Редактирование: KL (раздел)

==Publications==

{{medline-entry
|title=Alignment of Alzheimer's disease amyloid β-peptide and klotho.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32999998
|abstract=The cause of Alzheimer's disease (AD) is poorly understood. In 1991, the amyloid hypothesis postulated that β-amyloid (Aβ) accumulation is a key element. It follows that clearing the brain of Aβ would be beneficial, which has not been the case. Therefore, Aβ is likely a result, not a cause, of AD and may be protective rather than harmful. The apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for AD. Klotho ([[KL]]), encoded by the [[KL]] gene, may be another AD-related protein. [[FGF21]] is a circulating endocrine hormone, mainly secreted by the liver, mostly during fasting. [[FGF21]] acts by binding to its receptor [[FGFR1]] and co-receptor β-klotho. [[FGF21]] is neuroprotective and could delay onset of AD. In the present study, the [[KL]] protein structure was examined to determine whether it may interact with Aβ. Protein data bank (pdb) entries for klotho and Aβ were searched on the RCSB Protein Data Bank for β-[[KL]] and AD amyloid β-peptide. The protein structures were superimposed and aligned on PYMOL v2.3.4 with the super command, which super aligns two protein selections. To evaluate the conservation and alignment of the Aβ and [[KL]] genomes across species, BLAT, the Blast-Like Alignment Tool of the UCSC Genome Browser, was used. The amino acid residues phe76-val96 of [[KL]] aligned closely with residues asp7-asn27 of Aβ. Cross-species comparison of [[KL]] revealed a high degree of alignment and conservation in the chimp and 27 other primates; however, less alignment and conservation were observed in the mouse, dog and elephant, even less in the chicken, western clawed frog ([i]Xenopus tropicalis[/i]), zebrafish and lamprey. The current finding of amino acid residues phe76-val96 of klotho aligning closely with residues asp7-asn27 of Aβ suggests that Aβ can enhance the ability of klotho to draw [[FGF21]] to regions of incipient neurodegeneration in AD. The problem arises with age. Older individuals do not heal or repair tissue damage as well as younger individuals. As neurodegeneration advances in an older individual, perhaps caused by neuroinflammation related to herpes simplex virus type 1, increasing amounts of amyloid are produced, forming an adhesive web, as the brain tries to hold the pathologic process in check. Meanwhile, the damage increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome.

|keywords=* Alzheimer’s disease
* HSV-1
* aging
* alignment
* klotho
* neurodegeneration
* neuroinflammation
* protein
* ubiquitin
* β-amyloid
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521834
}}
{{medline-entry
|title=PTSD and the klotho longevity gene: Evaluation of longitudinal effects on inflammation via DNA methylation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32438247
|abstract=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. We further examined [[KL]] DNA methylation as a predictor of longitudinal changes in a peripheral biomarker of inflammation (C-reactive protein; [[CRP]]). The sample comprised 309 white non-Hispanic military veterans (93.5 % male; mean age: 32 years, range: 19-65; 30 % PTSD per structured diagnostic interview); 111 were reassessed approximately two years later. Analyses revealed a methylation quantitative trait locus at rs9527025 (C370S, previously implicated in numerous studies of aging) in association with a Cytosine-phosphate-Guanine site (cg00129557; B = -.65, p =  1.29 X 10 ), located within a DNase hypersensitivity site in the body of [[KL]]. There was also a rs9527025 x PTSD severity interaction (B = .004, p = .035) on methylation at this locus such that the minor allele was associated with reduced cg00129557 methylation in individuals with few or no PTSD symptoms while this effect was attenuated in those with elevated levels of PTSD. Path models revealed that methylation at cg00129557 was inversely associated with [[CRP]] over time (B = -.14, p = .005), controlling for baseline [[CRP]]. There was also an indirect effect of rs9527025 X PTSD on subsequent [[CRP]] via cg00129557 methylation (indirect B = -.002, p = .033). Results contribute to our understanding of the epigenetic correlates of inflammation in PTSD and suggest that [[KL]] methylation may be a mechanism by which [[KL]] genotype confers risk vs. resilience to accelerated aging in those experiencing traumatic stress.

|keywords=* Accelerated aging
* Inflammation
* Klotho
* Methylation
* PTSD
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293549
}}
{{medline-entry
|title=Epigenetic Regulation of [[KL]] (Klotho) via H3K27me3 (Histone 3 Lysine [K] 27 Trimethylation) in Renal Tubule Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32223380
|abstract=[[KL]] (klotho) levels decline with age, which is an important mechanistic driver of aging. [i][[KL]][/i] gene deficiency is associated with hypertension. The purpose of this study is to investigate the potential role of H3K27me3 (histone 3 lysine [K] 27 trimethylation) in the regulation of [i][[KL]][/i] gene expression and examine the related molecular pathways that may drive kidney cell aging. Kidneys were collected from 6-month-old WT (wild type; young WT), 30-month-old WT (aged WT), and 6- (young) and 20-month-old (aged) [i][[KL]][/i] mutant mice, respectively. We demonstrated that the H3K27me3 level was increased in kidneys of aged WT and [[KL]] mutant mice versus young WT mice. Elevation of H3K27me3 levels was likely due to downregulation of the H3K27 (histone H3 Lys 27)-specific demethylase JMJD3 (the Jumonji domain containing-3) in the aged kidneys. Inhibition of PRC2 (polycomb repressive complex C2; histone trimethyltransferase) decreased the H3K27me3 levels leading to an increase in the expression of [[KL]] in cultured primary renal tubule cells assessed by Western blot and [i][[KL]][/i] promoter activity assays. The chromatin immunoprecipitation qPCR assay revealed that H3K27me3 was physically associated with the [i][[KL]][/i] promoter region. Furthermore, aging impaired the [[SGK1]] (serum- and glucocorticoid-induced protein kinase 1)/FOXO3a (the forkhead box class O 3a) signaling leading to upregulation of p53 and p16 (aging markers) in the kidney of aged WT mice. [[KL]] may regulate the [[SGK1]]/FOXO3 signaling, which was decreased due to [[KL]] deficiency. Thus, aging-associated downregulation of [i][[KL]][/i] gene expression may be partly attributed to upregulation of H3K27me3 levels. Downregulation of [[KL]] may impair the [[SGK1]]/FOXO3 signaling contributing to kidney cell aging.

|keywords=* AKT
* EZH2
* aging
* mTOR
* p53
|full-text-url=https://sci-hub.do/10.1161/HYPERTENSIONAHA.120.14642
}}
{{medline-entry
|title=[[FGF23]] expression is stimulated in transgenic α-Klotho longevity mouse model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31801907
|abstract=Observations in transgenic α-Klotho (Kl) mice (KlTg) defined the antiaging role of soluble Klotho (s[[KL]]130). A genetic translocation that elevates s[[KL]] levels in humans is paradoxically associated with increased circulating fibroblast growth factor 23 ([[FGF23]]) levels and the potential of both membrane [[KL]] (m[[KL]]135) and s[[KL]]130 to act as coreceptors for [[FGF23]] activation of fibroblast growth factor receptors (FGFRs). Neither [[FGF23]] expression nor the contributions of [[FGF23]], m[[KL]]135, and s[[KL]]130 codependent and independent functions have been investigated in KlTg mice. In the current study, we examined the effects of Kl overexpression on [[FGF23]] levels and functions in KlTg mice. We found that m[[KL]]135 but not s[[KL]]130 stimulated [[FGF23]] expression in osteoblasts, leading to elevated Fgf23 bone expression and circulating levels in KlTg mice. Elevated [[FGF23]] suppressed 1,25(OH)2D and parathyroid hormone levels but did not cause hypophosphatemic rickets in KlTg mice. KlTg mice developed low aldosterone-associated hypertension but not left ventricular hypertrophy. Mechanistically, we found that m[[KL]]135 and s[[KL]]130 are essential cofactors for [[FGF23]]-mediated ERK activation but that they inhibited [[FGF23]] stimulation of PLC-γ and PI3K/AKT signaling. Thus, increased longevity in KlTg mice occurs in the presence of excess [[FGF23]] that interacts with m[[KL]] and s[[KL]] to bias FGFR pathways.
|mesh-terms=* Aldosterone
* Animals
* Bone and Bones
* Cardiovascular Diseases
* Disease Models, Animal
* Female
* Fibroblast Growth Factors
* Gene Knockout Techniques
* Glucuronidase
* Kidney
* Longevity
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Osteoblasts
* Protein Isoforms
* Transcriptome
|keywords=* Bone Biology
* Cardiovascular disease
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962016
}}
{{medline-entry
|title=The goddess who spins the thread of life: Klotho, psychiatric stress, and accelerated aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30872092
|abstract=Longevity gene klotho ([[KL]]) is associated with age-related phenotypes but has not been evaluated against a direct human biomarker of cellular aging. We examined [[KL]] and psychiatric stress, including posttraumatic stress disorder (PTSD), which is thought to potentiate accelerated aging, in association with biomarkers of cellular aging. The sample comprised 309 white, non-Hispanic genotyped veterans with measures of epigenetic age (DNA methylation age), telomere length (n = 252), inflammation (C-reactive protein), psychiatric symptoms, metabolic function, and white matter neural integrity (diffusion tensor imaging; n = 185). Genotyping and DNA methylation were obtained on epi/genome-wide beadchips. In gene by environment analyses, two [[KL]] variants (rs9315202 and rs9563121) interacted with PTSD severity (peak corrected p = 0.044) and sleep disturbance (peak corrected p = 0.034) to predict advanced epigenetic age. [[KL]] variant, rs398655, interacted with self-reported pain in association with slowed epigenetic age (corrected p = 0.048). A well-studied protective variant, rs9527025, was associated with slowed epigenetic age (p = 0.046). The peak PTSD interaction term (with rs9315202) also predicted C-reactive protein (p = 0.049), and white matter microstructural integrity in two tracts (corrected ps = 0.005 - 0.035). This SNP evidenced a main effect with an index of metabolic syndrome severity (p = 0.015). Effects were generally accentuated in older subjects. Rs9315202 predicted multiple biomarkers of cellular aging such that psychiatric stress was more strongly associated with cellular aging in those with the minor allele. [[KL]] genotype may contribute to a synchronized pathological aging response to stress and could be a therapeutic target to alter the pace of cellular aging.
|mesh-terms=* Adult
* Aging
* Alleles
* Brain
* C-Reactive Protein
* Cellular Senescence
* DNA Methylation
* Diffusion Tensor Imaging
* Epigenesis, Genetic
* Female
* Genotype
* Glucuronidase
* Humans
* Longevity
* Male
* Stress Disorders, Post-Traumatic
* Stress, Psychological
* Telomere Homeostasis
* Veterans
* White Matter

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660403
}}
{{medline-entry
|title=[i][[KL]]OTHO[/i] heterozygosity attenuates [i]APOE4[/i]-related amyloid burden in preclinical AD.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30867273
|abstract=To examine whether the [i][[KL]]OTHO[/i] gene variant [[KL]]-VS attenuates [i]APOE4-[/i]associated β-amyloid (Aβ) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine [[KL]]-VS and [i]APOE4[/i] status and underwent CSF sampling (n = 238) and/or  C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether [i]APOE4[/i] exerted expected effects on Aβ burden. Follow-up regression analyses stratified by [[KL]]-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of [i]APOE4[/i] on Aβ was different among [[KL]]-VS heterozygotes compared to noncarriers. [i]APOE4[/i] carriers exhibited greater Aβ burden than [i]APOE4[/i]-negative participants. This effect was stronger in CSF ([i]t[/i] = -5.12, [i]p[/i] < 0.001) compared with PiB-PET ([i]t[/i] = 3.93, [i]p[/i] < 0.001). In the stratified analyses, this [i]APOE4[/i] effect on Aβ load was recapitulated among [[KL]]-VS noncarriers (CSF: [i]t[/i] = -5.09, [i]p[/i] < 0.001; PiB-PET: [i]t[/i] = 3.77, [i]p[/i] < 0 .001). In contrast, among [[KL]]-VS heterozygotes, [i]APOE4[/i]-positive individuals did not exhibit higher Aβ burden than [i]APOE4[/i]-negative individuals (CSF: [i]t[/i] = -1.03, [i]p[/i] = 0.308; PiB-PET: t = 0.92, [i]p[/i] = 0.363). These differential [i]APOE4[/i] effects remained after [[KL]]-VS heterozygotes and noncarriers were matched on age and sex. In a cohort of at-risk late-middle-aged adults, [[KL]]-VS heterozygosity was associated with an abatement of [i]APOE4-[/i]associated Aβ aggregation, suggesting [[KL]]-VS heterozygosity confers protections against [i]APOE4-[/i]linked pathways to disease onset in AD.
|mesh-terms=* Adult
* Alzheimer Disease
* Amyloid beta-Peptides
* Apolipoprotein E4
* Heterozygote
* Humans
* Longevity
* Middle Aged
* Positron-Emission Tomography
* Wisconsin

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550504
}}
{{medline-entry
|title=Utilizing Atlas-Based Modeling to Predict Knee Joint Cartilage Degeneration: Data from the Osteoarthritis Initiative.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30547410
|abstract=Currently, there are no clinically available tools or applications which could predict osteoarthritis development. Some computational models have been presented to simulate cartilage degeneration, but they are not clinically feasible due to time required to build subject-specific knee models. Therefore, the objective of this study was to develop a template-based modeling method for rapid prediction of knee joint cartilage degeneration. Knee joint models for 21 subjects were constructed with two different template approaches (multiple templates and one template) based on the MRI data. Geometries were also generated by manual segmentation. Evaluated volumes of cartilage degeneration for each subject, as assessed with the degeneration algorithm, were compared with experimentally observed 4 year follow up Kellgren-Lawrence ([[KL]]) grades. Furthermore, the effect of meniscus was tested by generating models with subject-specific meniscal supporting forces and those with the average meniscal supporting force from all models. All tested models were able to predict most severe cartilage degeneration to those subjects who had the highest [[KL]] grade after 4 year follow up. Surprisingly, in terms of statistical significance, the best result was obtained with one template approach and average meniscal support. This model was fully able to categorize all subjects to their experimentally defined groups ([[KL]]0, [[KL]]2 and [[KL]]3) based on the 4 year follow-up data. The results suggest that a template- or population-based approach, which is much faster than fully subject-specific, could be applied as a clinical prediction tool for osteoarthritis.
|mesh-terms=* Adult
* Aged
* Aging
* Cartilage, Articular
* Female
* Femur
* Humans
* Knee Joint
* Male
* Menisci, Tibial
* Middle Aged
* Models, Biological
* Osteoarthritis, Knee
* Patient-Specific Modeling
* Tibia
* Young Adult
|keywords=* Articular cartilage
* Degeneration
* Finite element analysis
* Knee joint
* Osteoarthritis
* Template modeling
|full-text-url=https://sci-hub.do/10.1007/s10439-018-02184-y
}}
{{medline-entry
|title=Impaired proteostasis in senescent vascular endothelial cells: a perspective on estrogen and oxidative stress in the aging vasculature.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30499713
|abstract=The heat shock response is an important cytoprotective mechanism for protein homeostasis and is an essential protective response to cellular stress and injury. Studies on changes in the heat shock response with aging have been mixed with regard to whether it is inhibited, and this, at least in part, reflects different tissues and different models. Cellular senescence is a key feature in aging, but work on the heat shock response in cultured senescent (SEN) cells has largely been limited to fibroblasts. Given the prevalence of oxidative injury in the aging cardiovascular system, we investigated whether SEN primary human coronary artery endothelial cells have a diminished heat shock response and impaired proteostasis. In addition, we tested whether this downregulation of heat shock response can be mitigated by 17β-estradiol (E ), which has a critical cardioprotective role in women, as we have previously reported that E  improves the heat shock response in endothelial cells (Hamilton [[KL]], Mbai FN, Gupta S, Knowlton AA. Arterioscler Thromb Vasc Biol 24: 1628-1633, 2004). We found that SEN endothelial cells, despite their unexpectedly increased proteasome activity, had a diminished heat shock response and had more protein aggregation than early passage cells. SEN cells had increased oxidative stress, which promoted protein aggregation. E  treatment did not decrease protein aggregation or improve the heat shock response in either early passage or SEN cells. In summary, cellular senescence in adult human endothelial cells is accompanied by increased oxidative stress and a blunting of proteostasis, and E  did not mitigate these changes. NEW