The hypothalamus is an important regulator of autonomic and endocrine functions also involved in aging regulation. The aging process in the hypothalamus is accompanied by disturbed intracellular signaling including insulin/insulin-like growth factor-1 (IGF-1)/growth hormone (GH), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/the mammalian target of rapamycin (mTOR), mitogen activated protein kinase (MAPK), janus kinase (JAK)/signal transducer and activator of transcription (STAT), AMP-activated protein kinase (AMPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB), and nitric oxide (NO). In the current review, I have summarized the current understanding of the changes in the above-mentioned pathways in aging with a focus on hypothalamic alterations.

Changes of Signaling Pathways in Hypothalamic Neurons with Aging

Effects of MicroRNAs and Long Non-coding RNAs on Beneficial Action of Exercise on Cognition in Degenerative Diseases: A Review

To explore the effects of a group-based multicomponent exercise program on general cognitive functioning, depression, and social functioning in community-dwelling older adults with mild cognitive impairment (MCI) and whether the effects can be maintained.Fifty older adults with MCI were conveniently recruited from two communities in the study area and randomly assigned to the intervention group or control group. The intervention group received three sessions of 60-minute, multicomponent exercise per week for 3 months, plus MCI-related health education. The control group only received MCI-related health education. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Beijing Version (MoCA-BJ) were used to assess general cognitive function. The Functional Activities Questionnaire (FAQ) and Geriatric Depression Scale (GDS-30) were used to evaluate participants' social function and depression, respectively. Participants' exercise intensity was assessed using the Category Ratio Scale.After the 3-month intervention, there were significant improvements in general cognitive function (p = 0.046), attention (p = 0.009), delayed recall (p = 0.015), and social function (p = 0.011) in the intervention group compared with the control group. However, after 3-month postintervention follow up, no significant differences in MMSE, MoCA-BJ, GDS-30, and FAQ scores were noted between groups.The 3-month multicomponent exercise program improved general cognitive function and social functioning in community-dwelling older adults with MCI. However, there was no evidence that these benefits lasted for another 3 months after stopping the exercise program. [Research in Gerontological Nursing, 17(2), 65-79.]. 

Effects of Multicomponent Exercise on Community-Dwelling Older Adults With Mild Cognitive Impairment

The use of anesthetics during surgery can cause severe neurological damage and cognitive dysfunction in elderly patients. However, this health issue currently lacks corresponding therapeutic strategies. This research involved the utilization of single-cell RNA sequencing (scRNA-seq) and transcriptomic assessment to pinpoint crucial cell classifications and molecular pathways, as well as the lncRNA expression profiles, that undergo substantial alterations in aged rats experiencing sevoflurane-induced cognitive impairment. The results of our investigation pointed towards the enrichment of differentially expressed genes in neurons within the Nrf2/ARE signaling pathway, alongside an elevated expression of lncRNA NEAT1. Subsequently, by constructing a rat model to induce neuronal dysfunction with sevoflurane and performing experiments both in vivo and in vitro (including TUNEL staining, H&E staining, immunohistochemistry, immunofluorescence, and flow cytometry to assess apoptosis levels), we confirmed that NEAT1 inhibits the Nrf2/ARE/HO-1 pathway-related factors. Sevoflurane promotes oxidative stress and apoptosis in primary hippocampal neurons through the NEAT1/Nrf2/ARE/HO-1 axis. This study elucidates the molecular mechanism by which sevoflurane induces hippocampal neuronal damage and cognitive decline in elderly rats via the regulation of the lncRNA NEAT1/Nrf2 signaling axis. We discovered that upregulation of NEAT1 suppresses the Nrf2 signaling pathway, further inducing neuronal damage and cognitive dysfunction, furnishing an essential citation to grasp the molecular pathways involved in neuronal harm and devising corresponding treatment methodologies. 

Mechanistic insights into sevoflurane-induced hippocampal neuronal damage and cognitive dysfunction through the NEAT1/Nrf2 signaling axis in aged rats

Cognitive Dysfunction and Exercise: From Epigenetic to Genetic Molecular Mechanisms.

Aging-related cognitive impairment (ARCI) is rapidly becoming a healthcare priority. However, there is currently no excellent cure for it. Cognitive-exercise dual-task intervention (CEDI) is a promising method to improve ARCI, while the underlying mechanisms remain unclear. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are involved in the onset, development, and rehabilitation of ARCI. This study aimed to investigate the effects of CEDI and the role of regulation of the lncRNA NEAT1/miR-124-3p on the caveolin-1-PI3K/Akt/GSK3β pathway in CEDI improving cognitive function. Forty 18-month-old natural aging rats were randomly assigned to four groups: exercise training group, cognitive training group, CEDI group, and aging control group, and underwent 12 weeks of intervention. A novel object recognition test was performed to determine the cognitive function, and the hippocampus was separated three days after the behavioral tests for further molecular detection. In an in vitro study, the mouse hippocampal neuronal cell line HT22 was cultured. MiR-124-3p and lncRNA NEAT1 were over-expressed or down-expressed, respectively. The expressions of related proteins, lncRNA, and miRNA were examined by WB and/or qRT-PCR. The results showed that compared with the aging control group, the CEDI group had a higher discrimination index, and significantly decreased the expressions of lncRNA NEAT1, and the protein expressions of caveolin-1 and p-GSK3β, while significantly increased the expressions of miR-124-3p, and the protein expressions of p-PI3K and p-Akt. Inhibition of the lncRNA NEAT1 could significantly increase the protein expressions of p-PI3K and p-Akt in HT22 cells. Upregulation of miR-124-3p decreased the protein expressions of caveolin-1 and p-GSK3β, and increased the protein expressions of p-PI3K and p-Akt significantly. Inhibition of miR-124-3p had the opposite effects. Our study demonstrated that CEDI improved cognitive function in aging rats better than a single intervention. The mechanisms of cognitive improvement could be related to the regulation of the lncRNA NEAT1/miR-124-3p on the caveolin-1-PI3K/Akt/GSK3β pathway. 

Cognitive–exercise dual-task intervention ameliorates cognitive decline in natural aging rats via inhibiting the promotion of LncRNA NEAT1/miR-124–3p on caveolin-1-PI3K/Akt/GSK3β Pathway

Objectives To summarise the effects of various types of aerobic exercise on the global cognitive function of the elderly with mild cognitive impairment (MCI). Design A meta-analysis of randomised controlled trials (RCTs). Data sources PubMed, EMBASE and the Cochrane Library were searched for clinical RCTs from the earliest available records to March 2022. Eligibility criteria for selecting studies We included RCTs of subjects older than 60 years with MCI. The outcome indicators of cognitive function of interest were the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Data extraction and synthesis Two researchers independently screened the literature, extracted data and evaluated the quality of the included studies, with disagreements resolved by a third researcher. The Cochrane Handbook for Systematic Reviews of Interventions was used to assess the risk of bias. Meta-analysis was performed by Review Manager V.5.3 software. Random-effect models were used for meta-analysis. Results A total of 1680 patients who participated in 20 RCTs were included in this study. Based on outcomes of MMSE analysis, the aerobic exercise, which was beneficial for global cognitive function in MCI patients, included multicomponent aerobic exercise (MD=1.79, 95% CI (1.41 to 2.17), p<0.01) and mind–body exercise (MD=1.28, 95% CI (0.83 to 1.74), p<0.01). The results of the meta-analysis of conventional aerobic exercise (MD=0.51, 95% CI (0.09 to 0.93), p=0.02) turned out to be statistically insignificant after sensitivity analysis (MD=0.14, 95% CI (-0.47 to 0.75), p=0.65). With the evaluation of MoCA, multicomponent aerobic exercise (MD=5.74, 95% CI (5.02 to 6.46), p<0.01), mind–body exercise (MD=1.29, 95% CI (0.67 to 1.90), p<0.01) and conventional aerobic exercise (MD=2.06, 95% CI (1.46 to 2.65), p<0.01) were showed significant beneficial effects for the patient. However, there was a high degree of heterogeneity between the results of multicomponent aerobic exercise (MMSE) and conventional aerobic exercise (MoCA), which was analysed and explored. Conclusions In general, multicomponent aerobic exercise and mind–body exercise were beneficial in improving global cognitive function in the elderly with MCI. Nevertheless, the improvement effect of mind–body exercise is more reliable compared with multicomponent aerobic exercise and conventional aerobic exercise. PROSPERO registration number CRD42022327386.

Effects of different aerobic exercises on the global cognitive function of the elderly with mild cognitive impairment: a meta-analysis

COPYRIGHT © 2022 Tao, Sun, Han and Gong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Cognitive-motor dual task: An e ective rehabilitation method in aging-related cognitive impairment

https://www.frontiersin.org/articles/10.3389/fnagi.2022.1051056/pdf

Cognitive-motor dual task: An effective rehabilitation method in aging-related cognitive impairment

The prevalence of vascular cognitive impairment induced by chronic cerebral ischemia (CCI) is increasing year by year. Cognitive-exercise dual-task intervention has shown beneficial effects on improving cognitive performance in ischemic patients. It is well known that the tyrosine kinase ligand-receptor (Ephrin-Eph) system plays an important role in synaptic transmission and that the cAMP/PKA pathway is associated with cognitive function. However, it is unclear whether they are responsible for the dual-task improving cognitive impairment in CCI. Bilateral common carotid artery occlusion (BCCAO) in SD rats was used to establish the CCI model. The effects of dual-task and single-task on cognitive function and the expressions of EphrinA3, EphA4, cAMP, and PKA in rats were detected by the novel object recognition (NOR) test, immunofluorescence staining, quantitative real-time polymerase chain reaction (qPCR), and Western blotting (WB), respectively. Overexpression or knockdown of EphrinA3 in astrocytes or rats were constructed by lentivirus infection to verify the effects of EphrinA3/EphA4 on the cAMP/PKA pathway. After dual-task intervention, the discrimination index of rats increased significantly compared with the rats in the CCI group. The expressions of EphrinA3 and EphA4 were decreased, while the expressions of cAMP and PKA were increased. Furthermore, knockdown of EphrinA3 alleviated the trend of CCI-induced cognitive decline in rats and OGD-stimulated cellular damage. It also increased cAMP/PKA expression in hippocampal neurons. Cognitive-exercise dual-task can significantly improve the cognitive impairment induced by CCI, and this effect may be better than that of the cognitive or exercise single-task intervention. The improvement may be related to the inhibition of EphrinA3/EphA4, followed by activation of the cAMP/PKA pathway. 

Cognitive-exercise dual-task attenuates chronic cerebral ischemia-induced cognitive impairment by activating cAMP/PKA pathway through inhibiting EphrinA3/EphA4

Are more exercise components in combined cognitive and physical training better for older adults?: A systematic review and network meta-analysis of randomized controlled trials

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