Age-associated Cognitive Decline Research Articles

Chronic β3 adrenergic agonist treatment improves brain microvascular endothelial function and cognition in aged mice.

Microvascular endothelial dysfunction, characterized by impaired neurovascular coupling, reduced glucose uptake, blood-brain barrier disruption, and microvascular rarefaction, plays a critical role in the pathogenesis of age-related vascular cognitive impairment (VCI). Emerging evidence points to non-cell autonomous mechanisms mediated by adverse circulating milieu (an increased ratio of pro-geronic to anti-geronic circulating factors) in the pathogenesis of endothelial dysfunction leading to impaired cerebral blood flow and cognitive decline in the aging population. In particular, age-related adipose dysfunction contributes, at least in part, to an unfavorable systemic milieu characterized by chronic hyperglycemia, hyperinsulinemia, dyslipidemia, and altered adipokine profile, which together contribute to microvascular endothelial dysfunction. Hence, in the present study, we aimed to test whether thermogenic stimulation, an intervention known to improve adipose and systemic metabolism by increasing cellular energy expenditure, could mitigate brain endothelial dysfunction and improve cognition in the aging population. Eighteen-month-old old C57BL/6J mice were treated with saline or CL (β3-adrenergic agonist) for 6 weeks followed by functional analysis to assess endothelial function and cognition. CL treatment improved neurovascular coupling responses and rescued brain glucose uptake in aged animals. In addition, CL treatment also attenuated blood-brain barrier leakage and associated neuroinflammation in the cortex of aged animals. More importantly, these beneficial changes in microvascular function translated to improved cognitive performance in radial arm water maze and Y-maze tests. Our results suggest that β3-adrenergic agonist treatment improves multiple aspects of brain microvascular endothelial function and can be potentially repurposed for treating age-associated cognitive decline.

A comparison of different connected-speech tasks for detecting mild cognitive impairment using multivariate pattern analysis

ABSTRACT Background It is common for the elderly population to have age-associated cognitive decline and/or develop neurodegenerative diseases such as dementia. Several studies have suggested that classification algorithms based on linguistic features may be useful for the early detection of mild cognitive impairment (MCI). Aims The current study aimed to examine connected-speech performance in people with MCI and cognitively healthy controls (HC). It tests whether patterns of lexical-semantic features extracted from these tasks could distinguish participants with MCI from HC, using univariate and multivariate analyses. Methods & procedure We selected 16 English-speaking participants with MCI and 16 matched HC from the Delaware corpus. Four connected-speech tasks (a picture description, a story narrative, a story recall, and a procedural narrative). Eight lexical-semantic features were selected for analyses. Outcomes & results Univariate analyses showed inter-group differences in revision ratio, core lexicon, or open/closed class words ratio, depending on the task. Multivariate pattern analysis (MVPA) results demonstrated that the story recall task is the only task that can discriminate the two groups above chance. Conclusion To conclude, results showed that connected-speech tasks have the potential to detect subtle language changes in people with MCI. In particular, the story recall task had the potential to predict the group of a participant (MCI or HC).

Cognitive Rehabilitation Programme (CRP): An Effective Tool Against Mild Cognitive Impairment Among Elderly

Background: With a steady increase in life expectancy seen worldwide, age-associated cognitive decline and mild cognitive impairment in old age are major public health challenges. Objective: To determine the effectiveness of the Cognitive Rehabilitation Program on cognition parameters in old age people with mild cognitive impairment. Materials and Methods: Design: This study was a quasi-experimental design using a non-equivalent control group pretest post-test design. Setting/Location: Mullana and Adhoya villages of Ambala, Haryana. Subjects: Eighty old age people with mild cognitive impairment. Intervention: The pre- and post-interventional cognition parameters were assessed using Addenbrooke’s cognitive examination on Day 1 and Day 29. The cognitive Rehabilitation Program was administered in the experimental group once a day for 28 days. Outcome Measures: Dependent variables were cognition parameters. Results and Conclusion: In the experimental group, a significant increase in cognition parameters score was observed from Day 1 (62.28 ± 6.23) to Day 29 (63.25 ± 5.10) after administration of the Cognitive Rehabilitation Program. In the comparison group, there was a non-significant decrease in cognition parameters score from Day 1 (56.73 ± 8.24) to Day 29 (55.85 ± 8.90). The post-implementation cognition parameters score of old age people in the experimental group (mean = 63.25) was significantly higher than in the comparison group (mean = 55.85). The mean gain in cognition scores was significantly higher in the experimental group than in the comparison group with a moderate effect size. It is concluded that the cognitive rehabilitation program is an effective tool in improving cognition parameters score among old age people with mild cognitive impairment.

Time-Restricted Feeding Induces Beiging and Rejuvenates Adipose Tissue with Beneficial Effects on Cerebral Function in Old Mice

Adipose tissue, traditionally viewed as purely an energy reserve, has recently been unveiled as a critical endocrine organ. Through the secretion of bioactive molecules known as adipokines, adipose tissue plays a role in inter-organ communication, most notably with the brain to maintain metabolic homeostasis and cognitive function. Aberrant adipokine secretion or signaling, often exacerbated with aging, has emerged as a defining characteristic of dysfunctional adipose tissue. This dysregulation can lead to inflammatory conditions, potentially disrupting neural homeostasis and heightening the vulnerability of older individuals to cognitive impairments. This study investigated the capacity of time-restricted feeding (TRF) to promote beiging (induction of brown adipocytes positive for uncoupling protein 1(UCP1) within white adipose tissue depots) in aged mice, exploring its potential role in modulating adipokine profiles, attenuating inflammation, and mitigating age-associated cognitive decline. To test this hypothesis, we collected adipose tissue samples from 24-month-old mice that underwent 6 months of TRF and compared their profiles to both young and age-matched controls on an unrestricted (ad-lib) diet. Immunohistochemical analyses of brown adipose tissue (BAT), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) revealed a marked reduction in pro-inflammatory markers CD80 and F4/80hi across all adipose tissues. Notably, a shift towards an anti-inflammatory state was indicated by a pronounced increase in CD163 staining in the SAT and VAT. Additionally, the increased expression of UCP1, especially in BAT and SAT, pointed towards an enhanced thermogenic capacity, suggesting a potential metabolic advantage. This was further reinforced by an increase in electron transport chain (ETC) activity in all adipose tissues. These findings have powerful implications given the established links between systemic inflammation, disrupted adipokine signaling, and neurodegenerative conditions. The alleviated adipose inflammatory profiles measured in TRF mice not only underscore its potential metabolic benefits but also highlight its possible role in safeguarding cognitive health, especially in an aging demographic. Currently serum studies and RNA sequencing are being conducted to look at altered transcript production and to investigate the role of adipokines on the brain health of the aged TRF mice. Such insights pave the way for future research exploring dietary strategies to combat age-related cognitive decline. Stephenson Cancer Center, National Institute on Aging R03 AG070479, American Heart Association. 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.

Establishment of a mild cognitive impairment risk model in middle-aged and older adults: a longitudinal study.

Early identification individuals at high risk of mild cognitive impairment (MCI) is essential for prevention and intervention strategies of dementia, such as Alzheimer's disease. MCI prediction considering the interdependence of predictors in longitudinal data needs to be further explored. We aimed to employ machine learning (ML) to develop and verify a prediction model of MCI. In a longitudinal population-based cohort of China Health and Retirement Longitudinal Study (CHARLS), 8390 non-MCI participants were enrolled. The diagnosis of MCI was based on the aging-associated cognitive decline (AACD), and 13 factors (gender, education, marital status, residence, diabetes, hypertension, depression, hearing impairment, social isolation, physical activity, drinking status, body mass index and expenditure) were finally selected as predictors. We implemented a long short-term memory (LSTM) to predict the MCI risks in middle-aged and older adults within 7years. The Receiver Operating Characteristic curve (ROC) and calibration curve were used to evaluate the performance of the model. Through 7years of follow-up, 1925 participants developed MCI. The model for all incident MCI achieved an AUC of 0.774, and its deployment to the participants followed 2, 4, and 7years achieved results of 0.739, 0.747, and 0.750, respectively. The model was well-calibrated with predicted probabilities plotted against the observed proportions of cognitive impairment. Education level, gender, marital status, and depression contributed most to the prediction of MCI. This model could be widely applied to medical institutions, even in the community, to identify middle-aged and older adults at high risk of MCI.

A Long-Acting Lyotropic Liquid Crystalline Implant Promotes the Drainage of Macromolecules by Brain-Related Lymphatic System in Treating Aged Alzheimer's Disease.

Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer's disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer's disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Aβ accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer's diseases.

Review of cellular therapies provides new insights into the potential treatment of diverse neurologic diseases in horses and dogs.

Neurological diseases and injuries in veterinary patients (horses, dogs, and cats) are complex, and effective treatment options are limited. Neuronal loss, damage to nerve conduction pathways, and inflammation and scarring associated with spinal cord injury pose major challenges in managing many neurological diseases. Furthermore, most of these neuropathologies lack definitive pharmacological treatments, driving interest and research into novel interventions. Our objective is to provide a narrative review of the current literature surrounding cellular therapies including neuronal and glial stem cells, neurotrophic factors, mesenchymal stem or stromal cells, and cells derived from induced pluripotent stem cells for the treatment of diverse neurological pathologies. Cellular therapies have the potential for cellular replacement, immune modulation, and paracrine signaling and the flexibility of being used alone or alongside surgical intervention. Mesenchymal stem or stromal cells are arguably the most researched cellular therapy and have been administered intrathecally, IV, intra-arterially, intranasally, and intraspinally with few adverse reactions. Limited clinical and experimental studies have suggested efficacy in diseases including acute spinal cord injury and intervertebral disc disease. Little is currently known about the safety and efficacy of neural stem cells, precursor cell administration, and induced pluripotent stem cell-derived treatments. Further research is necessary to determine the efficacy and long-term safety of cellular therapies. Future aims should include larger controlled clinical trials in companion animals for common neurologic conditions including acute spinal cord injury, intervertebral disc disease, peripheral nerve injury, degenerative neuropathies, and age-associated cognitive decline.

Centella asiatica improves memory and executive function in middle-aged rats by controlling oxidative stress and cholinergic transmission

Ethnopharmacological relevanceCentella asiatica (L.) Urban, is a medicinal herb with rich history of traditional use in Indian subcontinent. This herb has been valued for its diverse range of medicinal properties including memory booster, and also as a folk treatment for skin diseases, wound healing and mild diuretic. Aim of studyAging is a gradual and continuous process of natural decay in the biological systems, including the brain. This work aims to evaluate the effectiveness of ethanolic extract of Centella asiatica (CAE) on age-associated cognitive impairments in rats, as well as the underlying mechanism. Material and methodsRats were allocated into five distinct groups of 5 animals each: Young rats (3 months old rats), middle-aged (m-aged) rats (13–14 months old), and the remaining three groups were comprised of m-aged rats treated with different concentrations of CAE, viz., 150, 300, and 450 mg/kg b. w., orally for 42 days. Y-maze, open field, novel object recognition, and elevated plus maze tests were used to assess animal behavior. The malondialdehyde (MDA), superoxide dismutase (SOD), and acetylcholinesterase (AChE) assays; and H&E staining were done in the rat brain to assess the biochemical and structural changes. CAE was also subjected to HPLC analysis, in vitro antioxidant and anti-cholinergic activity. The active compounds of CAE were docked with AChE and BuChE in molecular docking study. ResultsThe results showed that CAE treatment improves behavioral performance; attenuates the age-associated increase in MDA content, SOD, and AChE activity; and reduces neuronal loss. In vitro study showed that CAE has concentration-dependent antioxidant and anti-AChE activity. Furthermore, the presence of Asiatic acid and Madecassic acid in CAE and their good binding with cholinergic enzymes (in silico) also suggest the anticholinergic effect of CAE. ConclusionThe findings of the current study show that the anticholinergic and antioxidant effects of CAE are attributable to the presence of Asiatic acid and Madecassic acid, which not only provide neuroprotection against age-associated cognitive decline but also reverse it.

Next Generation Therapeutic Strategy for Treatment and Prevention of Alzheimer's Disease and Aging-Associated Cognitive Decline: Transient, Once-in-a-Lifetime-Only Depletion of Intraneuronal Aβ (iAβ) by Its Targeted Degradation via Augmentation of Intra-iAβ-Cleaving Activities of BACE1 and/or BACE2.

Although the long-standing Amyloid Cascade Hypothesis (ACH) has been largely discredited, its main attribute, the centrality of amyloid-beta (Aβ) in Alzheimer's disease (AD), remains the cornerstone of any potential interpretation of the disease: All known AD-causing mutations, without a single exception, affect, in one way or another, Aβ. The ACH2.0, a recently introduced theory of AD, preserves this attribute but otherwise differs fundamentally from the ACH. It posits that AD is a two-stage disorder where both stages are driven by intraneuronal (rather than extracellular) Aβ (iAβ) albeit of two distinctly different origins. The first asymptomatic stage is the decades-long accumulation of Aβ protein precursor (AβPP)-derived iAβ to the critical threshold. This triggers the activation of the self-sustaining AβPP-independent iAβ production pathway and the commencement of the second, symptomatic AD stage. Importantly, Aβ produced independently of AβPP is retained intraneuronally. It drives the AD pathology and perpetuates the operation of the pathway; continuous cycles of the iAβ-stimulated propagation of its own AβPP-independent production constitute an engine that drives AD, the AD Engine. It appears that the dynamics of AβPP-derived iAβ accumulation is the determining factor that either drives Aging-Associated Cognitive Decline (AACD) and triggers AD or confers the resistance to both. Within the ACH2.0 framework, the ACH-based drugs, designed to lower levels of extracellular Aβ, could be applicable in the prevention of AD and treatment of AACD because they reduce the rate of accumulation of AβPP-derived iAβ. The present study analyzes their utility and concludes that it is severely limited. Indeed, their short-term employment is ineffective, their long-term engagement is highly problematic, their implementation at the symptomatic stages of AD is futile, and their evaluation in conventional clinical trials for the prevention of AD is impractical at best, impossible at worst, and misleading in between. In contrast, the ACH2.0-guided Next Generation Therapeutic Strategy for the treatment and prevention of both AD and AACD, namely the depletion of iAβ via its transient, short-duration, targeted degradation by the novel ACH2.0-based drugs, has none of the shortcomings of the ACH-based drugs. It is potentially highly effective, easily evaluable in clinical trials, and opens up the possibility of once-in-a-lifetime-only therapeutic intervention for prevention and treatment of both conditions. It also identifies two plausible ACH2.0-based drugs: activators of physiologically occurring intra-iAβ-cleaving capabilities of BACE1 and/or BACE2.

Higher intake of certain nutrients among older adults is associated with better cognitive function: an analysis of NHANES 2011–2014

BackgroundAn increasing number of adults are over the age of 65, and there is concern about the increasing prevalence of age-associated cognitive decline and poor mental health status in older adults in the United States. Several nutrients are known to have important biological roles in brain health and neurological function, but many individuals fall short of recommended intake levels. The objective of this study was to examine the association between nutrient intake and cognitive function. We also explored whether nutrient intake was associated with depression.MethodsThis cross-sectional study was based on data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014 and included participants ≥ 60 years of age who had reliable day 1 dietary recall data and either valid cognitive function data (n = 2713) or valid depression score data (n = 2943). The sample was stratified by gender, and cognitive functioning test (CFT) composite z-scores were analyzed by quartiles. Depression status was assessed using the Patient Health Questionnaire (PHQ-9).ResultsHigher intake and adequacy of a number of different nutrients from food were associated with higher cognitive function in both males and females. Nutrients that showed the most consistent associations with cognitive function across intake and adequacy analyses for food in both males and females were vitamin A, vitamin E, thiamin, riboflavin, vitamin B6, folate, magnesium, potassium, zinc, vitamin K, and lutein and zeaxanthin (p < 0.05 for all). These associations were positive with increasing intake and adequacy being associated with higher CFT composite z-scores. Analysis of nutrient intake and depression yielded results that differed by gender. In females, the nutrients that showed consistent inverse associations with depression scores across both intake and adequacy analyses for food were vitamin A, vitamin C, magnesium, vitamin K, potassium, and dietary fiber (p < 0.05 for all). In males, no significant associations between nutrient intake from food and depression scores were observed.ConclusionsOur findings suggest that older adults with sufficient intakes of certain essential nutrients have higher cognitive function. Future studies are needed to confirm whether a well-balanced diet and/or dietary supplements which emphasize these nutrients are effective for prevention of age-related declines in cognitive function and mood.

Reduced tactile sensitivity is associated with mild cognitive impairment

Sensory impairment has been related to age-associated cognitive decline. While these associations were investigated primarily in the auditory and visual domain, other senses such as touch have rarely been studied. Thus, it remains open whether these results are specific for particular sensory domains, or rather point to a fundamental role of sensory deficits in cognitive decline. Data from 31 participants with mild cognitive impairment (MCI), 46 participants with frailty, and 23 non-clinical control participants (NCCs) were included. We assessed sensory function using visual acuity and contrast sensitivity, hearing threshold, and mechanical detection threshold. Cognitive function in participants with MCI was assessed using associative memory performance. Group differences on sensory thresholds were tested using analyses of covariance with age, sex, and years of education as covariates. Associations between measures within participants with MCI were evaluated using Spearman correlations. We found a significant difference in mechanical detection threshold between the groups (p<0.001, η2=0.18). Participants with MCI showed significantly reduced tactile sensitivity compared to participants with frailty and NCCs. In participants with MCI, lower associative memory performance was significantly related to reduced tactile sensitivity (rs=0.39, p=0.031) and auditory acuity (rs=0.41, p=0.022). Our results indicate that reduced tactile sensitivity is related to cognitive decline. Prospective studies should investigate the age-related alterations of multimodal sensory processes and their contribution to dementia-related processes. Deutsche Forschungsgemeinschaft (FL 156/41-1) and a grant of the Hector-Stiftung II, Weinheim, Germany.

Temporo-Parietal cortex activation during motor imagery in older adults: A case study of Baduanjin

Age-associated cognitive and motor decline is related to central nervous system injury in older adults. Motor imagery training (MIT), as an emerging rehabilitative intervention, can activate neural basis similar to that in actual exercise, so as to promote motor function in older adults. The complex motor skills rely on the functional integration of the cerebral cortex. Understanding the neural mechanisms underlying motor imagery in older adults would support its application in motor rehabilitation and slowing cognitive decline. Based on this, the present study used functional near infrared spectroscopy (fNIRS) to record the changes in oxygen saturation in older adults (20 participants; mean age, 64.8 ± 4.5 years) during Baduanjin motor execution (ME) and motor imagery (MI). ME significantly activated the left postcentral gyrus, while the oxy-hemoglobin concentration in the right middle temporal gyrus increased significantly during motor imagery. These results indicate that advanced ME activates brain regions related to sensorimotor function, and MI increases the activation of the frontal-parietal cortex related to vision. In older adults, MI overactivated the temporo-parietal region associated with vision, and tend to be activated in the right brain.

SAT033 Disruption Of GHR In “Middle Aged” Mice Enhances Insulin Sensitivity And Extends Male Lifespan

Abstract Disclosure: S. Duran-Ortiz: None. E.O. List: None. J.A. Young: None. S.C. Mathes: None. R. Basu: None. Y.B. Slama: None. D.E. Berryman: None. Reduced growth hormone (GH) action has been shown to extend healthspan and lifespan in several organisms. In fact, mice and humans with a congenital disruption in the GH receptor (R) gene (GHRKO mice and patients with Laron Syndrome, respectively) have improved insulin sensitivity and are resistant to diabetes, cancer and age-associated cognitive decline. Importantly, the GHRKO mice hold the record for the longest-lived laboratory mice, with a lifespan one week shy of five years of age. GHRKO mice also show reduced markers of aging such as adipose tissue senescence and mTORC1 signaling in liver, kidney, heart and muscle. However, as GH action is required for normal growth and development, we and others have hypothesized that targeted inhibition of GH action at an adult age could be a potent method to extend healthy lifespan. To test this hypothesis and to elucidate how far in development would disruption of GHR extend healthy lifespan, our laboratory recently reported on two mouse lines with post-natal ablation of the GHR at a pubertal age (1.5 months - 1.5mGHRKO mice) and at mature-adult age (6 months - 6mGHRKO mice). We found that ablation of the GHR gene at both 1.5- and 6-months of age extends maximal and mean lifespan preferentially in females. Furthermore, 6mGHRKO mice showed improved oxidative stress resistance while males had improved insulin sensitivity and reduced cancer incidence. With these promising results, we believe that interventions to extend aging should be effective when administered later in life. In the current study, we disrupted the GHR in middle aged mice (12 months - 12mGHRKO mice) using the Cre-Lox system. We found that 12mGHRKO mice exhibit GH insensitivity (high serum GH and low IGF-1 levels), increased adipose tissue mass, reduced lean mass, minimal impact on body weight and length, improved insulin sensitivity and reduced glucose levels in males as well as decreased adipose tissue fibrosis in females compared to males. Moreover, despite the increased fat mass, motor coordination and strength as measured by rotarod and grip strength tests show no deficit in 12mGHRKO mice compared to the controls. Importantly, the male 12mGHRKO mice showed a preferential and significant lifespan extension compared to control mice. Collectively, our results indicate that not only does post-natal GHR disruption does not affect growth and development, but it also confers several crucial healthspan and lifespan advantages. Acknowledgements: This work is supported by the State of Ohio's Eminent Scholar Program, by NIH grant AG059779, by the American Federation for Aging Research (AFAR) and by the Diabetes Institute and by the AMVETS. Presentation: Saturday, June 17, 2023

Physical Exercise as Disease-Modifying Alternative against Alzheimer's Disease: A Gut-Muscle-Brain Partnership.

Alzheimer's disease (AD) is a common cause of dementia characterized by neurodegenerative dysregulations, cognitive impairments, and neuropsychiatric symptoms. Physical exercise (PE) has emerged as a powerful tool for reducing chronic inflammation, improving overall health, and preventing cognitive decline. The connection between the immune system, gut microbiota (GM), and neuroinflammation highlights the role of the gut-brain axis in maintaining brain health and preventing neurodegenerative diseases. Neglected so far, PE has beneficial effects on microbial composition and diversity, thus providing the potential to alleviate neurological symptoms. There is bidirectional communication between the gut and muscle, with GM diversity modulation and short-chain fatty acid (SCFA) production affecting muscle metabolism and preservation, and muscle activity/exercise in turn inducing significant changes in GM composition, functionality, diversity, and SCFA production. This gut-muscle and muscle-gut interplay can then modulate cognition. For instance, irisin, an exercise-induced myokine, promotes neuroplasticity and cognitive function through BDNF signaling. Irisin and muscle-generated BDNF may mediate the positive effects of physical activity against some aspects of AD pathophysiology through the interaction of exercise with the gut microbial ecosystem, neural plasticity, anti-inflammatory signaling pathways, and neurogenesis. Understanding gut-muscle-brain interconnections hold promise for developing strategies to promote brain health, fight age-associated cognitive decline, and improve muscle health and longevity.

Transcriptomics and biochemical evidence of trigonelline ameliorating learning and memory decline in the senescence-accelerated mouse prone 8 (SAMP8) model by suppressing proinflammatory cytokines and elevating neurotransmitter release

In recent years, exploring natural compounds with functional properties to ameliorate aging-associated cognitive decline has become a research priority to ensure healthy aging. In the present study, we investigated the effects of Trigonelline (TG), a plant alkaloid, on memory and spatial learning in 16-week-old senescence-accelerated mouse model SAMP8 using an integrated approach for cognitive and molecular biology aspects. After 30 days of oral administration of TG at the dose of 5 mg/kg/day, the mice were trained in Morris Water Maze task. TG-treated SAMP8 mice exhibited significant improvement in the parameters of escape latency, distance moved, and annulus crossing index. Next, we performed a whole-genome transcriptome profiling of the mouse hippocampus using microarrays. Gene ontology analyses showed that a wide range of biological processes, including nervous system development, mitochondrial function, ATP synthesis, and several signaling pathways related to inflammation, autophagy, and neurotransmitter release, were significantly enriched in TG-treated SAMP8 compared to nontreated. Further, a nonlinear dimensionality reduction technique, Uniform Manifold Approximation and Projection (UMAP), was applied to identify clusters of functions that revealed TG primarily regulated pathways related to inflammation, followed by those involved in neurotransmitter release. In addition, a protein–protein interaction network analysis indicated that TG may exert its biological effects through negatively modulating Traf6-mediated NF-κB activation. Finally, ELISA test showed that TG treatment significantly decreased proinflammatory cytokines- TNFα and IL6 and increased neurotransmitters- dopamine, noradrenaline, and serotonin in mouse hippocampus. Altogether, our integrated bio-cognitive approach highlights the potential of TG in alleviating age-related memory and spatial impairment.

Sex differences in microglia function in aged rats underlie vulnerability to cognitive decline

Aging is associated with a significant shift in immune system reactivity (“inflammaging”), as basal inflammation increases but protective responses to infection are compromised. The immune system exhibits considerable sex differences, which may influence the process of inflammaging, including immune cell activation and behavioral consequences of immune signaling (i.e., impaired memory). Here, we test the hypothesis that sex differences in immune aging may mediate sex differences in cognitive decline. Aged male and female rats received peripheral immune stimulation using lipopolysaccharide (LPS), then molecular, cellular, and behavioral outcomes were assessed. We observed that LPS-treated aged male rats showed cognitive impairment and increased neuroinflammatory responses relative to adult males. In contrast, aged female rats did not display these aging-related deficits. Using transcriptomic and flow cytometry analyses, we further observed significant age- and sex- dependent changes in immune cell populations in the brain parenchyma and meninges, indicating a broad shift in the neuroinflammatory environment that may potentiate these behavioral effects. Ovariectomized aged female rats were also resistant to inflammation-induced memory deficits, indicating that ovarian hormones are not required for the attenuated neuroinflammation in aged females. Overall, our results indicate that males have amplified inflammatory priming with age, which contributes to age-associated cognitive decline. Our findings highlight sexual dimorphism in mechanisms of aging, and suggest that sex is a crucial consideration for identifying therapies for aging and neuroinflammation.

The effect of lipid metabolism on age-associated cognitive decline: Lessons learned from model organisms and human

Lipids are required as integral building blocks of cells to support cellular structures and functions. The intricate mechanisms underpinning lipid homeostasis are essential for the health and maintenance of the central nervous system. Here we summarize the recent advances in dissecting the effect of lipid metabolism on cognitive function and its age-associated decline by reviewing relevant studies ranging from invertebrate model organisms to mammals including human.

Principles of Design of Clinical Trials for Prevention and Treatment of Alzheimer's Disease and Aging-Associated Cognitive Decline in the ACH2.0 Perspective: Potential Outcomes, Challenges, and Solutions.

With the Amyloid Cascade Hypothesis (ACH) largely discredited, the ACH2.0 theory of Alzheimer's disease (AD) has been recently introduced. Within the framework of the ACH2.0, AD is triggered by amyloid-β protein precursor (AβPP)-derived intraneuronal Aβ (iAβ) and is driven by iAβ produced in the AβPP-independent pathway and retained intraneuronally. In this paradigm, the depletion of extracellular Aβ or suppression of Aβ production by AβPP proteolysis, the two sources of AβPP-derived iAβ, would be futile in symptomatic AD, due to its reliance on iAβ generated independently of AβPP, but effective in preventing AD and treating Aging-Associated Cognitive Decline (AACD) driven, in the ACH2.0 framework, by AβPP-derived iAβ. The observed effect of lecanemab and donanemab, interpreted in the ACH2.0 perspective, supports this notion and mandates AD-preventive clinical trials. Such trials are currently in progress. They are likely, however, to fail or to yield deceptive results if conducted conventionally. The present study considers concepts of design of clinical trials of lecanemab, donanemab, or any other drug, targeting the influx of AβPP-derived iAβ, in prevention of AD and treatment of AACD. It analyzes possible outcomes and explains why selection of high-risk asymptomatic participants seems reasonable but is not. It argues that outcomes of such AD preventive trials could be grossly misleading, discusses inevitable potential problems, and proposes feasible solutions. It advocates the initial evaluation of this type of drugs in clinical trials for treatment of AACD. Whereas AD protective trials of these drugs are potentially of an impractical length, AACD clinical trials are expected to yield unequivocal results within a relatively short duration. Moreover, success of the latter, in addition to its intrinsic value, would constitute a proof of concept for the former. Furthermore, this study introduces concepts of the active versus passive iAβ depletion, contends that targeted degradation of iAβ is the best therapeutic strategy for both prevention and treatment of AD and AACD, proposes potential iAβ-degrading drugs, and describes their feasible and unambiguous evaluation in clinical trials.

The Amyloid Cascade Hypothesis 2.0 for Alzheimer's Disease and Aging-Associated Cognitive Decline: From Molecular Basis to Effective Therapy.

With the long-standing amyloid cascade hypothesis (ACH) largely discredited, there is an acute need for a new all-encompassing interpretation of Alzheimer's disease (AD). Whereas such a recently proposed theory of AD is designated ACH2.0, its commonality with the ACH is limited to the recognition of the centrality of amyloid-β (Aβ) in the disease, necessitated by the observation that all AD-causing mutations affect, in one way or another, Aβ. Yet, even this narrow commonality is superficial since AD-causing Aβ of the ACH differs distinctly from that specified in the ACH2.0: Whereas in the former, the disease is caused by secreted extracellular Aβ, in the latter, it is triggered by Aβ-protein-precursor (AβPP)-derived intraneuronal Aβ (iAβ) and driven by iAβ generated independently of AβPP. The ACH2.0 envisions AD as a two-stage disorder. The first, asymptomatic stage is a decades-long accumulation of AβPP-derived iAβ, which occurs via internalization of secreted Aβ and through intracellular retention of a fraction of Aβ produced by AβPP proteolysis. When AβPP-derived iAβ reaches critical levels, it activates a self-perpetuating AβPP-independent production of iAβ that drives the second, devastating AD stage, a cascade that includes tau pathology and culminates in neuronal loss. The present study analyzes the dynamics of iAβ accumulation in health and disease and concludes that it is the prime factor driving both AD and aging-associated cognitive decline (AACD). It discusses mechanisms potentially involved in AβPP-independent generation of iAβ, provides mechanistic interpretations for all principal aspects of AD and AACD including the protective effect of the Icelandic AβPP mutation, the early onset of FAD and the sequential manifestation of AD pathology in defined regions of the affected brain, and explains why current mouse AD models are neither adequate nor suitable. It posits that while drugs affecting the accumulation of AβPP-derived iAβ can be effective only protectively for AD, the targeted degradation of iAβ is the best therapeutic strategy for both prevention and effective treatment of AD and AACD. It also proposes potential iAβ-degrading drugs.

Olive Oil Phenolic Compounds' Activity against Age-Associated Cognitive Decline: Clinical and Experimental Evidence.

Epidemiological studies have shown that consuming olive oil rich in phenolic bioactive compounds is associated with a lower risk of neurodegenerative diseases and better cognitive performance in aged populations. Since oxidative stress is a common hallmark of age-related cognitive decline, incorporating exogenous antioxidants could have beneficial effects on brain aging. In this review, we firstly summarize and critically discuss the current preclinical evidence and the potential neuroprotective mechanisms. Existing studies indicate that olive oil phenolic compounds can modulate and counteract oxidative stress and neuroinflammation, two relevant pathways linked to the onset and progression of neurodegenerative processes. Secondly, we summarize the current clinical evidence. In contrast to preclinical studies, there is no direct evidence in humans of the bioactivity of olive oil phenolic compounds. Instead, we have summarized current findings regarding nutritional interventions supplemented with olive oil on cognition. A growing body of research indicates that high consumption of olive oil phenolic compounds is associated with better preservation of cognitive performance, conferring an additional benefit, independent of the dietary pattern. In conclusion, the consumption of olive oil rich in phenolic bioactive compounds has potential neuroprotective effects. Further research is needed to understand the underlying mechanisms and potential clinical applications.