scholarly journals Cerebral Mitochondrial Function and Cognitive Performance during Aging: A Longitudinal Study in NMRI Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Martina Reutzel ◽  
Rekha Grewal ◽  
Benjamin Dilberger ◽  
Carmina Silaidos ◽  
Aljoscha Joppe ◽  
...  
Keyword(s):  
Longitudinal Data ◽  
Cognitive Performance ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Aging Process ◽  
Brain Aging ◽  
Model Organisms ◽  
Nmri Mice ◽  
Aged Mice ◽  
The Brain

Brain aging is one of the major risk factors for the development of several neurodegenerative diseases. Therefore, mitochondrial dysfunction plays an important role in processes of both, brain aging and neurodegeneration. Aged mice including NMRI mice are established model organisms to study physiological and molecular mechanisms of brain aging. However, longitudinal data evaluated in one cohort are rare but are important to understand the aging process of the brain throughout life, especially since pathological changes early in life might pave the way to neurodegeneration in advanced age. To assess the longitudinal course of brain aging, we used a cohort of female NMRI mice and measured brain mitochondrial function, cognitive performance, and molecular markers every 6 months until mice reached the age of 24 months. Furthermore, we measured citrate synthase activity and respiration of isolated brain mitochondria. Mice at the age of three months served as young controls. At six months of age, mitochondria-related genes (complex IV, creb-1, β-AMPK, and Tfam) were significantly elevated. Brain ATP levels were significantly reduced at an age of 18 months while mitochondria respiration was already reduced in middle-aged mice which is in accordance with the monitored impairments in cognitive tests. mRNA expression of genes involved in mitochondrial biogenesis (cAMP response element-binding protein 1 (creb-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), nuclear respiratory factor-1 (Nrf-1), mitochondrial transcription factor A (Tfam), growth-associated protein 43 (GAP43), and synaptophysin 1 (SYP1)) and the antioxidative defense system (catalase (Cat) and superoxide dismutase 2 (SOD2)) was measured and showed significantly decreased expression patterns in the brain starting at an age of 18 months. BDNF expression reached, a maximum after 6 months. On the basis of longitudinal data, our results demonstrate a close connection between the age-related decline of cognitive performance, energy metabolism, and mitochondrial biogenesis during the physiological brain aging process.

scholarly journals Effects of Long-Term Treatment with a Blend of Highly Purified Olive Secoiridoids on Cognition and Brain ATP Levels in Aged NMRI Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Martina Reutzel ◽  
Rekha Grewal ◽  
Carmina Silaidos ◽  
Jens Zotzel ◽  
Stefan Marx ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Citrate Synthase ◽  
Brain Aging ◽  
Mrna Levels ◽  
Nmri Mice ◽  
Aged Mice ◽  
Atp Levels ◽  
Long Term Treatment ◽  
The Brain

Aging represents a major risk factor for developing neurodegenerative diseases such as Alzheimer’s disease (AD). As components of the Mediterranean diet, olive polyphenols may play a crucial role in the prevention of AD. Since mitochondrial dysfunction acts as a final pathway in both brain aging and AD, respectively, the effects of a mixture of highly purified olive secoiridoids were tested on cognition and ATP levels in a commonly used mouse model for brain aging. Over 6 months, female NMRI mice (12 months of age) were fed with a blend containing highly purified olive secoiridoids (POS) including oleuropein, hydroxytyrosol and oleurosid standardized for 50 mg oleuropein/kg diet (equivalent to 13.75 mg POS/kg b.w.) or the study diet without POS as control. Mice aged 3 months served as young controls. Behavioral tests showed deficits in cognition in aged mice. Levels of ATP and mRNA levels of NADH-reductase, cytochrome-c-oxidase, and citrate synthase were significantly reduced in the brains of aged mice indicating mitochondrial dysfunction. Moreover, gene expression of Sirt1, CREB, Gap43, and GPx-1 was significantly reduced in the brain tissue of aged mice. POS-fed mice showed improved spatial working memory. Furthermore, POS restored brain ATP levels in aged mice which were significantly increased. Our results show that a diet rich in purified olive polyphenols has positive long-term effects on cognition and energy metabolism in the brain of aged mice.

scholarly journals A Walnut-enriched Diet and Physical Activity Enhanced Cognitive and Motor Function in Aged Mice (P14-010-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Carsten Esselun ◽  
Benjamin Dilberger ◽  
Carmina Silaidos ◽  
Gunter Eckert
Keyword(s):  
Physical Activity ◽  
Spatial Memory ◽  
Motor Function ◽  
Mitochondrial Function ◽  
Brain Aging ◽  
Enriched Environment ◽  
Motor Functions ◽  
Nmri Mice ◽  
Aged Mice ◽  
Y Maze

Abstract Objectives This study aims to investigate walnut's effect alone and in combination with an enriched environment on brain aging of aged NMRI mice by investigation of cognition and motor functions. Furthermore, it aims to identify the underlying mechanisms by evaluating the expression of relevant genes. Methods NMRI mice (12mo.) were fed with a 6% walnut-enriched diet (WED) or control diet respectively, for the duration of 6 months. Additionally, one WED group was exposed to an enriched environment. Cognition and motor functions were assessed to evaluate walnut's effect on spatial memory, general physical activity and motor coordination. Conducted tests included Y-Maze alternation, open field and rotarod. Expression levels of relevant genes including synaptophysin, NGF and BDNF were measured via qPCR in brain tissue. Mitochondrial function was investigated by testing for ATP levels and mitochondrial membrane potential in dissociated brain cells and oxygen consumption of the oxidative phosphorylation system of freshly isolated mitochondria. Results Intake of the walnut diet significantly increased the alternation rate in a Y-Maze experiment (P < 0.05). Physical activity did not further improve this effect on spatial memory of mice, but increased mice’ activity (P < 0.001) in general. Motor function in rotarod test was not improved by walnut intake alone, but significantly increased by added enrichment (P < 0.01). Gene expression of synaptophysin was significantly increased for walnuts alone (P < 0.05), while BDNF and NGF expression appeared to be unaffected. Additional enriched environment resulted in a trend for these genes to be increased as well. Results imply that mitochondrial function is not linked to these improvements. Conclusions Long term walnut diet significantly improved cognitive function in aged mice. Physical activity additionally improved motor functions. These benefits could possibly be explained by increased expression of genes involved in neuronal plasticity. Funding Sources Grant from California Walnut Commission.

scholarly journals A Walnut-Enriched Diet Modifies the Oxylipin Profile in Liver and Brain of Aged Mice — Impact on Inflammation Markers

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1203-1203
Author(s):  
Gunter Eckert ◽  
Gunter Esselun ◽  
Elisabeth Koch ◽  
Nils Schebb
Keyword(s):  
Physical Activity ◽  
Fatty Acids ◽  
Brain Aging ◽  
Inflammatory Marker ◽  
Inflammation Markers ◽  
Aged Mice ◽  
Funding Sources ◽  
Age Related ◽  
The Brain ◽  
Related Increase

Abstract Objectives Neuroinflammation contributes to brain-aging which may be mitigated by anti-inflammatory oxylipins. Based on our previous findings that a 6% walnut-enriched diet alone, and additional physical activity (PA), enhanced cognition in 18 months old NMRI, we now investigated the effects of this diet on oxylipin- and inflammatory marker levels in liver and brain. Methods 18 months and 3 months old female NMRI mice were fed with a 6% walnut-enriched diet. Oxylipins were determined in brain and liver sections using LC-MS. Expression of IL1β gene was determined by qRT-PCR. Results The walnut diet compensates for the age related increase in IL1β gene expression in the liver of mice, whereas expression in the brain was not affected. Basal levels of oxylipins in brain and liver samples isolated from young mice were generally lower compared to aged mice. The walnut diet further increased oxylipin levels of walnut specific fatty acids in liver and brain of aged mice. Enrichment of linoleic acid (LA) and α-linolenic acid (ALA) derived oxylipin levels were quantitatively higher in the liver compared to the brain (P &lt; 0.0001). Hydroxy-oxylipins (HO) based on fatty acid LA were significantly increased in brain (P &lt; 0.001) and liver (P &lt; 0.0001) compared to control mice, while ALA based HO were only detected in the brains of walnut fed mice. The walnut diet in combination with physical activity (PA) reduced ARA based oxylipin levels (P &lt; 0.05). Across all groups, concentrations of prostanoids were higher in the brain as compared to liver (P &lt; 0.001). In the liver, walnuts tended to decrease PGD2 and TxB2 levels while increasing 6-keto PGF1α. The latter, as well as TxB2 tended to be decreased in the brain. Other ARA based prostanoids were unaffected. Effects of PA were contrary to each other, tending to increase ARA based prostanoids in the liver while decreasing them in the brain. PA further enhanced this effect in the brain, but tended to increase the inflammatory response in the liver. Conclusions A walnut diet differentially affects the oxylipin profile of liver and brain in aged mice. Production of oxylipins based on walnut fatty acids is generally increased. Attenuation of age-related, chronic inflammation in might be one of walnut's benefits and may contribute to a healthier aging of the brain. Funding Sources Research was supported by grants from California Walnut Commission.

Abstract 13: Relations of Midlife Exercise Blood Pressure, Heart Rate and Fitness to Late Life Brain Structure and Function

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Nicole L Spartano ◽  
Jayandra J Himali ◽  
Alexa S Beiser ◽  
Charles DeCarli ◽  
Ramachandran S Vasan ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Frontal Lobe ◽  
Cognitive Performance ◽  
Brain Aging ◽  
Later Life ◽  
Older Age ◽  
Vascular Stiffness ◽  
Response To Exercise ◽  
The Brain

Background: Exaggerated blood pressure (BP) and vascular stiffness have been associated with lower cognitive performance and brain atrophy in older age. The brain is a high-flow, low impedance organ that is susceptible to fluctuation in BP. Poor cardiovascular (CV) fitness is also emerging as a factor associated with cognitive decline in older age. The BP and heart rate (HR) response to exercise are impacted by CV fitness; and exercise BP is also highly determined by vascular stiffness. The objective of this investigation was to examine whether poor fitness and exaggerated BP and HR response to exercise in midlife are associated with worse brain morphology in later life. Methods: A subset of Framingham Offspring Study participants (n=1340, 54.5% F) free from dementia and CV disease underwent an exercise treadmill test (the modified Bruce protocol) in midlife [mean age of 41±9 y] and continued until exhaustion or until 85% HR maximum (age- and sex- predicted) was reached. Exercise test duration was used to estimate VO2max. BP and HR were measured during stage 2. MRI scans of the brain and neurocognitive tests (Trail Making Tests [Trails] B-A) were administered in later life [mean age of 59±9 y]. Results: A greater exercise systolic (S)BP and HR response at midlife was associated with smaller total cerebral brain volume (TCBV) in later life (β=-0.09 ±0.04, p=0.042; β=-0.10 ±0.05, p=0.033) after adjustment models including resting SBP and HR; an effect equal to approximately 0.5 y brain aging for every 11.1 mm Hg increase in SBP or 10 beats per min increase in HR. Higher estimated VO2max at midlife was associated with larger TCBV in later life (β=0.03 ±0.01, p=0.014). Additionally, greater exercise HR response at midlife was associated with smaller frontal lobe volume in later life (β=-0.012 ±0.05, p=0.002). Exercise diastolic (D)BP at midlife was associated with poorer performance on Trails B-A in later life (β=-0.009 ±0.004, p=0.017) and the achievement of target HR during exercise was associated with better performance on Trails B-A in later life (β=0.03 ±0.01, p=0.044). Resting SBP at midlife was associated with greater white matter hyperintensity volume in later life (β=0.05 ±0.02, p=0.031); and resting SBP and DBP at midlife were also associated with smaller frontal lobe volume in later life (β=-0.17 ±0.07, p=0.011; β=-0.21 ±0.10, p=0.030). Conclusion: Our investigation provides new evidence that lower midlife fitness and worse exercise BP and HR responses are associated with smaller brain volumes and poorer cognitive performance nearly two decades later. Promotion of midlife physical fitness may be an important step towards ensuring healthy brain aging in the population.

scholarly journals CDKN2A Gene Expression as a Potential Aging Biomarker in Dogs

2021 ◽  
Vol 8 ◽  
Author(s):  
Sára Sándor ◽  
Kitti Tátrai ◽  
Kálmán Czeibert ◽  
Balázs Egyed ◽  
Enikő Kubinyi
Keyword(s):  
Gene Expression ◽  
Kinase Inhibitor ◽  
Brain Aging ◽  
Model Organisms ◽  
Aging Research ◽  
Temporal Muscle ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Age Related ◽  
The Brain

Describing evolutionary conserved physiological or molecular patterns, which can reliably mark the age of both model organisms and humans or predict the onset of age-related pathologies has become a priority in aging research. The age-related gene-expression changes of the Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) gene have been well-documented in humans and rodents. However, data is lacking from other relevant species, including dogs. Therefore, we quantified the CDKN2A mRNA abundance in dogs of different ages, in four tissue types: the frontal cortex of the brain, temporal muscle, skin, and blood. We found a significant, positive correlation between CDKN2A relative expression values and age in the brain, muscle, and blood; however, no correlation was detected in the skin. The strongest correlation was detected in the brain tissue (CDKN2A/GAPDH: r = 0.757, p &lt; 0.001), similarly to human findings, while the muscle and blood showed weaker, but significant correlation. Our results suggest that CDKN2A might be a potential blood-borne biomarker of aging in dogs, although the validation and optimization will require further, more focused research. Our current results also clearly demonstrate that the role of CDKN2A in aging is conserved in dogs, regarding both tissue specificity and a pivotal role of CDKN2A in brain aging.

scholarly journals Oroxylum Indicum ameliorates chemotherapy induced cognitive impairment

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252522
Author(s):  
Satyanarayana R. Pondugula ◽  
Mohammed Majrashi ◽  
Mohammed Almaghrabi ◽  
Sindhu Ramesh ◽  
Kodye L. Abbott ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Performance ◽  
Mitochondrial Function ◽  
Chemical Constituents ◽  
Lipid Peroxide ◽  
Chemotherapeutic Agents ◽  
Glutathione Depletion ◽  
Spatial Learning And Memory ◽  
Oroxylum Indicum ◽  
The Brain

While chemotherapy is the most effective therapeutic approach for treating a variety of cancer patients, commonly used chemotherapeutic agents, often induce several adverse effects. Escalating evidence indicates that chemotherapeutics, particularly doxorubicin (DOX) and cyclophosphamide (CPS), induce cognitive impairment associated with central nervous system toxicity. This study was performed to determine neuroprotective effects of Oroxylum indicum extract (OIE) in regard to preventing chemotherapy induced cognitive impairment (CICI) occurring after 4 cycles of DOX (2mg/kg) and CPS (50mg/kg) combination chemotherapy in male C57BL/6J mice. OIE significantly prevented the chemotherapy impaired short-term cognitive performance, exploratory behavior associated with cognitive performance, cognitive performance, and spatial learning and memory in the Y-maze, Open-Field, Novel Object Recognition, and Morris Water Maze tests, respectively. These data suggest that OIE protects from the CICI. OIE decreased the reactive oxygen species and lipid peroxide generated by the chemotherapy treatment in the brain, while also blocking the chemotherapy-induced glutathione depletion. These results establish that OIE exhibits potent antioxidant activity in chemotherapy treated mice. Notably, OIE significantly increased the Complex-I and Complex-IV activities in the brain, indicating that OIE enhances mitochondrial function in the brain. In silico analysis of the major active chemical constituents (Oroxylin A, Baicalein and Chrysin) of OIE indicated that OIE has a favorable absorption, distribution, metabolism and excretion (ADME) profile. Taken together, our results are consistent with the conclusion that OIE prevents CICI by counteracting oxidative stress and perhaps by improving mitochondrial function.

scholarly journals The Role of AhR in the Hallmarks of Brain Aging: Friend and Foe

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2729
Author(s):  
Emmanuel S. Ojo ◽  
Shelley A. Tischkau
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
Aging Process ◽  
Cell Activation ◽  
Brain Aging ◽  
Aryl Hydrocarbon ◽  
Glial Cell Activation ◽  
The Impact ◽  
The Brain

In recent years, aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has been considered to be involved in aging phenotypes across several species. This receptor is a highly conserved biosensor that is activated by numerous exogenous and endogenous molecules, including microbiota metabolites, to mediate several physiological and toxicological functions. Brain aging hallmarks, which include glial cell activation and inflammation, increased oxidative stress, mitochondrial dysfunction, and cellular senescence, increase the vulnerability of humans to various neurodegenerative diseases. Interestingly, many studies have implicated AhR signaling pathways in the aging process and longevity across several species. This review provides an overview of the impact of AhR pathways on various aging hallmarks in the brain and the implications for AhR signaling as a mechanism in regulating aging-related diseases of the brain. We also explore how the nature of AhR ligands determines the outcomes of several signaling pathways in brain aging processes.

scholarly journals An Augmented Aging Process in Brain White Matter in HIV

2018 ◽  
Author(s):  
T. Kuhn ◽  
T. Kaufmann ◽  
N.T. Doan ◽  
L.T. Westlye ◽  
J. Jones ◽  
...  
Keyword(s):  
White Matter ◽  
Hiv Infection ◽  
Cognitive Performance ◽  
Aging Process ◽  
Brain Aging ◽  
Diffusion Tensor ◽  
Adult Life ◽  
Support Vector ◽  
Support Vector Regression Model ◽  
Brain White Matter

AbstractObjectiveHIV infection and aging are both associated with neurodegeneration. However, whether the aging process alone or other factors associated with advanced age account for the progression of neurodegeneration in the aging HIV-positive (HIV+) population remains unclear.MethodsHIV+ (n=70) and HIV-negative (HIV-, n=34) participants underwent diffusion tensor imaging (DTI) and metrics of microstructural properties were extracted from regions of interest (ROIs). A support vector regression model was trained on two independent datasets of healthy adults across the adult life-span (n=765, Cam-CAN = 588; UiO = 177) to predict participant age from DTI metrics, and applied to the HIV dataset. Predicted brain age gap (BAG) was computed as the difference between predicted age and chronological age, and statistically compared between HIV groups. Regressions assessed the relationship between BAG and HIV severity/medical comorbidities. Finally, correlation analyses tested for associations between BAG and cognitive performance.ResultsBAG was significantly higher in the HIV+ group than the HIV-group F (1, 103) = 12.408, p = 0.001). HIV RNA viral load was significantly associated with BAG, particularly in older HIV+ individuals (R2 = 0.29, F(7, 70) = 2.66, p = 0.021). Further, BAG was negatively correlated with domain-level cognitive function (learning: r = −0.26, p = 0.008; memory: r = −0.21, p = 0.034).ConclusionsHIV infection is associated with augmented white matter aging, and greater brain aging is associated with worse cognitive performance in multiple domains.

scholarly journals Accelerated Brain Aging in Mild Traumatic Brain Injury: Longitudinal Pattern Recognition With White Matter Integrity

2020 ◽  
Author(s):  
Shuoqiu Gan ◽  
Wen Shi ◽  
Shan Wang ◽  
Yingxiang Sun ◽  
Bo Yin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Prediction Model ◽  
Mild Traumatic Brain Injury ◽  
Aging Process ◽  
Brain Aging ◽  
Post Injury ◽  
Brain Age ◽  
The Brain ◽  
Age Prediction

Abstract Background: Long-term effects of mild traumatic brain injury (mTBI) resemble brain aging changes (i.e., microstructure integrity loss), which implies an accelerated age-associated process. This study aimed to develop a quantifiable neuroimaging marker to characterize the brain-aging process accelerated by mTBI from acute to chronic phases. Methods: A brain-age prediction model was defined using relevance vector regression (RVR) in 523 healthy individuals, based on fractional anisotropy metrics from diffusion-tensor imaging. The model was adopted to estimate brain-predicted age difference (brain-PAD = predicted brain age - chronological age) in 116 acute mTBI patients and 63 healthy controls (HCs). Fifty patients were followed up 6~12 month post-injury to evaluate the longitudinal changes in brain-PAD. Another mTBI group containing 70 acute patients were included as a replicated cohort. We investigated whether brain-PAD was greater in patients with elderly age, post-concussion complaints, and risky apolipoprotein E (APOE) genotype, and whether it had the potential to predict neuropsychological outcomes for information processing speed (IPS). Between-group and longitudinal comparison in brain-PAD was conducted with analysis of covariance and linear mixed-effects model, respectively. The correlation between brain-PAD and continuous variables was analyzed with Spearman rank-order correlation.Results: The RVR brain-age prediction model predicted brain age accurately (r = 0.96, R2 = 0.93). The brain age of mTBI patients was estimated to be "older" in the acute phase, with mean brain-PAD of 2.59 (± 5.97) years compared with HCs (0.12 ± 3.19 years) (P < 0.05) and replicated in another mTBI cohort (brain-PAD: 3.26 ± 4.55 years). The increased brain age in mTBI kept stable at 6-12 month post-injury (2.50 ± 4.54 years). Patients with older age or severer post-concussion complaints obtained greater brain-PAD (P < 0.001, P = 0.024), while patients with APOE ε4 didn’t obtain greater brain-PAD than those without. Additionally, brain-PAD in the acute phase predicted patients’ IPS profile at 6~12 month follow-up (rho = -0.36, P = 0.01). Conclusion: Mild TBI, even a single one, accelerates the brain-aging process. The brain-PAD can be considered as a quantitative neuroimaging marker to evaluate the susceptibility to neurodegeneration or other age-associated conditions following mTBI. Trial registration: NCT02868684.

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