Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging

Aging is a physiological process that can develop without the appearance of concurrent diseases. However, very frequently, older people suffer from memory loss and an accelerated cognitive decline. Studies of the neurobiology of aging are beginning to decipher the mechanisms underlying not only the physiology of aging of the brain but also the mechanisms that make people more vulnerable to cognitive dysfunction and neurodegenerative diseases. Today we know that the aging brain retains a considerable functional plasticity, and that this plasticity is positively promoted by genes activated by different lifestyle factors. In this article some of these lifestyle factors and their mechanisms of action are reviewed, including environmental enrichment and the importance of food intake and some nutrients. Aerobic physical exercise and reduction of chronic stress are also briefly reviewed. It is proposed that lifestyle factors are powerful instruments to promote healthy and successful aging of the brain and delay the appearance of age-related cognitive deficits in elderly people.

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Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish

Cell Death and Disease ◽

10.1038/s41419-021-03438-9 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Ting Zhao ◽

Shengfan Ye ◽

Zimu Tang ◽

Liwei Guo ◽

Zhipeng Ma ◽

...

Keyword(s):

Replicative Senescence ◽

Brain Aging ◽

Ventricular Zone ◽

Human Fibroblasts ◽

Cell Lineage ◽

Lineage Tracing ◽

Dependent Manner ◽

Loss Of Function ◽

Antioxidant Genes ◽

Age Related

AbstractReactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. EDU-labeling and cell lineage tracing showed that Δ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly, Δ113p53M/M mutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Δ113p53M/M zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate that Δ113p53 protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.

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Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology

Science Advances ◽

10.1126/sciadv.abe4601 ◽

2021 ◽

Vol 7 (21) ◽

pp. eabe4601

Author(s):

Sandro Da Mesquita ◽

Jasmin Herz ◽

Morgan Wall ◽

Taitea Dykstra ◽

Kalil Alves de Lima ◽

...

Keyword(s):

T Cells ◽

Cognitive Decline ◽

Brain Aging ◽

Therapeutic Potential ◽

T Cell Response ◽

Age Related ◽

Lymphatic Vasculature ◽

Amyloid Aβ ◽

Β Amyloid ◽

Old Mice

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

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Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

Aging Cell ◽

10.1111/acel.12498 ◽

2016 ◽

Vol 15 (5) ◽

pp. 893-902 ◽

Cited By ~ 46

Author(s):

Yan‐Fang Mao ◽

Zhangyu Guo ◽

Tingting Zheng ◽

Yasi Jiang ◽

Yaping Yan ◽

...

Keyword(s):

Young Adult ◽

Cognitive Deficits ◽

Intranasal Insulin ◽

Amyloid Pathology

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Chronic administration of ellagic acid improved the cognition in middle-aged overweight men

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2017-0583 ◽

2018 ◽

Vol 43 (3) ◽

pp. 266-273 ◽

Cited By ~ 11

Author(s):

Ying Liu ◽

Shuyi Yu ◽

Fen Wang ◽

Haitao Yu ◽

Xueli Li ◽

...

Keyword(s):

Lipid Metabolism ◽

Cognitive Deficits ◽

Ellagic Acid ◽

Acid Treatment ◽

Density Lipoprotein ◽

Normal Weight ◽

Middle Aged ◽

Adult Intelligence Scale ◽

Saliva Cortisol ◽

Age Related

This study aimed to investigate if ellagic acid has beneficial effects on cognitive deficits in middle-aged overweight individuals and to propose a possible mechanism. A total of 150 middle-aged male participants, including 76 normal-weight and 74 overweight men, aged between 45 to 55 years, were recruited for this study. Both normal-weight and overweight participants were administered either 50 mg ellagic acid or placebo cellulose daily for 12 weeks. Blood lipids, peripheral brain-derived neurotrophic factor (BDNF), and saliva cortisol were assessed on the last day of the procedure to investigate the effects induced by ellagic acid. The results revealed that ellagic acid treatment improved the levels of blood lipid metabolism with a 4.7% decline in total cholesterol, 7.3% decline in triglycerides, 26.5% increase in high-density lipoprotein, and 6.5% decline in low-density lipoprotein. Additionally, ellagic acid increased plasma BDNF by 21.2% in the overweight group and showed no effects on normal-weight participants. Moreover, the increased saliva cortisol level in overweight individuals was inhibited by 22.7% in a 12-week ellagic acid treatment. Also, compared with placebo, overweight individuals who consumed ellagic acid showed enhanced cognitive function as measured by the Wechsler Adult Intelligence Scale-Revised and the Montreal Cognitive Assessment. To the best of our knowledge, this is the first report showing that ellagic acid prevents cognitive deficits through normalization of lipid metabolism, increase in plasma BDNF level, and reduction of saliva cortisol concentration. These results indicate that ellagic acid has a potential to restore cognitive performance related to mild age-related declines.

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Age-related disturbances in DNA (hydroxy)methylation in APP/PS1 mice

Translational Neuroscience ◽

10.1515/tnsci-2018-0028 ◽

2018 ◽

Vol 9 (1) ◽

pp. 190-202 ◽

Cited By ~ 3

Author(s):

Leonidas Chouliaras ◽

Roy Lardenoije ◽

Gunter Kenis ◽

Diego Mastroeni ◽

Patrick R. Hof ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Dna Methylation ◽

Brain Aging ◽

Wild Type ◽

Dna Hydroxymethylation ◽

Quantitative Immunohistochemistry ◽

Age Related ◽

Aberrant Dna Methylation ◽

Methylation Patterns ◽

Age Related Changes

Abstract Brain aging has been associated with aberrant DNA methylation patterns, and changes in the levels of DNA methylation and associated markers have been observed in the brains of Alzheimer’s disease (AD) patients. DNA hydroxymethylation, however, has been sparsely investigated in aging and AD. We have previously reported robust decreases in 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the hippocampus of AD patients compared to non-demented controls. In the present study, we investigated 3- and 9-month-old APPswe/PS1ΔE9 transgenic and wild-type mice for possible age-related alterations in 5-mC and 5-hmC levels in three hippocampal sub-regions using quantitative immunohistochemistry. While age-related increases in levels of both 5-mC and 5-hmC were found in wild-type mice, APPswe/PS1ΔE9 mice showed decreased levels of 5-mC at 9 months of age and no age-related changes in 5-hmC throughout the hippocampus. Altogether, these findings suggest that aberrant amyloid processing impact on the balance between DNA methylation and hydroxymethylation in the hippocampus during aging in mice.

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Impairments in Brain Bioenergetics in Aging and Tau Pathology: A Chicken and Egg Situation?

Cells ◽

10.3390/cells10102531 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2531

Author(s):

Amandine Grimm

Keyword(s):

Brain Metabolism ◽

Brain Aging ◽

Cognitive Impairments ◽

Tau Phosphorylation ◽

The Body ◽

Tau Pathology ◽

Age Related ◽

Energy Consuming ◽

Effects Of Aging ◽

The Brain

The brain is the most energy-consuming organ of the body and impairments in brain energy metabolism will affect neuronal functionality and viability. Brain aging is marked by defects in energetic metabolism. Abnormal tau protein is a hallmark of tauopathies, including Alzheimer’s disease (AD). Pathological tau was shown to induce bioenergetic impairments by affecting mitochondrial function. Although it is now clear that mutations in the tau-coding gene lead to tau pathology, the causes of abnormal tau phosphorylation and aggregation in non-familial tauopathies, such as sporadic AD, remain elusive. Strikingly, both tau pathology and brain hypometabolism correlate with cognitive impairments in AD. The aim of this review is to discuss the link between age-related decrease in brain metabolism and tau pathology. In particular, the following points will be discussed: (i) the common bioenergetic features observed during brain aging and tauopathies; (ii) how age-related bioenergetic defects affect tau pathology; (iii) the influence of lifestyle factors known to modulate brain bioenergetics on tau pathology. The findings compiled here suggest that age-related bioenergetic defects may trigger abnormal tau phosphorylation/aggregation and cognitive impairments after passing a pathological threshold. Understanding the effects of aging on brain metabolism may therefore help to identify disease-modifying strategies against tau-induced neurodegeneration.

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Electrophysiological signatures of brain aging in autism spectrum disorder

10.1101/2021.03.18.434885 ◽

2021 ◽

Author(s):

Abigail Dickinson ◽

Shafali Jeste ◽

Elizabeth Milne

Keyword(s):

Autism Spectrum Disorder ◽

Brain Aging ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Aging Brain ◽

Significant Group ◽

Care Plans ◽

Alpha Frequency ◽

Age Related ◽

Adults With Asd

AbstractEmerging evidence suggests that aging processes may be altered in adults with autism spectrum disorder (ASD). However, it remains unclear if oscillatory slowing, a key neurophysiological change in the aging brain, manifests atypically in this population. This study sought to examine patterns of age-related oscillatory slowing in adults with ASD, captured by reductions in the brain’s peak alpha frequency. Resting-state EEG data from adults (18-70 years) with ASD (N=93) and age-matched neurotypical (NT) controls (N=87) were pooled from three independent datasets. A robust curve-fitting procedure quantified the peak frequency of alpha oscillations (7-13Hz) across all brain regions. Associations between peak alpha frequency and age were assessed and compared between groups. Consistent with characteristic patterns of oscillatory slowing, peak alpha frequency was negatively associated with age across the entire sample (p<.0001). A significant group by age interaction revealed that this relationship was more pronounced in adults with ASD (p<.01), suggesting that that age-related oscillatory slowing may be accelerated in this population. Scalable EEG measures such as peak alpha frequency could provide insights into neural aging that are crucially needed to inform care plans and preventive interventions that can promote successful aging in ASD.

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Tip60 protects against amyloid-β peptide-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegenerative progression

10.1101/2020.06.09.142885 ◽

2020 ◽

Author(s):

Haolin Zhang ◽

Bhanu Chandra Karisetty ◽

Akanksha Bhatnagar ◽

Ellen M. Armour ◽

Mariah Beaver ◽

...

Keyword(s):

Cell Death ◽

Cognitive Deficits ◽

Late Stage ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Neuronal Cell ◽

Amyloid Β Peptide ◽

Histone Deacetylase 2 ◽

Age Related ◽

Late Stages

ABSTRACTAlzheimer’s disease (AD) is an age-related neurodegenerative disorder hallmarked by amyloid-β (Aβ) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferases (HAT) Tip60 and increased histone deacetylase 2 (HDAC2) levels, can directly contribute to AD pathology. However, whether such AD-associated neuroepigenetic alterations occur in response to Aβ peptide production and can be protected against by increasing Tip60 levels over the course of neurodegenerative progression remains unknown. Here we profile Tip60 HAT/HDAC2 dynamics and transcriptome-wide changes across early and late stage AD pathology in the Drosophila brain produced solely by human amyloid-β42. We show that early Aβ42 induction leads to disruption of Tip60 HAT/HDAC2 balance during early neurodegenerative stages preceding Aβ plaque accumulation that persists into late AD stages. Correlative transcriptome-wide studies reveal alterations in biological processes we classified as transient (early-stage only), late-onset (late-stage only), and constant (both). Increasing Tip60 HAT levels in the Aβ42 fly brain protects against AD functional pathologies that include Aβ plaque accumulation, neural cell death, cognitive deficits, and shorter life-span. Strikingly, Tip60 protects against Aβ42-induced transcriptomic alterations via distinct mechanisms during early and late stages of neurodegeneration. Our findings reveal distinct modes of neuroepigenetic gene changes and Tip60 neuroprotection in early versus late stages in AD that can serve as early biomarkers for AD, and support the therapeutic potential of Tip60 over the course of AD progression.

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