Lentivirus-mediated klotho up-regulation improves aging-related memory deficits and oxidative stress in senescence-accelerated mouse prone-8 mice

Zhou, Hongjing; Zeng, Chenye; Yang, Tingting; Long, Fangyi; Kuang, Xi; Du, Jun-Rong

doi:10.1016/j.lfs.2018.03.027

Cited by 43 publications

(36 citation statements)

References 28 publications

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“…These aged macaque monkeys exhibited traits similar to those of human patients with Alzheimer's disease ( 26 , 27 ). It was recently demonstrated that gene therapy via Clustered Regularly Interspaced Short Palindromic Repeats technology increased the expression of Klotho, which improved the cognitive ability of experimental mice ( 28 , 29 ).…”

Section: Discussionmentioning

confidence: 99%

Aerobic exercise‑stimulated Klotho upregulation extends life span by attenuating the excess production of reactive oxygen species in the brain and kidney

Luan

et al. 2018

Exp Ther Med

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Aerobic exercise induces many adaptive changes in the whole body and improves metabolic characteristics. Klotho, an anti-aging gene, is mainly expressed in the brain and kidney. The roles of Klotho in the brain and kidney during aerobic exercise remain largely unknown. The present study aimed to determine whether aerobic exercise could influence the expression of Klotho, decrease reactive oxygen species (ROS) and prolong life span. Sprague Dawley rats were exercised on a motor treadmill. Klotho mRNA and protein expression levels in rat brain and kidney tissues were examined using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. ROS production was detected following intermittent aerobic exercise (IAE) or continuous aerobic exercise (CAE). Kaplan-Meier curve analysis demonstrated that aerobic exercise significantly improved rat survival (P<0.001). The ROS levels in rat brain and kidney tissues were decreased in the aerobic exercise groups compared with the control group (P<0.05). In addition, Klotho mRNA and protein expression levels were increased significantly following aerobic exercise compared with controls (P<0.05). There was no significant difference between the IAE and CAE groups in any experiments (P>0.05). These results suggest that aerobic exercise-stimulated Klotho upregulation extends the life span by attenuating the excess production of ROS in the brain and kidney. As Klotho exhibits a potential anti-aging effect, promoting Klotho expression through aerobic exercise may be a novel approach for the prevention and treatment of aging and aging-related diseases.

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Section: Discussionmentioning

confidence: 99%

Aerobic exercise‑stimulated Klotho upregulation extends life span by attenuating the excess production of reactive oxygen species in the brain and kidney

Luan

et al. 2018

Exp Ther Med

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“…The confirmation of oxidative stress increase with age of diverse organisms, and the generation of transgenic invertebrates overexpressing the antioxidant enzymes with increased lifespan were among the most important results of these studies 36–39. Nevertheless, there were no alterations in the lifespan in most of the examined mouse models, which under- or overexpressed a wide variety of genes coding for antioxidant enzymes 40–42. Thus, the role of oxidative stress in aging mammals is not fully understood and still demands further inquiries 43,44…”

Section: Introductionmentioning

confidence: 99%

<p>Changes in the blood antioxidant defense of advanced age people</p>

Kozakiewicz¹,

Kornatowski²,

Krzywińska³

et al. 2019

CIA

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Introduction: Since 1956 there have been numerous scientific articles about free radical theory of aging which both confirm and deny the theory. Due to oxygen metabolism, there are relatively high concentrations of molecular oxygen in human cells, especially in mitochondria. Under normal physiological conditions, a small fraction of oxygen is constantly converted to ROS, such as superoxide radical (O2 −• ), H 2 O 2 , and related metabolites. Aim of the study: The aim of this work was to show the relation between the activity of main antioxidative enzymes and the age of the examined patients. Materials and methods: The analysis of antioxidant defense was performed on the blood samples from 184 “aged“ individuals aged 65–90+ years, and compared to the blood samples of 37 individuals just about at the beginning of aging, aged 55–59 years. Results: The statistically significant decreases of Zn,Cu-superoxide dismutase (SOD-1), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were observed in elderly people in comparison with the control group. Moreover, an inverse correlation between the activities of SOD-1, CAT, and GSH-Px and the age of the examined persons was found. No age-related changes in glutathione reductase activities and malondialdehyde concentrations were observed. Conclusion: Lower activities of fundamental antioxidant enzymes in the erythrocytes of elderly people, which indicate the impairment of antioxidant defense in the aging organism and the intensity of peroxidative lipid structures, were observed.

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“…Since it has been shown previously that overexpression of full-length α-Klotho affects neurogenesis (Zhou et al, 2018), we tested whether human secreted Klotho expressed in CA1 neurons enhances pluripotency in the SGZ (Laszczyk et al, 2017). Several transcription factors have been described that can be utilized to evaluate the state of newly developed cells (Salech et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…For example, transgenic mice with systemic overexpression of Klotho-VS, a lifespan-extending variant of the human klotho gene, have been found to age-independently perform better than control mice in Morris water maze and Y-maze tests (Dubal et al, 2014), two tests that evaluate spatial memory. Another study found that overexpression of secreted Klotho in response to infection of neurons by intraventricular injection with a lentivirus-based expression system significantly improved the performance of SAMP8 mice in the Y-maze task (Zhou et al, 2018). Surprisingly, peripheral administration of a recombinant α-Klotho fragment (KL1+KL2) was found to be sufficient to enhance memory performance in the Morris water maze and Y-maze in young, aging, and transgenic α-synuclein mice (Leon et al, 2017), even though this fragment does not cross the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Expression of Secreted α-Klotho in the Hippocampus Alters Nesting Behavior and Memory Formation in Mice

Jing

Liu

et al. 2019

Front. Cell. Neurosci.

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The klotho gene family consists of α-, β-, and γ-Klotho, which encode type I single-pass transmembrane proteins with large extracellular domains. α-Klotho exists as a full-length membrane-bound and as a soluble form after cleavage of the extracellular domain. Due to gene splicing, a short extracellular Klotho form can be expressed and secreted. Inactivation of α-Klotho leads to a phenotype that resembles accelerated aging, as the expression level of the α-Klotho protein in the hippocampal formation of mice decreases with age. Here, we show that intrahippocampal viral expression of secreted human α-Klotho alters social behavior and memory formation. Interestingly, overexpression of secreted human α-Klotho in the CA1 changed the nest-building behavior and improved object recognition, object location and passive avoidance memory. Moreover, α-Klotho overexpression increased hippocampal synaptic transmission in response to standardized stimulation strengths, altered paired-pulse facilitation of synaptic transmission, and enhanced activity-dependent synaptic plasticity. These results indicate that memory formation benefits from an augmented level of secreted α-Klotho.

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Lentivirus-mediated klotho up-regulation improves aging-related memory deficits and oxidative stress in senescence-accelerated mouse prone-8 mice

Cited by 43 publications

References 28 publications

Aerobic exercise‑stimulated Klotho upregulation extends life span by attenuating the excess production of reactive oxygen species in the brain and kidney

Aerobic exercise‑stimulated Klotho upregulation extends life span by attenuating the excess production of reactive oxygen species in the brain and kidney

<p>Changes in the blood antioxidant defense of advanced age people</p>

Enhanced Expression of Secreted α-Klotho in the Hippocampus Alters Nesting Behavior and Memory Formation in Mice

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