Age-related Impairment Research Articles

Genome-wide association study for age-related hearing loss in CFW mice.

Age-related hearing impairment is the most common cause of hearing loss and is one of the most prevalent conditions affecting the elderly globally. It is influenced by a combination of environmental and genetic factors. The mouse and human inner ears are functionally and genetically homologous. Investigating the genetic basis of age-related hearing loss (ARHL) in an outbred mouse model may lead to a better understanding of the molecular mechanisms of this condition. We used Carworth Farms White (CFW) outbred mice, because they are genetically diverse and exhibit variation in the onset and severity of ARHL. The goal of this study was to identify genetic loci involved in regulating ARHL. Hearing at a range of frequencies was measured using Auditory Brainstem Response (ABR) thresholds in 946 male and female CFW mice at the age of 1, 6, and 10 months. We obtained genotypes at 4.18 million single nucleotide polymorphisms (SNP) using low-coverage (mean coverage 0.27x) whole-genome sequencing followed by imputation using STITCH. To determine the accuracy of the genotypes we sequenced 8 samples at >30x coverage and used calls from those samples to estimate the discordance rate, which was 0.45%. We performed genetic analysis for the ABR thresholds for each frequency at each age, and for the time of onset of deafness for each frequency. The SNP heritability ranged from 0 to 42% for different traits. Genome-wide association analysis identified several regions associated with ARHL that contained potential candidate genes, including Dnah11, Rapgef5, Cpne4, Prkag2, and Nek11. We confirmed, using functional study, that Prkag2 deficiency causes age-related hearing loss at high frequency in mice; this makes Prkag2 a candidate gene for further studies. This work helps to identify genetic risk factors for ARHL and to define novel therapeutic targets for the treatment and prevention of ARHL.

Pretraining alpha rhythm enhancement by neurofeedback facilitates short-term perceptual learning and improves visual acuity by facilitated consolidation.

Learning through perceptual training using the Gabor patch (GP) has attracted attention as a new vision restoration technique for myopia and age-related deterioration of visual acuity (VA). However, the task itself is monotonous and painful and requires numerous training sessions and some time before being effective, which has been a challenge for its widespread application. One effective means of facilitating perceptual learning is the empowerment of EEG alpha rhythm in the sensory cortex before neurofeedback (NF) training; however, there is a lack of evidence for VA. We investigated whether four 30-min sessions of GP training, conducted over 2 weeks with/without EEG NF to increase alpha power (NF and control group, respectively), can improve vision in myopic subjects. Contrast sensitivity (CS) and VA were measured before and after each GP training. The NF group showed an improvement in CS at the fourth training session, not observed in the control group. In addition, VA improved only in the NF group at the third and fourth training sessions, this appears as a consolidation effect (maintenance of the previous training effect). Participants who produced stronger alpha power during the third training session showed greater VA recovery during the fourth training session. These results indicate that enhanced pretraining alpha empowerment strengthens the subsequent consolidation of perceptual learning and that even a short period of GP training can have a positive effect on VA recovery. This simple protocol may facilitate use of a training method to easily recover vision.

Clinical characteristics and otolith dysfunction in presbyvestibulopathy: A retrospective cross-sectional analysis

ObjectiveThe Bárány Society recently established diagnostic criteria for presbyvestibulopathy, an age-related bilateral vestibular impairments in older individuals. Drawing upon a cross-sectional database, this study delves into the demographic and clinical features of presbyvestibulopathy patients and investigates the implications of otolith dysfunction. MethodsThe study retrospectively analyzed 1218 patients aged 60 years or older who visited the tertiary dizziness clinic in 2020, due to symptoms of dizziness or instability. By reviewing medical records, we gathered clinical information and laboratory vestibular test results, such as cervical and ocular vestibular evoked myogenic potentials, and subjective visual vertical. ResultsOut of 1218 patients aged 60 and above who reported dizziness or unsteadiness, 33 patients (2.7 %, with an average age of 74.2 ± 9.2 years) were diagnosed with presbyvestibulopathy. Deficiencies in horizontal angular vestibulo-ocular reflex were found in caloric tests (75 %), video head impulse tests (51.7 %), and rotatory chair tests (47.8 %), respectively. Otolith dysfunction was also observed, as shown by abnormal ocular and cervical vestibular evoked myogenic potentials in 62.96 % and 51.85 % of patients, and abnormal subjective visual vertical in 45.8 % of the cases. ConclusionsAmong elderly patients experiencing consistent dizziness or instability, the incidence of presbyvestibulopathy was approximately 2.7 % over one year. Alongside the abnormalities detected in the horizontal angular vestibulo-ocular reflex, significant changes were also noted in the ocular and cervical vestibular evoked myogenic potentials, as well as in the subjective visual vertical tests. As a result, it's vital to underscore the significance of both otolithic function and vestibulo-ocular reflex in the fundamental mechanisms of presbyvestibulopathy.

Mendelian randomization reveals the causal association between gout and hearing impairment in older adults.

With the global aging trend escalating, the holistic well-being of the elderly has become a paramount concern within public health. Traditional observational studies often struggle with confounding factors and establishing causality, leaving the relationship between age-related hearing loss (ARHL) and gout largely unexplored. Employing bidirectional two-sample Mendelian randomization (MR) analysis, this investigation elucidated the genetic underpinnings associated with age-related hearing impairment, gout, and urate levels within the IEU Open-GWAS database, thereby uncovering potential causal connections that underlie the intricate interplay between gout, serum urate concentrations, and auditory decline in the geriatric demographic. In the forward MR phase, a cohort of 30 single nucleotide polymorphisms was leveraged to dissect the causal dynamics between ARHL and both gout and urate concentrations. Conversely, in the reverse MR phase, gout and urate levels were posited as the exposome to delineate their impact on hearing acuity, employing an array of models for rigorous validation and sensitivity scrutiny. In the forward MR analysis, a statistically significant correlation was discerned between ARHL and gout (P = .003, odds ratio = 1.01, 95% confidence interval: 1.00-1.02), alongside a notable association with serum urate levels (P = .031, odds ratio = 1.39, 95% confidence interval: 1.03-1.88), intimating that ARHL could potentially influence the incidence of gout and urate concentrations. Conversely, the reverse MR investigation revealed that neither gout nor serum urate levels exerted significant impact on auditory degradation (P > .05), insinuating that these factors might not predominantly contribute to hearing loss. Sensitivity analyses concurred with this inference. This study enriches the comprehension of geriatric health intricacies and unveils that ARHL potentially influences gout and serum urate concentrations. This suggests that monitoring ARHL may play a crucial role in the early identification and management of gout and hyperuricemia, potentially contributing to a comprehensive approach to improving geriatric health outcomes.

Hypotension with neurovascular changes and cognitive dysfunction: An epidemiological, pathobiological, and treatment review.

Hypotension is a leading cause of age-related cognitive impairment. The available literature evidences that vascular factors are associated with dementia and that hypotension alters cerebral perfusion flow and can aggravate the neurodegeneration of Alzheimer's disease (AD). Despite the discovery of biomarkers and the recent progress made in neurovascular biology, epidemiology, and brain imaging, some key issues remain largely unresolved: the potential mechanisms underlying the neural deterioration observed in AD, the effect of cerebrovascular alterations on cognitive deficits, and the positive effects of hypotension treatment on cognition. Therefore, further well-designed studies are needed to unravel the potential association between hypotension and cognitive dysfunction and reveal the potential benefits of hypotension treatment for AD patients. Here, we review the current epidemiological, pathobiological, and treatment-related literature on neurovascular changes and hypotension-related cognitive dysfunction and highlight the unsettled but imminent issues that warrant future research endeavors.

SVHRSP Alleviates Age-Related Cognitive Deficiency by Reducing Oxidative Stress and Neuroinflammation.

Our previous studies have shown that scorpion venom heat-resistant synthesized peptide (SVHRSP) induces a significant extension in lifespan and improvements in age-related physiological functions in worms. However, the mechanism underlying the potential anti-aging effects of SVHRSP in mammals remains elusive. Following SVHRSP treatment in senescence-accelerated mouse resistant 1 (SAMR1) or senescence-accelerated mouse prone 8 (SAMP8) mice, behavioral tests were conducted and brain tissues were collected for morphological analysis, electrophysiology experiments, flow cytometry, and protein or gene expression. The human neuroblastoma cell line (SH-SY5Y) was subjected to H2O2 treatment in cell experiments, aiming to establish a cytotoxic model that mimics cellular senescence. This model was utilized to investigate the regulatory mechanisms underlying oxidative stress and neuroinflammation associated with age-related cognitive impairment mediated by SVHRSP. SVHRSP significantly ameliorated age-related cognitive decline, enhanced long-term potentiation, restored synaptic loss, and upregulated the expression of synaptic proteins, therefore indicating an improvement in synaptic plasticity. Moreover, SVHRSP demonstrated a decline in senescent markers, including SA-β-gal enzyme activity, P16, P21, SIRT1, and cell cycle arrest. The underlying mechanisms involve an upregulation of antioxidant enzyme activity and a reduction in oxidative stress-induced damage. Furthermore, SVHRSP regulated the nucleoplasmic distribution of NRF2 through the SIRT1-P53 pathway. Further investigation indicated a reduction in the expression of proinflammatory factors in the brain after SVHRSP treatment. SVHRSP attenuated neuroinflammation by regulating the NF-κB nucleoplasmic distribution and inhibiting microglial and astrocytic activation through the SIRT1-NF-κB pathway. Additionally, SVHRSP significantly augmented Nissl body count while suppressing neuronal loss. SVHRSP could remarkably improve cognitive deficiency by inhibiting oxidative stress and neuroinflammation, thus representing an effective strategy to improve brain health.

Relationship between Social Participation and Cognitive Impairment in Low-Educated Older Adults Based on Indonesian Family Life Survey-5.

The increasing older adult population requires attention in terms of education and health, as higher education levels contribute to cognitive reserve and may protect against age-related cognitive impairment. Cognitive reserve is an individual's cognitive flexibility in using cognitive functions affected by brain aging, neurological diseases, and injury. Indonesia has a high prevalence of low-educated older adults, which strongly correlates with progressive cognitive impairment. Identifying risk factors for cognitive decline in this population is crucial. This study determines the factors affecting cognitive impairment in low-educated older adults using cross-sectional data from the Indonesian Family Life Survey-5. This descriptive study analyzed 2,313 low-educated older adults ≥60 years old. Univariate and bivariate analyses were used to describe the sample and identify the relationships between categorical variables. Logistic regression identified the most significant factor affecting cognitive impairment. The prevalence of cognitive impairment in low-educated older adults is 22.6%. The chi-square test revealed significant relationships between those who are aged 75 years, a status other than married, female, living in rural areas, and not participating in social activities. Age is the most prominent factor affecting cognitive impairment in such adults (P<0.001; adjusted odds ratio, 3.232; 95% confidence interval, 2.500-4.180). Cognitive impairment in the aforementioned adults is associated with being ≥75 years old, being a status other than married, being female, living in rural areas, and not participating in social activities. After controlling other variables, low-educated older adults who participated in at least ≥1 social activity in the last 12 months experienced cognitive impairment 0.64 times compared to those who did not participate in social activities.

Addressing class-imbalanced learning in real-time aero-engine gas-path fault diagnosis via feature filtering and mapping

Condition-based maintenance of aero-engines requires real-time gas-path fault diagnosis, which is crucial for reducing costs and enhancing aircraft attendance. It is imperative to ensure a low false alarm rate in fault diagnosis algorithms. Inherent variations between engines and age-related performance deterioration can lead to an increase in false alarms, necessitating online algorithm tuning. However, insufficient fault data in online tuning may lead to class imbalance and algorithmic forgetfulness of fault features, compromising effectiveness. To tackle this issue, this paper introduces a novel hybrid diagnosis algorithm that utilizes feature filtering and mapping. This method entails an engine model, a feature extractor, a feature filter, a fault classifier, and several feature mappers. The feature mappers are designed to generate fault features based on the incoming fault free data for rebalancing the tuning dataset. And the feature filter is introduced to prevent weight collapse during the online tuning. Validation through a 400-hour life cycle simulation test and a real data test indicate that the method outperforms the benchmark methods. It overcomes the class-imbalanced learning problem, showcasing its potential for aero-engine gas-path fault diagnosis.

Fucoidan Improves D-Galactose-Induced Cognitive Dysfunction by Promoting Mitochondrial Biogenesis and Maintaining Gut Microbiome Homeostasis.

Recent studies have indicated that fucoidan has the potential to improve cognitive impairment. The objective of this study was to demonstrate the protective effect and possible mechanisms of fucoidan in D-galactose (D-gal)-induced cognitive dysfunction. Sprague Dawley rats were injected with D-galactose (200 mg/kg, sc) and administrated with fucoidan (100 mg/kg or 200 mg/kg, ig) for 8 weeks. Our results suggested that fucoidan significantly ameliorated cognitive impairment in D-gal-exposed rats and reversed histopathological changes in the hippocampus. Fucoidan reduced D-gal-induced oxidative stress, declined the inflammation level and improved mitochondrial dysfunction in hippocampal. Fucoidan promoted mitochondrial biogenesis by regulating the PGC-1α/NRF1/TFAM pathway, thereby improving D-gal-induced mitochondrial dysfunction. The regulation effect of fucoidan on PGC-1α is linked to the upstream protein of APN/AMPK/SIRT1. Additionally, the neuroprotective action of fucoidan could be related to maintaining intestinal flora homeostasis with up-regulation of Bacteroidota, Muribaculaceae and Akkermansia and down-regulation of Firmicutes. In summary, fucoidan may be a natural, promising candidate active ingredient for age-related cognitive impairment interventions.

Osteosarcopenia and Mortality in Older Adults Undergoing Transcatheter Aortic Valve Replacement

Osteosarcopenia is an emerging geriatric syndrome characterized by age-related deterioration in muscle and bone. Despite the established relevance of frailty and sarcopenia among older adults undergoing transcatheter aortic valve replacement (TAVR), osteosarcopenia has yet to be investigated in this setting. To determine the association between osteosarcopenia and adverse outcomes following TAVR. This is a post hoc analysis of the Frailty in Aortic Valve Replacement (FRAILTY-AVR) prospective multicenter cohort study and McGill extension that enrolled patients aged 70 years or older undergoing TAVR from 2012 through 2022. FRAILTY-AVR was conducted at 14 centers in Canada, the United States, and France between 2012 and 2016, and patients at the McGill University-affiliated center in Montreal, Québec, Canada, were enrolled on an ongoing basis up to 2022. Osteosarcopenia as measured on computed tomography (CT) scans prior to TAVR. Clinically indicated CT scans acquired prior to TAVR were analyzed to quantify psoas muscle area (PMA) and vertebral bone density (VBD). Osteosarcopenia was defined as a combination of low PMA and low VBD according to published cutoffs. The primary outcome was 1-year all-cause mortality. Secondary outcomes were 30-day mortality, hospital length of stay, disposition, and worsening disability. Multivariable logistic regression was used to adjust for potential confounders. Of the 605 patients (271 [45%] female) in this study, 437 (72%) were octogenarian; the mean (SD) age was 82.6 (6.2) years. Mean (SD) PMA was 22.1 (4.5) cm2 in men and 15.4 (3.5) cm2 in women. Mean (SD) VBD was 104.8 (35.5) Hounsfield units (HU) in men and 98.8 (34.1) HU in women. Ninety-one patients (15%) met the criteria for osteosarcopenia and had higher rates of frailty, fractures, and malnutrition at baseline. One-year mortality was highest in patients with osteosarcopenia (29 patients [32%]) followed by those with low PMA alone (18 patients [14%]), low VBD alone (16 patients [11%]), and normal bone and muscle status (21 patients [9%]) (P < .001). Osteosarcopenia, but not low VBD or PMA alone, was independently associated with 1-year mortality (odds ratio [OR], 3.18; 95% CI, 1.54-6.57) and 1-year worsening disability (OR, 2.11; 95% CI, 1.19-3.74). The association persisted in sensitivity analyses adjusting for the Essential Frailty Toolset, Clinical Frailty Scale, and geriatric conditions such as malnutrition and disability. The findings suggest that osteosarcopenia detected using clinical CT scans could be used to identify frail patients with a 3-fold increase in 1-year mortality following TAVR. This opportunistic method for osteosarcopenia assessment could be used to improve risk prediction, support decision-making, and trigger rehabilitation interventions in older adults.

Age- and sex-related changes in motor functions: a comprehensive assessment and component analysis.

Age-related motor impairments often cause caregiver dependency or even hospitalization. However, comprehensive investigations of the different motor abilities and the changes thereof across the adult lifespan remain sparse. We, therefore, extensively assessed essential basic and complex motor functions in 444 healthy adults covering a wide age range (range 21 to 88 years). Basic motor functions, here defined as simple isolated single or repetitive movements in one direction, were assessed by means of maximum grip strength (GS) and maximum finger-tapping frequency (FTF). Complex motor functions, comprising composite sequential movements involving both proximal and distal joints/muscle groups, were evaluated with the Action Research Arm Test (ARAT), the Jebsen-Taylor Hand Function Test (JTT), and the Purdue Pegboard Test. Men achieved higher scores than women concerning GS and FTF, whereas women stacked more pins per time than men during the Purdue Pegboard Test. There was no significant sex effect regarding JTT. We observed a significant but task-specific reduction of basic and complex motor performance scores across the adult lifespan. Linear regression analyses significantly predicted the participants' ages based on motor performance scores (R2 = 0.502). Of note, the ratio between the left- and right-hand performance remained stable across ages for all tests. Principal Component Analysis (PCA) revealed three motor components across all tests that represented dexterity, force, and speed. These components were consistently present in young (21-40 years), middle-aged (41-60 years), and older (61-88 years) adults, as well as in women and men. Based on the three motor components, K-means clustering analysis differentiated high- and low-performing participants across the adult life span. The rich motor data set of 444 healthy participants revealed age- and sex-dependent changes in essential basic and complex motor functions. Notably, the comprehensive assessment allowed for generating robust motor components across the adult lifespan. Our data may serve as a reference for future studies of healthy subjects and patients with motor deficits. Moreover, these findings emphasize the importance of comprehensively assessing different motor functions, including dexterity, force, and speed, to characterize human motor abilities and their age-related decline.

Ageing, Cognitive Decline, and Effects of Physical Exercise: Complexities, and Considerations from Animal Models.

In our ageing global population, the cognitive decline associated with dementia and neurodegenerative diseases represents a major healthcare problem. To date, there are no effective treatments for age-related cognitive impairment, thus preventative strategies are urgently required. Physical exercise is gaining traction as a non-pharmacological approach to promote brain health. Adult hippocampal neurogenesis (AHN), a unique form of brain plasticity which is necessary for certain cognitive functions declines with age and is enhanced in response to exercise. Accumulating evidence from research in rodents suggests that physical exercise has beneficial effects on cognition through its proneurogenic capabilities. Given ethical and technical limitations in human studies, preclinical research in rodents is crucial for a better understanding of such exercise-induced brain and behavioural changes. In this review, exercise paradigms used in preclinical research are compared. We provide an overview of the effects of different exercise paradigms on age-related cognitive decline from middle-age until older-age. We discuss the relationship between the age-related decrease in AHN and the potential impact of exercise on mitigating this decline. We highlight the emerging literature on the impact of exercise on gut microbiota during ageing and consider the role of the gut-brain axis as a future possible strategy to optimize exercise-enhanced cognitive function. Finally, we propose a guideline for designing optimal exercise protocols in rodent studies, which would inform clinical research and contribute to developing preventative strategies for age-related cognitive decline.

Association between executive functions and COMT Val108/158Met polymorphism among healthy younger and older adults: A preliminary study.

Genetic variability in the dopaminergic system could contribute to age-related impairments in executive control. In this study, we examined whether genetic polymorphism for catechol-O-methyltransferase (COMT Val158Met) is related to performance on updating, shifting and inhibition tasks. We administered a battery of executive tasks assessing updating, shifting and inhibition functions to 45 older and 55 younger healthy participants, and created composite z-scores associated to each function. Six groups were created based on genetic alleles (Val/Val, Val/Met, Met/Met) derived from the COMT gene and age (younger, older). Age and genotype effects were assessed with t-test and ANOVA (p<0.05). A lower performance was observed in the older group for the three executive processes, and more particularly for inhibition. Moreover, older participants homozygous for the Val allele have a lower performance on the inhibition composite in comparison to younger Val/Val. These results confirm presence of executive performance decrease in healthy aging. With regard to genetic effect, older participants seem particularly disadvantaged when they have a lower baseline dopamine level (i.e., Val/Val homozygous) that is magnified by aging, and when the executive measure emphasize the need of stable representations (as in inhibition task requiring to maintain active the instruction to not perform an automated process).

Radiofrequency Treatment Attenuates Age-Related Changes in Dermal-Epidermal Junctions of Animal Skin.

The dermal-epidermal junction (DEJ) is essential for maintaining skin structural integrity and regulating cell survival and proliferation. Thus, DEJ rejuvenation is key for skin revitalization, particularly in age-related DEJ deterioration. Radiofrequency (RF) treatment, known for its ability to enhance collagen fiber production through thermal mechanisms and increase heat shock protein (HSP) expression, has emerged as a promising method for skin rejuvenation. Additionally, RF activates Piezo1, an ion channel implicated in macrophage polarization toward an M2 phenotype and enhanced TGF-β production. This study investigated the impact of RF treatment on HSP47 and HSP90 expression, known stimulators of DEJ protein expression. Furthermore, using in vitro and aged animal skin models, we assessed whether RF-induced Piezo1 activation and the subsequent M2 polarization could counter age-related DEJ changes. The RF treatment of H2O2-induced senescent keratinocytes upregulated the expression of HSP47, HSP90, TGF-β, and DEJ proteins, including collagen XVII. Similarly, the RF treatment of senescent macrophages increased Piezo1 and CD206 (M2 marker) expression. Conditioned media from RF-treated senescent macrophages enhanced the expression of TGF-β and DEJ proteins, such as nidogen and collagen IV, in senescent fibroblasts. In aged animal skin, RF treatment increased the expression of HSP47, HSP90, Piezo1, markers associated with M2 polarization, IL-10, and TGF-β. Additionally, RF treatment enhanced DEJ protein expression. Moreover, RF reduced lamina densa replication, disrupted lesions, promoted hemidesmosome formation, and increased epidermal thickness. Overall, RF treatment effectively enhanced DEJ protein expression and mitigated age-related DEJ structural changes by increasing HSP levels and activating Piezo1.

Small effects of olfactory identification and discrimination on global cognitive and executive performance over 1 year in aging people without a history of age-related cognitive impairment

Olfactory and cognitive performance share neural correlates profoundly affected by physiological aging. However, whether odor identification and discrimination scores predict global cognitive status and executive function in healthy older people with intact cognition is unclear. Therefore, in the present study, we set out to elucidate these links in a convenience sample of 204 independently living, cognitively intact healthy Czech adults aged 77.4 ± 8.7 (61–97 years) over two waves of data collection (one-year interval). We used the Czech versions of the Montreal Cognitive Assessment (MoCA) to evaluate global cognition, and the Prague Stroop Test (PST), Trail Making Test (TMT), and several verbal fluency (VF) tests to assess executive function. As a subsidiary aim, we aimed to examine the contribution of olfactory performance towards achieving a MoCA score above vs. below the published cut-off value. We found that the MoCA scores exhibited moderate associations with both odor identification and discrimination. Furthermore, odor identification significantly predicted PST C and C/D scores. Odor discrimination significantly predicted PST C/D, TMT B/A, and standardized composite VF scores. Our findings demonstrate that olfaction, on the one hand, and global cognition and executive function, on the other, are related even in healthy older people.

Age-related enhancement of the association between episodic memory and gray matter volume in medial temporal and frontal lobes

BackgroundEpisodic memory (EM) deteriorates as a result of normal aging as well as Alzheimer’s disease. The neural underpinnings of such age-related memory impairments in older individuals are not well-understood. Although previous research has unveiled the association between gray matter volume (GMV) and EM in the elderly population, such findings exhibit variances across distinct age cohorts. Consequently, an investigation into the dynamic evolution of this relationship with advancing age is imperative.ResultThe present study utilized a sliding window approach to examine how the correlation between EM and GMV varied with age in a cross-sectional sample of 926 Chinese older adults. We found that both verbal EM (VEM) and spatial EM (SEM) exhibited positive correlations with GMV in extensive areas primarily in the temporal and frontal lobes and that these correlations typically became stronger with older age. Moreover, there were variations in the strength of the correlation between EM and GMV with age, which differed based on sex and the specific type of EM. Specifically, the association between VEM and GMVs in the insula and parietal regions became stronger with age for females but not for males, whereas the association between SEM and GMVs in the parietal and occipital regions became stronger for males but not for females. At the brain system level, there is a significant age-related increase in the correlations between both types of EM and the GMV of both the anterior temporal (AT) system and the posterior medial (PM) system in male group. In females, both types of EM show stronger age-related correlations with the GMV of the AT system compared to males.ConclusionsOur study revealed a significant positive correlation between GMV in most regions associated with EM and age, particularly in the frontal and temporal lobes. This discovery offers new insights into the connection between brain structure and the diminishing episodic memory function among older individuals.

Increased intestinal bile acid absorption contributes to age-related cognitive impairment

Cognitive impairment in the elderly is associated with alterations in bile acid (BA) metabolism. In this study, we observe elevated levels of serum conjugated primary bile acids (CPBAs) and ammonia in elderly individuals, mild cognitive impairment, Alzheimer's disease, and aging rodents, with a more pronounced change in females. These changes are correlated with increased expression of the ileal apical sodium-bile acid transporter (ASBT), hippocampal synapse loss, and elevated brain CPBA and ammonia levels in rodents. Invitro experiments confirm that a CPBA, taurocholic acid, and ammonia induced synaptic loss. Manipulating intestinal BA transport using ASBT activators or inhibitors demonstrates the impact on brain CPBA and ammonia levels as well as cognitive decline in rodents. Additionally, administration of an intestinal BA sequestrant, cholestyramine, alleviates cognitive impairment, normalizing CPBAs and ammonia in aging mice. These findings highlight the potential of targeting intestinal BA absorption as a therapeutic strategy for age-related cognitive impairment.

Differential Effects of Aging on Regional Corpus Callosum Microstructure and the Modifying Influence of Pulse Pressure.

The corpus callosum is composed of several subregions, distinct in cellular and functional organization. This organization scheme may render these subregions differentially vulnerable to the aging process. Callosal integrity may be further compromised by cardiovascular risk factors, which negatively influence white matter health. Here, we test for heterochronicity of aging, hypothesizing an anteroposterior gradient of vulnerability to aging that may be altered by the effects of cardiovascular health. In 174 healthy adults across the adult lifespan (mean age = 53.56 ± 18.90; range, 20-94 years old, 58.62% women), pulse pressure (calculated as participant's systolic minus diastolic blood pressure) was assessed to determine cardiovascular risk. A deterministic tractography approach via diffusion-weighted imaging was utilized to extract fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) from each of five callosal subregions, serving as estimates of microstructural health. General linear models tested the effects of age, hypertension, and pulse pressure on these cross-sectional metrics. We observed no significant effect of hypertensive diagnosis on callosal microstructure. We found a significant main effect of age and an age-pulse pressure interaction whereby older age and elevated pulse pressure were associated with poorer FA, AD, and RD. Age effects revealed nonlinear components and occurred along an anteroposterior gradient of severity in the callosum. This gradient disappeared when pulse pressure was considered. These results indicate that age-related deterioration across the callosum is regionally variable and that pulse pressure, a proxy of arterial stiffness, exacerbates this aging pattern in a large lifespan cohort.

Acute Hypoxia Following Disuse Atrophy in Aged Mice Enhances Cellular Remodeling and Whole-body Strength During Early Recovery

Age-related impairments in muscle recovery following disuse atrophy are associated with altered macrophage metabolism and blunted inflammatory function. HIF-1α is a key regulator of macrophage metabolism and inflammatory function. Therefore, we investigated the effects of acute hypoxia on muscle recovery following disuse in aging. We hypothesized that transient hypoxic exposure following disuse in aged mice would enhance macrophage metabolism and inflammatory status, resulting in improved muscle cellular remodeling and recovery. Accordingly, old (~20 months) and young adult male mice (~4 months) were exposed to acute (24 hours) normobaric hypoxia (8% O2) immediately following 14-days hindlimb unloading. We characterized muscle phenotype and function during early recovery (4- and 7-days) with and without hypoxia exposure. We found that acute hypoxia stimulated the expression of inflammatory (TNF-α, VEGF p&lt;0.01) and glycolytic transcripts (PFK-1 p&lt;0.05), LDH, PDH p=0.08) downstream of HIF-1α in aged skeletal muscle under basal conditions. Following disuse atrophy, transient hypoxic exposure enhanced macrophage inflammatory function, indicated by increased phagocytosis capacity (p&lt;0.01), and promoted early skeletal muscle cellular remodeling events, including enhanced muscle satellite cell content (p&lt;0.05). Furthermore, these effects facilitated the recovery of whole-body strength in aged mice indicated by a return to baseline values (p&gt;0.05). The results of this investigation suggest that hypoxic exposure following disuse atrophy promoted inflammatory macrophage function, muscle cellular remodeling, and enhanced early recovery in aged mice. These findings elucidate the potential benefits of hypoxia in manipulating macrophage function to ameliorate age-related deficits in muscle recovery following disuse atrophy. This research was supported by R01AG076075 (MJD) and the National Institutes of Health Ruth L. Kirschstein National Research Service Award 5T32DK091317 from the National Institute of Diabetes and Digestive and Kidney Diseases. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Augmented muscle mass blunts aging-induced cerebrovascular oxidant stress and inflammation

Cerebrovascular dysfunction is a key driver in the cognitive and sensorimotor decline that accompanies aging, contributing to the overall progression of vascular dementia. Exercise is an effective intervention to improve brain health and cognitive function, demonstrating positive effects on cerebral vasculature via a reduction in oxidant stress, thus delaying or partially reversing dementia symptoms. Age-related muscle loss (sarcopenia), however, is prevalent in adults over 50 and sarcopenic older individuals are frequently unable to take advantage of regular exercise, the most effective therapy to reduce risk of cognitive impairment, at a level that confers benefit. Interventions that can effectively replicate the effect of exercise are thus urgently needed to address the medical needs of a large population at exceedingly elevated risk for age-related cognitive impairment. The objective of the work is to determine if augmented muscle mass, a by-product of exercise, can ameliorate both skeletal and cerebrovascular dysfunction in an aging mouse model. Myokine myostatin is a potent negative regulator of skeletal muscle growth that contributes to reduced muscle mass in many muscle-wasting diseases, including aging. To date, research has focused on the protective effect of augmented muscle mass, using genetic or pharmaceutical inhibition of myostatin, in young and obese animals. Our hypothesis is that augmented muscle mass, via myostatin deletion, will improve muscle function and further, blunt the increase in oxidant stress and inflammation that drive cerebrovascular dysfunction in the aging brain. Young adult (3 mo.) and aged (24 mo.) male C57Bl/6J mice were used as controls, in combination with aged mice (24 mo.) with myostatin constitutively deleted. Augmented muscle mass and function were assessed using in vivo plantarflexion. Oxidant stress and inflammatory makers were assessed in micro vessels isolated from the whole brain, using commercially available ELISA’s and mRNA expression. Vascular function is being assessed using pressure myography and immunohistochemistry using the middle cerebral artery. Results show that augmented muscle mass, via myostatin deletion, was successful at increasing muscle mass in the aging mouse, blunting sarcopenia, and improving skeletal muscle function. Further, the aging cerebrovasculature had significantly increased expression of two of the NADPH oxidase isoforms (NOX1, NOX4), along with pivotal cytokines/chemokines associated with vascular inflammation, activation of microglia and astrocytes, and neuroinflammation (IL-1β and CCL5/RANTES). Biomarkers of oxidant stress (3-nitrotyrosine and 8-isoprostane) were also significantly elevated with aging. Taken together, augmented muscle mass may be an effective therapeutic target to prevent and rescue cerebrovascular function and inhibit cognitive decline in an aging population. This research gratefully acknowledges support from the NIA (K01 AG064121), OCAST (HR21-045-1) and the Niblack Research Scholars Program. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.