Age-related Impairment Research Articles

Age-related alterations in meningeal immunity drive impaired CNS lymphatic drainage.

The meningeal lymphatic network enables the drainage of cerebrospinal fluid (CSF) and facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer's disease, impaired meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins in the CNS. Reversing this age-related dysfunction represents a promising strategy to augment CNS waste clearance; however, the mechanisms underlying this decline remain elusive. Here, we demonstrate that age-related alterations in meningeal immunity underlie this lymphatic impairment. Single-cell RNA sequencing of meningeal lymphatic endothelial cells from aged mice revealed their response to IFNγ, which was increased in the aged meninges due to T cell accumulation. Chronic elevation of meningeal IFNγ in young mice via AAV-mediated overexpression attenuated CSF drainage-comparable to the deficits observed in aged mice. Therapeutically, IFNγ neutralization alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable approach to normalize CSF drainage and alleviate the neurological deficits associated with impaired waste removal.

Antibiotic Misuse Behaviours of Older People: Confirmation of the Factor Structure of the Antibiotic Use Questionnaire.

Antibacterial resistance (AR) is responsible for steadily rising numbers of untreatable bacterial infections, most prevalently found in the older adult (OA) population due to age-related physical and cognitive deterioration, more frequent and long-lasting hospital visits, and reduced immunity. There are currently no established measures of antibiotic use behaviours for older adults, and theory-informed approaches to identifying the drivers of antibiotic use in older adults are lacking in the literature. The objective of this study was to identify predictors of antibiotic use and misuse in older adults using the Antibiotic Use Questionnaire (AUQ), a measure informed by the factors of the Theory of Planned Behaviour (TPB): attitudes and beliefs, social norms, perceived behavioural control, behaviour, and a covariate-knowledge. A measure of social desirability was included, and participants scoring highly were excluded to control for social desirability bias. Confirmatory Factor Analyses and regression analyses were conducted to test the hypotheses in a cross-sectional, anonymous survey. A total of 211 participants completed the survey, 47 of which were excluded due to incompletion and high social desirability scores (≥5). Results of the factor analysis confirmed that some (but not all) factors from previous research in the general population were confirmed in the OA sample. No factors were found to be significant predictors of antibiotic use behaviour. Several suggestions for the variance in results from that of the first study are suggested, including challenges with meeting requirement for statistical power. The paper concludes that further research is required to determine the validity of the AUQ in an older adult population.

Association of Loneliness With the Incidence of Disability in Older Adults With Hearing Impairment in Japan

Loneliness is suggested to negatively affect physical and mental health and influence the development of disability; however, a consensus on the relationship between loneliness and disability has not been reached. Age-related hearing impairment worsens the daily-life activities of older adults, and the association between loneliness and the incidence of disability may be influenced by hearing impairment. To examine the association between loneliness and the incidence of disability among older adults stratified by hearing impairment. This prospective observational cohort study included 5563 community-dwelling adults 65 years or older who participated in functional health examinations in Tokai City, Aichi Prefecture, Japan, between September 2017 and June 2018. Data analysis was conducted from August 2022 to February 2023. Cox proportional hazards regression models were used to examine the association between loneliness and the incidence of disability stratified by hearing impairment. Among the 4739 participants who met the inclusion criteria (mean [SD] age, 73.8 [5.5] years; 2622 [55.3%] female), 3792 (80.0%) were without hearing impairment and 947 (20.0%) were with hearing impairment. Of those who reported experiencing loneliness, 1215 (32.0%) were without hearing impairment, and 441 (46.6%) were with hearing impairment. After 2 years, the number of individuals with disabilities was 172 (4.5%) without hearing impairment and 79 (8.3%) with hearing impairment. Cox proportional hazards regression analysis showed no statistically significant association between loneliness and the incidence of disability in a model adjusted for potential confounding factors among community-dwelling older adults without hearing impairment (hazard ratio, 1.10; 95% CI, 0.80-1.52). Among community-dwelling older adults with hearing impairment, a model adjusted for potential confounding factors showed a statistically significant association between loneliness and the incidence of disability (hazard ratio, 1.71; 95% CI, 1.04-2.81). This cohort study found that the association between loneliness and the incidence of disability was moderated by the presence or absence of hearing impairment. Hearing impairment is the most common symptom of geriatric syndromes, showing that among the various risk factors, loneliness may require special attention in the prevention of disability in people with hearing impairment.

Evidence for the role of affective theory of mind in face-name associative memory

ABSTRACT Poor face-name recall has been associated with age-related impairments in cognitive functioning, namely declines in episodic memory and executive control. However, the role of social cognitive function – the ability to remember, process, and store information about others – has been largely overlooked in this work. Extensive work has shown that social and nonsocial cognitive processes rely on unique, albeit overlapping, mechanisms. In the current study, we explored whether social cognitive functioning – specifically the ability to infer other people’s mental states (i.e., theory of mind) – facilitates better face-name learning. To do this, a sample of 289 older and young adults completed a face-name learning paradigm along with standard assessments of episodic memory and executive control alongside two theory of mind measures, one static and one dynamic. In addition to expected age differences, several key effects emerged. Age-related differences in recognition were explained by episodic memory, not social cognition. However, age effects in recall were explained by both episodic memory and social cognition, specifically affective theory of mind in the dynamic task. Altogether, we contend that face-name recall can be supported by social cognitive functioning, namely understanding emotions. While acknowledging the influence of task characteristics (i.e., lures, target ages), we interpret these findings in light of existing accounts of age differences in face-name associative memory.

Feasibility and Efficacy of the Cogmed Working Memory Training in Forensic Mental Health Inpatients With Schizophrenia Spectrum Disorders: A Pilot Study

Introduction Schizophrenia spectrum disorders are characterised by notable deficits in executive function, working memory, attention and social cognition. Previous studies in cognitive remediation therapies, of various dose and duration, have shown behavioural and neurobiological improvements. The current pilot study will be the first to test the Cogmed Working Memory Training (CWMT) program in schizophrenia spectrum disorder. Methods This pilot study was conducted using purposive sampling of consumers with schizophrenia spectrum disorders from a forensic mental health inpatient unit in Australia was used. Eleven participants completed 30 sessions of CWMT over a 2-month period. One participant completed 28 sessions. The primary outcome measure was the CogState Schizophrenia Battery (CSB). Secondary measures included the Brock Adaptive Functioning Questionnaire (BAFQ) and the Allen Cognitive Level Screen (ACLS). Measures were taken before and after the intervention, and at 6-months follow-up to detect maintenance of improvements. Results Significant improvements were seen in social cognition and emotionality. Trends toward improvement in executive function and working memory were observed in younger participants, but were not significant. Conclusion Findings indicate that the CWMT may be a beneficial tool for improving social cognition in patients with schizophrenia. CWMT interventions of longer than 2 months may be required to see measurable improvements in other cognitive functions. Age-related cognitive impairment should be controlled for in future studies. Larger studies should be conducted to confirm these findings.

Cohort profile: Netherlands Longitudinal Study on Hearing (NL-SH)

PurposeThe Netherlands Longitudinal Study on Hearing (NL-SH) was set up to examine associations of hearing ability with psychosocial, work and health outcomes in working age adults.ParticipantsInclusion started in 2006 and...

Aging reduces calreticulin expression and alters spontaneous calcium signals in astrocytic endfeet of the mouse dorsolateral striatum

Aging-related impairment of the blood brain barrier (BBB) and neurovascular unit (NVU) increases the risk for neurodegeneration. Among various cells that participate in BBB and NVU function, calcium signals in astrocytic endfeet are crucial for maintaining BBB and NVU integrity. To assess if aging is associated with altered calcium signals within astrocytic endfeet of the dorsolateral striatum (DLS), we expressed GCaMP6f in DLS astrocytes of young (3–4 months), middle-aged (12–15 months) and aging (20–30 months) mice. Compared to endfeet in young mice, DLS endfeet in aging mice demonstrated decreased calreticulin expression, and alterations to both spontaneous membrane-associated and mitochondrial calcium signals. While young mice required both extracellular and endoplasmic reticulum calcium sources for endfoot signals, middle-aged and aging mice showed heavy dependence on endoplasmic reticulum calcium. Thus, astrocytic endfeet show significant changes in calcium buffering and sources throughout the lifespan, which is important for understanding mechanisms by which aging impairs the BBB and NVU.

Just write it down: Similarity in the benefit from cognitive offloading in young and older adults.

Past research conducted primarily in young adults has demonstrated the utility of cognitive offloading for benefitting performance of memory-based tasks, particularly at high memory loads. At the same time, older adults show declines in a variety of memory abilities, including subtle changes in short-term memory, suggesting that cognitive offloading could also benefit performance of memory-based tasks in this group. To this end, 94 participants (62 young adults, 32 older adults) were tested on a retrospective audiovisual short-term memory task in two blocked conditions. Offloading was permitted in the offloading choice condition but not in the internal memory condition. Performance was improved for both age groups in the offloading choice condition compared to the internal memory condition. Moreover, the choice to use the offloading strategy was similar across age groups at high memory loads, and use of the offloading strategy benefitted performance for young and older adults similarly. These data suggest that older adults can make effective use of cognitive offloading to rescue performance of memory-based activities, and invites future research on the benefits of cognitive offloading for older adults in other, more complex tasks where age-related memory impairment is expected to be more prominent.

Sesamin Metabolites Suppress the Induction of Cellular Senescence

Cellular senescence induces inflammation and is now considered one of the causes of organismal aging. Accumulating evidence indicates that age-related deterioration of mitochondrial function leads to an increase in reactive oxygen species (ROS) and DNA damage, which in turn causes cellular senescence. Thus, it is important to maintain mitochondrial function and suppress oxidative stress in order to inhibit the accumulation of senescent cells. Sesamin and its isomer episesamin are types of lignans found in sesame oil, and after being metabolized in the liver, their metabolites have been reported to exhibit antioxidant properties. However, their effects on cellular senescence remain unknown. In this study, the effects of sesamin, episesamin, and their metabolites SC1 and EC1-2 on replicative senescence were evaluated using human diploid lung fibroblasts, and TIG-3 cells. The results showed that sesamin and episesamin treatment had no effect on proliferative capacity compared to the untreated late passage group, whereas SC1 and EC1-2 treatment improved proliferative capacity and mitigated DNA damage of TIG-3 cells. Furthermore, other cellular senescence markers, such as senescence-associated secretory phenotype (SASP), mitochondria-derived ROS, and mitochondrial function (ROS/ATP ratio) were also reduced by SC1 and EC1-2 treatment. These results suggest that SC1 and EC1-2 can maintain proper mitochondrial function and suppress the induction of cellular senescence.

Cognitive heterogeneity reveals molecular signatures of age-related impairment.

The greatest risk factor for cognitive decline is aging. The biological mechanisms for this decline remain enigmatic due, in part, to the confounding of normal aging mechanisms and those that contribute to cognitive impairment. Importantly, many individuals exhibit impaired cognition in age, while some retain functionality despite their age. Here, we establish a behavioral testing paradigm to characterize age-related cognitive heterogeneity in inbred aged C57BL/6 mice and reliably separate animals into cognitively "intact" (resilient) and "impaired" subgroups using a high-resolution home-cage testing paradigm for spatial discrimination. RNA sequencing and subsequent pathway analyses of cognitively stratified mice revealed molecular signatures unique to cognitively impaired animals, including transcriptional down-regulation of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) and sirtuin (Sirt1 and Sirt3) expression in the hippocampus. Mitochondrial function assessed using high-resolution respirometry indicated a reduced OXPHOS coupling efficiency in cognitively impaired animals with subsequent hippocampal analyses revealing an increase in the oxidative damage marker (3-nitrotyrosine) and an up-regulation of antioxidant enzymes (Sod2, Sod1, Prdx6, etc.). Aged-impaired animals also showed increased levels of IL-6 and TNF-α gene expression in the hippocampus and increased serum levels of proinflammatory cytokines, including IL-6. These results provide critical insight into the diversity of brain aging in inbred animals and reveal the unique mechanisms that separate cognitive resilience from cognitive impairment. Our data indicate the importance of cognitive stratification of aging animals to delineate the mechanisms underlying cognitive impairment and test the efficacy of therapeutic interventions.

Even periconceptional alcohol consumption can have long-term consequences on heart health in the offspring.

Even periconceptional alcohol consumption can have long-term consequences on heart health in the offspring.

Associative memory is more strongly predicted by age-related differences in the prefrontal cortex than medial temporal lobes

It is well established that episodic memory declines with age and one of the primary explanations for this decline is an age-related impairment in the ability to form new associations. At a neural level, both the medial temporal lobe (MTL) and lateral prefrontal cortex (PFC) are thought to be critical for associative memory, and grey matter volume loss in these regions has been associated with age-related declines in episodic memory. While some recent work has compared the relative contributions of grey matter volume in MTL and PFC regions to item and associative memory, studies investigating the unique and shared contributions of age-related differences in the MTL and PFC to memory differences are still rare. In this study, we use a lifespan approach to examine the relationship between grey matter volume within substructures of the MTL and PFC on the one hand and item and associative memory on the other. To this end, we used data from over 300 healthy individuals uniformly spread across the adult lifespan from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) and tested the multivariate relationship between grey matter volumes and item/associative memory scores using canonical correlation analysis. We show that structures of the PFC alone predict memory performance better than either structures of the MTL alone or PFC and MTL combined. Moreover, our results also indicate that grey matter volume in the inferior frontal gyrus - pars opercularis, superior frontal gyrus, and middle frontal gyrus relates most strongly to memory (particularly associative memory, which loaded higher than item memory) and this effect persists when controlling for age and education. Finally, we also show that the relationship between frontal grey matter volume and memory is not moderated by age or sex. Taken together, these findings emphasize the critical role of the frontal lobes, and the control processes they subserve, in determining the effects of age on associative memory.

The role of endothelial TRP channels in age-related vascular cognitive impairment and dementia.

Transient receptor potential (TRP) proteins are part of a superfamily of polymodal cation channels that can be activated by mechanical, physical, and chemical stimuli. In the vascular endothelium, TRP channels regulate two fundamental parameters: the membrane potential and the intracellular Ca2+ concentration [(Ca2+)i]. TRP channels are widely expressed in the cerebrovascular endothelium, and are emerging as important mediators of several brain microvascular functions (e.g., neurovascular coupling, endothelial function, and blood-brain barrier permeability), which become impaired with aging. Aging is the most significant risk factor for vascular cognitive impairment (VCI), and the number of individuals affected by VCI is expected to exponentially increase in the coming decades. Yet, there are currently no preventative or therapeutic treatments available against the development and progression of VCI. In this review, we discuss the involvement of endothelial TRP channels in diverse physiological processes in the brain as well as in the pathogenesis of age-related VCI to explore future potential neuroprotective strategies.

Visually Driven Behavior Assays to Study Functionality and Recovery after Damage of the Aged African Turquoise Killifish Visual System.

Loss of vision is a prominent feature of aging and vision is considered by many to be the most valuable sense to be lost. In our graying society, we are increasingly challenged by age-related deterioration of the central nervous system (CNS), as well as by age-associated neurodegenerative diseases and brain injuries, all often affecting the visual system and thus its performance. Here, we describe two visually driven behavior assays to evaluate visual performance upon aging or CNS damage in the fast-aging killifish. The first test, the optokinetic response (OKR), measures the reflexive eye movement triggered by motion in the visual field and allows assessment of visual acuity. The second assay, the dorsal light reflex (DLR), evaluates the swimming angle based on input of light coming from above. The OKR can be used to study the effect of aging on visual acuity as well as visual improvement and recovery after rejuvenation therapy or visual system injury or disease, whereas the DLR is best used to assess functional repair after a unilateral optic nerve crush.

Breathlessness in older adults: What we know and what we still need to know.

Breathlessness is common among older adults, but it is often hidden as "normal aging "or considered narrowly as a symptom of cardio-respiratory diseases. Studies on breathlessness in older adults are mostly focused on specific diseases, whereas older adults are characterized by multimorbidity and multi-system age-related impairments. This article aims to provide an overview of what is known so far on breathlessness in the general population of older adults and identify areas for further research. Research shows that breathlessness in older adults is a multifactorial geriatric condition, crossing the borders of system-based impairments and diseases, and a valuable independent prognostic indicator for adverse outcomes. Further research needs to investigate (1) the multi-factorial mechanisms of breathlessness in community-dwelling older adults including the role of respiratory sarcopenia; (2) the influence of affective and cognitive changes of older age on the perception and report of breathlessness; (3) the best way to assess and use breathlessness for risk prediction of adverse outcomes in general geriatric assessments; and (4) the most appropriate multi-modal rehabilitation interventions and their outcomes. Clinicians need to shift their approach to dyspnea from a disease symptom to a multifactorial geriatric condition that should be proactively searched for, as it identifies higher risk for adverse outcomes, and can be addressed with evidence-based interventions that can improve the quality of life and may reduce the risk of adverse outcomes in older adults.

Reduced Autophagy in Aged Trigeminal Neurons Causes Amyloid β Diffusion

The relationship between oral health and the development of Alzheimer’s disease (AD) in the elderly is not yet well understood. In this regard, the association between aging or neurodegeneration of the trigeminal nervous system and the accumulation of amyloid-β(1–42) (Aβ42) oligomers in the pathogenesis of AD is unknown. We focused on selective autophagy in the trigeminal mesencephalic nucleus (Vmes) and the diffusion of Aβ42 oligomers with respect to aging of the trigeminal nervous system and whether the degeneration of Vmes neurons affects the diffusion of Aβ42 oligomers. We used female 2- to 8-mo-old transgenic 3xTg-AD mice and App NL-G-F knock-in mice and immunohistochemically examined aging-related changes in selective autophagy and Aβ42 oligomer processing in the Vmes, which exhibits high amyloid-β (Aβ) expression. We induced degeneration of Vmes neurons by extracting the maxillary molars and examined the changes in Aβ42 oligomer kinetics. Autophagosome-like membranes, which stained positive for Aβ, HO-1, and LC3B, were observed in Vmes neurons of 3xTg-AD mice, while there was weak immunoreactivity of the membranes for intraneuronal Aβ in App NL-G-F mice. By contrast, there was strong immunopositivity for extracellular Aβ42 oligomers with the formation of Aβ42 oligomer clusters in App NL-G-F mice. The expression of Rubicon, which indicates age-related deterioration of autophagy, increased the diffusion of Aβ42 oligomer with the age of Vmes neurons. Tooth extraction increased the extracellular immunopositivity for Aβ42 oligomers in App NL-G-F mice. These results suggest that autophagy maintains homeostasis in Vmes neurons and that deterioration of autophagy due to aging or neurodegeneration leads to the diffusion of Aβ42 oligomers into the extracellular space and possibly the development of AD.

Aging attenuated theta response during multistable perception.

Multistable stimuli are physically unchanging, but elicit spontaneous perceptual reversals between multiple internally generated perceptual alternatives. Perceptual reversal rates seem to decrease in older adults; however, there is no literature on the electrophysiological correlates of this performance decrease. Here, we aimed to identify age-related changes in theta activity that relate to decreased reversal rates of older adults. Electroencephalography (EEG) of young (n=15) and older adults (n=15) was recorded during presentation of stroboscopic alternative motion (SAM) and a control stimulus. Time-frequency amplitudes were extracted in 4-8Hz via Morlet wavelet convolution. Older adults had lower SAM reversals as well as decreased accuracy, increased reaction time (RT) and increased RT variability in the control task. In older adults, reversal-related frontal theta response was diminished, yet parietal theta was intact. In the parietal area, the relationship between theta response and reversal rates was robust, but in the frontal area, was dependent on age-related variance. Result indicated that, in older adults, top-down facilitation of perceptual reversals was impaired. This appears to result in a predominantly bottom-up resolution of perceptual multistability. Age-related degradation of sensory areas in this bottom-up-driven resolution process might have slowed reversals. This study presents the first electrophysiological correlates of age-related impairment in multistable perceptual integration.

Aging-Related Ovarian Failure and Infertility: Melatonin to the Rescue

Aging has a major detrimental effect on the optimal function of the ovary with changes in this organ preceding the age-related deterioration in other tissues, with the middle-aged shutdown leading to infertility. Reduced fertility and consequent inability to conceive by women in present-day societies who choose to have children later in life leads to increased frustration. Melatonin is known to have anti-aging properties related to its antioxidant and anti-inflammatory actions. Its higher follicular fluid levels relative to blood concentrations and its likely synthesis in the oocyte, granulosa, and luteal cells suggest that it is optimally positioned to interfere with age-associated deterioration of the ovary. Additionally, the end of the female reproductive span coincides with a significant reduction in endogenous melatonin levels. Thus, the aims are to review the literature indicating melatonin production in mitochondria of oocytes, granulosa cells, and luteal cells, identify the multiple processes underlying changes in the ovary, especially late in the cessation of the reproductive life span, summarize the physiological and molecular actions of melatonin in the maintenance of normal ovaries and in the aging ovaries, and integrate the acquired information into an explanation for considering melatonin in the treatment of age-related infertility. Use of supplemental melatonin may help preserve fertility later in life and alleviate frustration in women delaying childbearing age, reduce the necessity of in vitro fertilization-embryo transfer (IVF-ET) procedures, and help solve the progressively increasing problem of non-aging-related infertility in women throughout their reproductive life span. While additional research is needed to fully understand the effects of melatonin supplementation on potentially enhancing fertility, studies published to date suggest it may be a promising option for those struggling with infertility.

Physical fitness, cognition, and structural network efficiency of brain connections across the lifespan

Inadequate levels of exercise is one of the most potent modifiable risk factors for preventing cognitive decline and dementia as we age. Meanwhile, network science-based measures of structural brain network global and local efficiency show promise as robust biomarkers of aging, cognitive decline, and pathological disease progression. Despite this, little to no work has established how maintaining physical activity (PA) and physical fitness might relate to cognition and network efficiency measures across the lifespan. Therefore the purpose of this study was to determine the relationship between (1) PA and fitness and cognition, (2) fitness and network efficiency, and (3) how network efficiency measures relate to cognition. To accomplish this, we analyzed a large cross-sectional data set (n = 720; 36–100 years) from the aging human connectome project, which included the Trail Making Task (TMT) A and B, a measure of fitness (2-min walk test), physical activity (International Physical Activity Questionnaire), and high-resolution diffusion imaging data. Our analysis consisted of employing multiple linear regression while controlling for age, sex, and education. Age was associated with lower global and local brain network efficiency and poorer Trail A & B performance. Meanwhile, fitness, but not physical activity, was related to better Trail A and B performance and fitness, and was positively associated with local and global brain efficiency. Finally, local efficiency was related to better TMT B performance and partially mediated the relationship between fitness and TMT B performance. These results indicate aging may be associated with a shift towards less efficient local and global neural networks and that maintaining physical fitness might protect against age-related cognitive performance deterioration by bolstering structural network efficiency.

Proceedings of the Post-Genome Analysis for Musculoskeletal Biology Workshop.

Herein, we report on the proceedings of the workshop entitled "Post-Genome analysis for musculoskeletal biology" that was held in July of 2022 in Safed, Galilee, Israel. Supported by the Israel Science Foundation, the goal of this workshop was to bring together established investigators and their trainees who were interested in understanding the etiology of musculoskeletal disease, from Israel and from around the world. Presentations at this workshop spanned the spectrum from basic science to clinical studies. A major emphasis of the discussion centered on genetic studies in humans, and the limitations and advantages of such studies. The power of coupling studies using human data with functional follow-up studies in pre-clinical models such as mice, rats, and zebrafish was discussed in depth. The advantages and limitations of mice and zebrafish for faithfully modelling aspects of human disease were debated, specifically in the context of age-related diseases such as osteoporosis, osteoarthritis, adult-onset auto-immune disease, and osteosarcopenia. There remain significant gaps in our understanding of the nature and etiology of human musculoskeletal disease. While therapies and medications exist, much work is still needed to find safe and effective interventions for all patients suffering from diseases associated with age-related deterioration of musculoskeletal tissues. The potential of forward and reverse genetic studies has not been exhausted for diseases of muscles, joints, and bones.