Knockout of the longevity gene Klotho perturbs aging and Alzheimer's disease-linked brain microRNAs and tRNA fragments.

Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse formation. However, comprehensive analysis of Klotho knockout effects on mammalian brain transcriptomics is lacking. Here, we report that Klotho knockout alters the levels of aging- and cognition related mRNAs, long non-coding RNAs, microRNAs and tRNA fragments.

Knockout of the longevity gene Klotho perturbs aging- and Alzheimer's disease-linked brain microRNAs and tRNA fragments.

Overexpression of the longevity gene Klotho prolongs, while its knockout shortens lifespan and impairs cognition via altered fibroblast growth factor signaling that perturbs myelination and synapse formation; however, comprehensive analysis of Klotho's knockout consequences on mammalian brain transcriptomics is lacking. Here, we report the altered levels under Klotho knockout of 1059 long RNAs, 27 microRNAs (miRs) and 6 tRNA fragments (tRFs), reflecting effects upon aging and cognition. Perturbed transcripts included key neuronal and glial pathway regulators that are notably changed in murine models of aging and Alzheimer's Disease (AD) and in corresponding human post-mortem brain tissue.

Differential toxicity profile of secreted and processed α-Klotho expression over mineral metabolism and bone microstructure.

The aging-protective gene α-Klotho (KL) produces two main transcripts. The full-length mRNA generates a transmembrane protein that after proteolytic ectodomain shedding can be detected in serum as processed Klotho (p-KL), and a shorter transcript which codes for a putatively secreted protein (s-KL). Both isoforms exhibit potent pleiotropic beneficial properties, although previous reports showed negative side effects on mineral homeostasis after increasing p-KL concentration exogenously.

Aging-suppressor Klotho: Prospects in diagnostics and therapeutics.

Introduction: The protein Klotho (KL) was first discovered in KL-deficient mice, which developed a syndrome similar to premature aging in humans. Since then, KL has been implicated in multiple molecular signaling pathways and diseases. KL has been shown to have anti-aging, healthspan and lifespan extending, cognitive enhancing, anti-oxidative, anti-inflammatory, and anti-tumor properties.

A Transgenic Model Reveals the Role of Klotho in Pancreatic Cancer Development and Paves the Way for New Klotho-Based Therapy.

Klotho is an anti-aging transmembrane protein, which can be shed and can function as a hormone. Accumulating data indicate that klotho is a tumor suppressor in a wide array of malignancies, and designate the subdomain KL1 as the active region of the protein towards this activity. We aimed to study the role of klotho as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC).

miR-142-3p regulates cortical oligodendrocyte gene co-expression networks associated with tauopathy.

Oligodendrocytes exist in a heterogenous state and are implicated in multiple neuropsychiatric diseases including dementia. Cortical oligodendrocytes are a glial population uniquely positioned to play a key role in neurodegeneration by synchronizing circuit connectivity but molecular pathways specific to this role are lacking. We utilized oligodendrocyte-specific translating ribosome affinity purification and RNA-seq (TRAP-seq) to transcriptionally profile adult mature oligodendrocytes from different regions of the central nervous system.

Klotho, PTSD, and advanced epigenetic age in cortical tissue.

This study examined the klotho (KL) longevity gene polymorphism rs9315202 and psychopathology, including posttraumatic stress disorder (PTSD), depression, and alcohol-use disorders, in association with advanced epigenetic age in three postmortem cortical tissue regions: dorsolateral and ventromedial prefrontal cortices and motor cortex. Using data from the VA National PTSD Brain Bank (n = 117), we found that rs9315202 interacted with PTSD to predict advanced epigenetic age in motor cortex among the subset of relatively older (>=45 years), white non-Hispanic decedents (corrected p = 0.014, n = 42).

PTSD and the klotho longevity gene: Evaluation of longitudinal effects on inflammation via DNA methylation.

Background: Longevity gene klotho (KL) is associated with age-related phenotypes including lifespan, cardiometabolic disorders, cognition, and brain morphology, in part, by conferring protection against inflammation. We hypothesized that the KL/inflammation association might be altered in the presence of psychiatric stress and operate via epigenetic pathways. We examined KL polymorphisms, and their interaction with posttraumatic stress disorder (PTSD) symptoms, in association with KL DNA methylation in blood.

A method to specifically activate the Klotho promoter by using zinc finger proteins constructed from modular building blocks and from naturally engineered Egr1 transcription factor backbone.

There is an unmet need for treatments for diseases associated with aging. The antiaging, life-extending, and cognition-enhancing protein Klotho is neuroprotective due to its anti-inflammatory, antioxidative, and pro-myelinating effects. In addition, Klotho is also a tumor suppressor and has beneficial roles in multiple organs.

Identification of the cleavage sites leading to the shed forms of human and mouse anti-aging and cognition-enhancing protein Klotho.

Klotho is an age-extending, cognition-enhancing protein found to be down-regulated in aged mammals when age-related diseases start to appear. Low levels of Klotho occur in neurodegenerative diseases, kidney disease and many cancers. Many normal and pathologic processes involve the proteolytic shedding of membrane proteins.

Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress.

Proteinuria is associated with renal function decline and cardiovascular mortality. This association may be attributed in part to alterations of Klotho expression induced by albuminuria, yet the underlying mechanisms are unclear. The presence of albumin decreased Klotho expression in the POD-ATTAC mouse model of proteinuric kidney disease as well as in kidney epithelial cell lines.

Klotho Is Neuroprotective in the Superoxide Dismutase (SOD1) Mouse Model of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of motor neurons in the brain and spinal cord. ALS neuropathology is associated with increased oxidative stress, excitotoxicity, and inflammation. We and others reported that the anti-aging and cognition-enhancing protein Klotho is a neuroprotective, antioxidative, anti-inflammatory, and promyelinating protein.

Circulating fibroblast growth factor 23 levels and incident dementia: The Framingham heart study.

Background: Fibroblast growth factor 23 is an emerging vascular biomarker, recently associated with cerebral small vessel disease and poor cognition in patients on dialysis. It also interacts with klotho, an anti-aging and cognition enhancing protein.

Objective: To determine if circulating Fibroblast growth factor 23 (FGF23) is associated with new-onset cognitive outcomes in a community-based cohort of cognitively healthy adults with long-term follow-up.

Small Molecule Amyloid-β Protein Precursor Processing Modulators Lower Amyloid-β Peptide Levels via cKit Signaling.

Alzheimer's disease (AD) is characterized by the accumulation of neurotoxic amyloid-β (Aβ) peptides consisting of 39-43 amino acids, proteolytically derived fragments of the amyloid-β protein precursor (AβPP), and the accumulation of the hyperphosphorylated microtubule-associated protein tau. Inhibiting Aβ production may reduce neurodegeneration and cognitive dysfunction associated with AD. We have previously used an AβPP-firefly luciferase enzyme complementation assay to conduct a high throughput screen of a compound library for inhibitors of AβPP dimerization, and identified a compound that reduces Aβ levels.

Tau Phosphorylation is Impacted by Rare AKAP9 Mutations Associated with Alzheimer Disease in African Americans.

We studied the effect of two rare mutations (rs144662445 and rs149979685) in the A-kinase anchoring protein 9 (AKAP9) gene, previously associated with Alzheimer disease (AD) in African Americans (AA), on post-translational modifications of AD-related pathogenic molecules, amyloid precursor protein (APP) and microtubule-associated protein Tau using lymphoblastoid cell lines (LCLs) from 11 AA subjects with at least one AKAP9 mutation and 17 AA subjects lacking these mutations. LCLs were transduced by viral vectors expressing causative AD mutations in APP or human full-length wild type Tau. Cell lysates were analyzed for total APP, Aβ, and total and T181 phospho-Tau (pTau).

Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys.

Mammalian aging is associated with decline in cognitive functions. Studies searching for a cause of cognitive aging initially focused on neuronal loss but quantitative investigations of rat, monkey, and human brain using stereology demonstrated that in normal aging, unlike in neurodegenerative disease, neurons are not lost. Instead, electron microscopic and MRI studies in normal aging monkeys revealed age-related damage to myelin sheaths, loss of axons, and reduction in white matter volume which correlates with cognitive impairments.

Activation of the Anti-Aging and Cognition-Enhancing Gene Klotho by CRISPR-dCas9 Transcriptional Effector Complex.

Multiple lines of evidence show that the anti-aging and cognition-enhancing protein Klotho fosters neuronal survival, increases the anti-oxidative stress defense, and promotes remyelination of demyelinated axons. Thus, upregulation of the Klotho gene can potentially alleviate the symptoms and/or prevent the progression of age-associated neurodegenerative diseases such as Alzheimer's disease and demyelinating diseases such as multiple sclerosis. Here we used a CRISPR-dCas9 complex to investigate single-guide RNA (sgRNA) targeting the Klotho promoter region for efficient transcriptional activation of the Klotho gene.

The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination.

The current study examined whether overexpression of Klotho (KL) in transgenic mice can enhance remyelination following cuprizone-induced demyelination and improves the clinical outcome in experimental autoimmune encephalomyelitis (EAE). Demyelination was achieved by feeding transgenic mice overexpressing the transmembrane form of Klotho (KL-OE) and wild-type (WT) littermates cuprizone-containing chow for 6 weeks. The animals were then allowed to remyelinate for 3 weeks.

Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice.

Aging is the principal demographic risk factor for Alzheimer disease (AD), the most common neurodegenerative disorder. Klotho is a key modulator of the aging process and, when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition. Whether klotho can counteract deficits related to neurodegenerative diseases, such as AD, is unknown.

Identification of cleavage sites leading to the shed form of the anti-aging protein klotho.

Membrane protein shedding is a critical step in many normal and pathological processes. The anti-aging protein klotho (KL), mainly expressed in kidney and brain, is secreted into the serum and CSF, respectively. KL is proteolytically released, or shed, from the cell surface by ADAM10 and ADAM17, which are the α-secretases that also cleave the amyloid precursor protein and other proteins.

PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation.

Objective: Much of the genetic basis for Alzheimer disease (AD) is unexplained. We sought to identify novel AD loci using a unique family-based approach that can detect robust associations with infrequent variants (minor allele frequency < 0.10).

The neuroprotective effect of Klotho is mediated via regulation of members of the redox system.

Generation of reactive oxygen species (ROS), leading to oxidative damage and neuronal cell death, plays an important role in the pathogenesis of neurodegenerative disorders, including Alzheimer disease. The present study aimed to examine the mechanism by which the anti-aging protein Klotho exerts neuroprotective effects against neuronal damage associated with neurodegeneration and oxidative stress. Pretreatment of rat primary hippocampal neurons and mouse hippocampal neuronal cell line HT22 with recombinant Klotho protected these cells from glutamate and oligomeric amyloid β (oAβ)-induced cytotoxicity.

The anti-aging and tumor suppressor protein Klotho enhances differentiation of a human oligodendrocytic hybrid cell line.

Klotho functions as an aging suppressor, which, in mice, extends lifespan when overexpressed and accelerates development of aging-like phenotypes when disrupted. Klotho is mainly expressed in brain and kidney and is secreted into the serum and CSF. We have previously shown that Klotho is reduced in brains of old monkeys, rats, and mice.

Life extension factor klotho enhances cognition.

Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers.

Biochemical and functional characterization of the klotho-VS polymorphism implicated in aging and disease risk.

Klotho (KL) is an age-regulating protein named after the Greek goddess who spins the thread of life. Mice deficient in KL are normal throughout development, but rapidly degenerate and display a variety of aging-associated abnormalities that eventually lead to decreased life expectancy. While multiple genetic association studies have identified KL polymorphisms linked with changes in disease risk, there is a paucity of concrete mechanistic data to explain how these amino acid substitutions alter KL protein function.