frailty is an independent syndrome that involves increased multidimensional age-related deficits, heightens vulnerability to stressors, and involves physical deficits in mainly the locomotor/muscular capacity, but also in physical appearance and cognition. For sporadic Alzheimer's disease, age per se is one of the most relevant risk factors, but frailty has also been associated with this disease. Therefore, we aimed to answer the two following questions within a cross-sectional study: (1) do Alzheimer's model mice show increased frailty, and (2) what changes of the microbiota occur concerning chronological age or frailty? Indeed, aged 5xFAD mice showed increased frailty compared to wild type littermates. In addition, 5xFAD mice had significantly lower quantities of Bacteroides spp. when only considering frailty, and lower levels of Bacteroidetes in terms of both frailty and chronological age compared to their wild type littermates. Thus, the quality of ageing-as assessed by frailty measures-should be taken into account to unravel potential changes in the gut microbial community in Alzheimer's disease.

TonEBP Haploinsufficiency Attenuates Microglial Activation and Memory Deficits in Middle-Aged and Amyloid β Oligomer-Treated Mice.

Age-related microglial activation is associated with cognitive impairment. Tonicity-responsive enhancer-binding protein (TonEBP) is a critical mediator of microglial activation in response to neuroinflammation. However, the precise role of TonEBP in the middle-aged brain is not yet known. We used TonEBP haploinsufficient mice to investigate the role of TonEBP in middle-aged or amyloid β oligomer (AβO)-injected brains and examined the effect of TonEBP knockdown on AβO-treated BV2 microglial cells. Consistent with an increase in microglial activation with aging, hippocampal TonEBP expression levels were increased in middle-aged (12-month-old) and old (24-month-old) mice compared with young (6-month-old) mice. Middle-aged TonEBP haploinsufficient mice showed reduced microglial activation and fewer memory deficits than wild-type mice. Electron microscopy revealed that synaptic pruning by microglial processes was reduced by TonEBP haploinsufficiency. TonEBP haploinsufficiency also reduced dendritic spine loss and improved memory deficits in AβO-treated mice. Furthermore, TonEBP knockdown attenuated migration and phagocytosis in AβO-treated BV2 cells. These findings suggest that TonEBP plays important roles in age-related microglial activation and memory deficits.

Increasing NPYergic transmission in the hippocampus rescues aging-related deficits of long-term potentiation in the mouse dentate gyrus.

Loss of neuropeptide Y (NPY)-expressing interneurons in the hippocampus and decaying cholinergic neuromodulation are thought to contribute to impaired cognitive function during aging. However, the interaction of these two neuromodulatory systems in maintaining hippocampal synaptic plasticity during healthy aging has not been explored so far. Here we report profound sex differences in the Neuropeptide-Y (NPY) levels in the dorsal dentate gyrus (DG) with higher NPY concentrations in the male mice compared to their female counterparts and a reduction of NPY levels during aging specifically in males. This change in aged males is accompanied by a deficit in theta burst-induced long-term potentiation (LTP) in the medial perforant path-to-dorsal DG (MPP-DG) synapse, which can be rescued by enhancing cholinergic activation with the acetylcholine esterase blocker, physostigmine. Importantly, NPYergic transmission is required for this rescue of LTP. Moreover, exogenous NPY application alone is sufficient to recover LTP induction in aged male mice, even in the absence of the cholinergic stimulator. Together, our results suggest that in male mice NPYergic neurotransmission is a critical factor for maintaining dorsal DG LTP during aging.

Diminished State Space Theory of Human Aging.

Many new technologies, such as smartphones, computers, or public-access systems (like ticket-vending machines), are a challenge for older adults. One feature that these technologies have in common is that they involve underlying, partially observable, structures (state spaces) that determine the actions that are necessary to reach a certain goal (e.g., to move from one menu to another, to change a function, or to activate a new service). In this work we provide a theoretical, neurocomputational account to explain these behavioral difficulties in older adults. Based on recent findings from age-comparative computational- and cognitive-neuroscience studies, we propose that age-related impairments in complex goal-directed behavior result from an underlying deficit in the representation of state spaces of cognitive tasks. Furthermore, we suggest that these age-related deficits in adaptive decision-making are due to impoverished neural representations in the orbitofrontal cortex and hippocampus.

Parsing memory and nonmemory contributions to age-related declines in mnemonic discrimination performance: a hierarchical Bayesian diffusion decision modeling approach.

The mnemonic discrimination task (MDT) is a widely used cognitive assessment tool. Performance in this task is believed to indicate an age-related deficit in episodic memory stemming from a decreased ability to pattern-separate among similar experiences. However, cognitive processes other than memory ability might impact task performance. In this study, we investigated whether nonmnemonic decision-making processes contribute to the age-related deficit in the MDT. We applied a hierarchical Bayesian version of the Ratcliff diffusion model to the MDT performance of 26 younger and 31 cognitively normal older adults. It allowed us to decompose decision behavior in the MDT into different underlying cognitive processes, represented by specific model parameters. Model parameters were compared between groups, and differences were evaluated using the Bayes factor. Our results suggest that the age-related decline in MDT performance indicates a predominantly mnemonic deficit rather than differences in nonmnemonic decision-making processes. In addition, this mnemonic deficit might also involve a slowing in processes related to encoding and retrieval strategies, which are relevant for successful memory as well. These findings help to better understand what cognitive processes contribute to the age-related decline in MDT performance and may help to improve the diagnostic value of this popular task.

Testing can enhance episodic memory updating in younger and older adults.

Older adults sometimes show impaired memory for recent episodes, especially those that are similar but not identical to existing memories. Two experiments examined if interpolated testing between episodes improves recent memories for older and younger adults (N = 60 per group and experiment). Participants studied two lists of cue-response word pairs. Some pairs included the same cue in both lists with changed responses. Between lists, List 1 pairs were tested (Experiments 1 and 2), tested with corrective feedback (Experiment 1 only), or restudied (Experiment 2 only). On a final cued recall test, participants attempted to recall the List 2 response, indicated if responses had changed between lists, and if so, attempted to recall the List 1 response. List 2 recalls for changed pairs operationalized episodic memory updating. Older adults showed poorer List 2 recall than younger adults. But both age groups showed improved List 2 recall following interpolated testing with or without feedback compared to no-test and restudy contrast conditions. This so-called forward testing effect was accompanied by improved memory for responses having changed across lists. These results contrast with the inhibitory deficit proposal that older adults should be more interference prone than younger adults when competing responses are more accessible during encoding. These findings are more compatible with the view that retrieval practice of competing responses can support the encoding of cross-episode associations and potentially mitigate interference, thus improving age-related associative memory deficits. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

First Optimization of Novel, Potent, Selective PDE11A4 Inhibitors for Age-Related Cognitive Decline.

Phosphodiesterase 11A4 (PDE11A4) is a dual-acting cyclic nucleotide hydrolase expressed in neurons in the CA1, subiculum, amygdalostriatal transition area and amygdalohippocampal area of the extended hippocampal formation. PDE11A4 is the only PDE enzyme to emanate solely from hippocampal formation, a key brain region for the formation of long-term memory. PDE11A4 expression increases in the hippocampal formation of both humans and rodents as they age. Interestingly, PDE11A knockout mice do not show age-related deficits in associative memory and show no gross histopathology. This suggests that inhibition of PDE11A4 might serve as a therapeutic option for age-related cognitive decline. A novel, yeast-based high throughput screen previously identified moderately potent, selective PDE11A4 inhibitors, and this work describes initial efforts that improved potency more than 10-fold and improved some pharmaceutical properties of one of these scaffolds, leading to selective, cell-penetrant PDE11A4 inhibitors, one of which is 10-fold more potent compared to tadalafil in cell-based activity.

Age differences in inhibitory and working memory functioning: limited evidence of system interactions

ABSTRACT Debate persists regarding the nature of age-related deficits in inhibition, and whether inhibitory functioning depends on working memory systems. The current research aimed to measure age-related differences in inhibition and working memory, characterize the relationship between inhibitory functions and working memory performance, and determine how these relationships are affected by age. Toward these ends, we measured performance on a range of established paradigms in 60 young adults (18–30 years) and 60 older adults (60–88 years). Our findings support age-related increases in reflexive inhibition (based on the fixation offset effect and inhibition of return) and age-related decrements in volitional inhibition (based on several paradigms: antisaccade, Stroop, flanker, and Simon). This evidence of stronger reflexive inhibition combined with weaker volitional inhibition suggests that age-related deterioration of cortical structures may allow subcortical structures to operate less controlled. Regarding working memory, older adults had lower backward digit scores and lower forward and backward spatial scores. However, of the 32 analyses (16 in each age group) that tested for dependence of inhibitory functioning on working memory functioning, only one (in young adults) indicated that inhibition performance significantly depended on working memory performance. These results indicate that inhibition and working memory function largely independently in both age groups, and age-related working memory difficulties cannot account for age-related declines in inhibitory control.

Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity

Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of familial ALS, and generate toxic arginine-containing dipeptide repeats (DPRs), which interfere with membraneless organelles, such as the nucleolus. Here we considered senataxin (SETX), the genetic cause of ALS4, as a modifier of C9orf72 ALS, because SETX is a nuclear helicase that may regulate RNA–protein interactions involved in ALS dysfunction. After documenting that decreased SETX expression enhances arginine-containing DPR toxicity and C9orf72 repeat expansion toxicity in HEK293 cells and primary neurons, we generated SETX fly lines and evaluated the effect of SETX in flies expressing either (G4C2)58 repeats or glycine-arginine-50 [GR(50)] DPRs. We observed dramatic suppression of disease phenotypes in (G4C2)58 and GR(50) Drosophila models, and detected a striking relocalization of GR(50) out of the nucleolus in flies co-expressing SETX. Next-generation GR(1000) fly models, that show age-related motor deficits in climbing and movement assays, were similarly rescued with SETX co-expression. We noted that the physical interaction between SETX and arginine-containing DPRs is partially RNA-dependent. Finally, we directly assessed the nucleolus in cells expressing GR-DPRs, confirmed reduced mobility of proteins trafficking to the nucleolus upon GR-DPR expression, and found that SETX dosage modulated nucleolus liquidity in GR-DPR-expressing cells and motor neurons. These findings reveal a hitherto unknown connection between SETX function and cellular processes contributing to neuron demise in the most common form of familial ALS.

Assessing the impact of age on everyday cognitive function with a virtual environment task: The EcoKitchen

More realistic assessment tools are imperative for a better understanding of the impact of age-related cognitive deficits on functional status. With this in mind, we probed the ability of the EcoKitchen, a non-immersive virtual environment task with increasing executively demanding kitchen chores, to detect the effects of aging on the simulated everyday functioning of healthy adults. Fifty-three adults (age between 23 and 77 years) were assessed with the EcoKitchen and a set of conventional paper-and-pencil neuropsychological tests. The associations between the baseline features of study participants and each of the two different assessment methods were examined. The associations between the EcoKitchen variables and an executive composite score were also explored. Our results showed that older individuals present deficits in the performance of both the EcoKitchen task and standard assessment methods. Notably, we found that, unlike conventional tests, accuracy in the EcoKitchen task was not related to the education level and IQ score of participants. Moreover, the EcoKitchen performance time was significantly correlated with executive tests. We have demonstrated that the EcoKitchen task, an ecologically relevant computerized neuropsychological assessment tool, might be more suitable than classic paper-and-pencil tests to capture the impact of aging on everyday cognitive function, as it proved to be less prone to the influence of confounding factors. Additionally, we have shown that executive function plays an important role in the timely performance of cognitively challenging virtual environment tasks.

Stable isotope tracing reveals disturbed cellular energy and glutamate metabolism in hippocampal slices of aged male mice

Neurons and astrocytes work in close metabolic collaboration, linking neurotransmission to brain energy and neurotransmitter metabolism. Dysregulated energy metabolism is a hallmark of the aging brain and may underlie the progressive age-dependent cognitive decline. However, astrocyte and neurotransmitter metabolism remains understudied in aging brain research. In particular, how aging affects metabolism of glutamate, being the primary excitatory neurotransmitter, is still poorly understood. Here we investigated critical aspects of cellular energy metabolism in the aging male mouse hippocampus using stable isotope tracing in vitro. Metabolism of [U–13C]glucose demonstrated an elevated glycolytic capacity of aged hippocampal slices, whereas oxidative [U–13C]glucose metabolism in the TCA cycle was significantly reduced with aging. In addition, metabolism of [1,2–13C]acetate, reflecting astrocyte energy metabolism, was likewise reduced in the hippocampal slices of old mice. In contrast, uptake and subsequent metabolism of [U–13C]glutamate was elevated, suggesting increased capacity for cellular glutamate handling with aging. Finally, metabolism of [15N]glutamate was maintained in the aged slices, demonstrating sustained glutamate nitrogen metabolism. Collectively, this study reveals fundamental alterations in cellular energy and neurotransmitter metabolism in the aging brain, which may contribute to age-related hippocampal deficits.

Older Adults Catch Up to Younger Adults on Cognitive Tasks After Extended Training

Cognitive decline often accompanies natural aging, which results in younger adults outperforming older adults, on average, on cognitive tasks requiring skills such as attention, memory, or reasoning. This performance gap between age groups persists even after people train on these tasks, but it remains unclear whether the gap persists when individuals, rather than groups, are compared at different training levels. In this paper, we analyzed 9,923 users between 18-90 years old (63% over 60) who performed a variety of cognitive tasks on an online cognitive training platform. We quantified an older adult’s potential to catch up to, or perform as well as, a younger adult. We found that the probability of catching up to someone decades younger increases with differential amounts of training on a variety of cognitive tasks. These findings suggest that age-related performance deficits can be overcome with additional training.

Specific quinone reductase 2 inhibitors reduce metabolic burden and reverse Alzheimer's disease phenotype in mice.

Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer's disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constraint and metabolic buffer within neurons. QR2 becomes overexpressed with age, and it is possibly a novel contributing factor to age-related metabolic stress and cognitive deficit. We found that, in human cells, genetic removal of QR2 produced a shift in the proteome opposing that found in AD brains while simultaneously reducing oxidative stress. We therefore created highly specific QR2 inhibitors (QR2is) to enable evaluation of chronic QR2 inhibition as a means to reduce biological age-related metabolic stress and cognitive decline. QR2is replicated results obtained by genetic removal of QR2, while local QR2i microinjection improved hippocampal and cortical-dependent learning in rats and mice. Continuous consumption of QR2is in drinking water improved cognition and reduced pathology in the brains of AD-model mice (5xFAD), with a noticeable between-sex effect on treatment duration. These results demonstrate the importance of QR2 activity and pathway function in the healthy and neurodegenerative brain and what we believe to be the great therapeutic potential of QR2is as first-in-class drugs.

Olivocochlear efferent system degeneration and plasticity with aging and noise exposure

Contributions of the ascending peripheral and central auditory pathways to age-related and noise-induced hearing deficits have been well-characterized, but we know comparatively little about how the descending projections from the brain to the cochlea contribute to hearing deficits. Studies have shown dynamic structural and neurochemical changes in the olivocochlear system associated with acoustic experience and age, indicating that olivocochlear efferents cannot be considered a static system when attempting to reveal effects on hearing. I will summarize our efforts to understand how these pathways are involved in hearing dysfunction measured using physiological, behavioral, and anatomical assays in mouse models. Our work suggests that loss of olivocochlear efferent neurons is most detrimental to hearing in aged and aged, noise-exposed auditory systems which are already working with reduced afferent input to the brain. Furthermore, noise-induced changes in the lateral olivocochlear efferents appear to compensate for diminished medial olivocochlear activity—an effect that may explain the variable behavioral outcomes in hearing in noise studies involving the medial olivocochlear reflex in humans and animal models.

Global research trends of immunosenescence: A bibliometric study

BackgroundImmunosenescence, an age-related deficit in immunity, associated with multiple disorders and making the successful aging a challenge. Although nearly 4000 articles have been published, only few review articles have summarized the research status. In order to better understand the most recent advances, hotspots and development trends in immunosenescence, it is very necessary to conduct a comprehensive bibliometric analysis. Hence, commonly used bibliometric analysis software CiteSpace and VOSviewer were employed to conduct a quantitative analysis and critical evaluation of publications in this study. MethodsImmunosenescence publications were screened from the Web of Science Core Collection (WoSCC). Microsoft Excel 2021, CiteSpace 5.8.R3, and VOSviewer 1.6.17 were used for bibliometric study. ResultsA total of 3875 publications were retrieved from WoSCC. After screening by document type (article or review) (352 publications were excluded) and language of English (85 were excluded), 3438 studies were finally used for bibliometric analysis. The literature on immunosenescence had been continuously growing since 1991, and by 2020 it has skyrocketed 312 publications from 240 in 2019. USA (1111 publications, 35.01%) was the leading country of publications, followed by ITALY (379, 11.94%) and ENGLAND (366, 11.53%). Of the authors, Pawelec G from the Tubingen University of GERMANY contributed the greatest articles (93 publications). All the keywords could be divided into five clusters, and additional potent visualization bursts revealed that “gut microbiota,” “health,” “dysfunction,” and “nivolumab” were the active hotspots presently. ConclusionBased on the current data, we firstly concluded that there will be a dramatically rising publications on immunosenescence, and research teams from USA or GERMANY might be the best chooses for collaboration. Moreover, We particularly emphasized the development potential of mechanism and intervening strateges like “gut microbiota” and “nivolumab” in immunosenescence. We hope to provide new ideas for promoting the basic research and clinical application of immunosenescence.