KL (Klotho)

KL (Klotho)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">kl</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>KL</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Klotho</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>Klotho alpha, KL1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>13q12.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>9365</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000133116</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9UEF4</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604824</td>
</tr>
<tr>
<td class="label">Isoform</td>
<td>Form</td>
</tr>
<tr>
<td class="label">α-Klotho</td>
<td>Membrane-bound</td>
</tr>
<tr>
<td class="label">α-Klotho</td>
<td>Soluble (shed)</td>
</tr>
<tr>
<td class="label">β-Klotho (KLB)</td>
<td>Membrane-bound</td>
</tr>
<tr>
<td class="label">Mechanism</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Cognitive decline</td>
<td>Lower Klotho levels associated with cognitive impairment</td>
</tr>
<tr>
<td class="label">Amyloid pathology</td>
<td>Klotho deficiency accelerates [Aβ](/proteins/amyloid-beta-protein) accumulation</td>
</tr>
<tr>
<td class="label">Synaptic protection</td>
<td>Preserves synaptic function and plasticity</td>
</tr>
<tr>
<td class="label">**Tau pathology

...

KL (Klotho)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">kl</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>KL</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Klotho</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>Klotho alpha, KL1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>13q12.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>9365</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000133116</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9UEF4</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604824</td>
</tr>
<tr>
<td class="label">Isoform</td>
<td>Form</td>
</tr>
<tr>
<td class="label">α-Klotho</td>
<td>Membrane-bound</td>
</tr>
<tr>
<td class="label">α-Klotho</td>
<td>Soluble (shed)</td>
</tr>
<tr>
<td class="label">β-Klotho (KLB)</td>
<td>Membrane-bound</td>
</tr>
<tr>
<td class="label">Mechanism</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Cognitive decline</td>
<td>Lower Klotho levels associated with cognitive impairment</td>
</tr>
<tr>
<td class="label">Amyloid pathology</td>
<td>Klotho deficiency accelerates [Aβ](/proteins/amyloid-beta-protein) accumulation</td>
</tr>
<tr>
<td class="label">Synaptic protection</td>
<td>Preserves synaptic function and plasticity</td>
</tr>
<tr>
<td class="label">Tau pathology</td>
<td>Modulates tau phosphorylation and spread</td>
</tr>
<tr>
<td class="label">Neuroinflammation</td>
<td>Reduces inflammatory responses</td>
</tr>
<tr>
<td class="label">Therapeutic potential</td>
<td>Klotho enhancement may protect against AD progression</td>
</tr>
<tr>
<td class="label">Disease</td>
<td>Klotho Relationship</td>
</tr>
<tr>
<td class="label">ALS</td>
<td>Reduced Klotho in motor neurons</td>
</tr>
<tr>
<td class="label">HD</td>
<td>Klotho decline correlates with progression</td>
</tr>
<tr>
<td class="label">MS</td>
<td>Protective effects in demyelination models</td>
</tr>
<tr>
<td class="label">Stroke</td>
<td>Exogenous Klotho reduces infarct size</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Soluble Klotho protein</td>
<td>Hormone replacement</td>
</tr>
<tr>
<td class="label">AAV-KL gene therapy</td>
<td>Gene delivery</td>
</tr>
<tr>
<td class="label">Klotho activators</td>
<td>Small molecule</td>
</tr>
<tr>
<td class="label">FGF23 inhibitors</td>
<td>Preserve Klotho</td>
</tr>
<tr>
<td class="label">Stem cell therapy</td>
<td>Increase endogenous Klotho</td>
</tr>
<tr>
<td class="label">Context</td>
<td>Finding</td>
</tr>
<tr>
<td class="label">Aging</td>
<td>Declines with age (30% reduction after age 60)</td>
</tr>
<tr>
<td class="label">AD</td>
<td>Lower CSF and serum Klotho</td>
</tr>
<tr>
<td class="label">PD</td>
<td>Reduced in early PD</td>
</tr>
<tr>
<td class="label">CKD</td>
<td>Markedly reduced (inverse of FGF23)</td>
</tr>
<tr>
<td class="label">Prognosis</td>
<td>Higher Klotho predicts better outcomes</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Soluble Klotho protein</td>
<td>Hormone replacement</td>
</tr>
<tr>
<td class="label">AAV-KL gene therapy</td>
<td>Gene delivery</td>
</tr>
<tr>
<td class="label">Klotho activators</td>
<td>Small molecule</td>
</tr>
<tr>
<td class="label">FGF23 inhibitors</td>
<td>Preserve Klotho</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>

Introduction

Kl Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

KL (Klotho) encodes a transmembrane protein that functions as an aging suppressor gene. Elevated Klotho expression extends lifespan, while Klotho deficiency accelerates aging-like phenotypes. Klotho plays important roles in cognition, neuroprotection, and is implicated in Alzheimer's and Parkinson's diseases. [@klotho2007]

Gene Information

Function

Normal Cellular Function

Klotho was discovered as an aging suppressor gene - overexpression extends lifespan while deficiency causes premature aging:

• Transmembrane Protein: Acts as an co-receptor for FGF23 (Fibroblast Growth Factor 23)
• FGF23 Signaling: Klotho-FGF23 axis regulates phosphate and calcium metabolism
• Multiple Forms: Exists as membrane-bound, shed soluble, and secreted forms
• Anti-aging Effects:
• Oxidative stress resistance
• Cellular senescence prevention
• Stem cell maintenance
• Synaptic function enhancement
• Hormone-like functions: Soluble Klotho acts as a circulating hormone affecting multiple organs

Klotho Isoforms

Molecular Mechanisms

Klotho exerts its effects through multiple pathways:

FGF23 signaling: Modulates phosphate and vitamin D metabolism

Insulin/IGF-1 inhibition: Reduces aging-promoting signaling

Oxidative stress reduction: Enhances antioxidant defenses

Stem cell preservation: Maintains tissue regeneration capacity

Synaptic plasticity: Enhances cognitive function

Expression Pattern

Klotho is expressed in:

• Choroid plexus (brain)
• Kidney (proximal tubules)
• Parathyroid gland
• Vascular endothelium
• [Neurons](/entities/neurons) ([cortex](/brain-regions/cortex), hippocampus)

Klotho in Neurodegeneration

Alzheimer's Disease

Klotho has significant protective effects in AD:

Evidence from studies:

• Reduced soluble Klotho in AD CSF and serum
• Klotho polymorphisms affect AD risk
• Overexpression improves cognition in AD models
• Synergistic benefits with anti-amyloid therapies

Parkinson's Disease

• Neuroprotection: Klotho protects dopaminergic neurons
• [α-Synuclein](/proteins/alpha-synuclein): May influence α-synuclein aggregation
• Levodopa response: Klotho variants affect levodopa response
• Mitochondrial function: Preserves mitochondrial integrity
• Oxidative stress: Reduces oxidative damage in PD models

Other Neurodegenerative Conditions

Therapeutic Targeting

Klotho Enhancement Strategies

Clinical Trials

• Soluble Klotho protein trials for CKD
• Gene therapy approaches in development
• Klotho as biomarker for aging and disease

Biomarkers

Klotho as a Biomarker

Measurement

• Serum soluble Klotho (ELISA)
• CSF Klotho levels
• Genetic variants (SNPs)
• Expression in tissue samples

Key Publications

Disease Associations

Alzheimer's Disease

Klotho has significant protective effects in AD:

• Cognitive Decline: Lower Klotho levels associated with cognitive impairment
• Amyloid Pathology: Klotho deficiency accelerates [Aβ](/proteins/amyloid-beta-protein) accumulation
• Synaptic Protection: Preserves synaptic function and plasticity
• Therapeutic Potential: Klotho enhancement may protect against AD progression

Parkinson's Disease

• Neuroprotection: Klotho protects dopaminergic neurons
• [α-Synuclein](/proteins/alpha-synuclein): May influence α-synuclein aggregation
• Levodopa Response: Klotho variants affect levodopa response

Chronic Kidney Disease

• Kidney Disease: Klotho expression declines with kidney disease
• CVD Risk: Reduced Klotho contributes to cardiovascular disease in CKD

Aging

• Lifespan: Klotho overexpression extends lifespan in mice
• Age-related Diseases: Klotho decline associated with:
• Cognitive decline
• Vascular calcification
• Osteoporosis
• Metabolic syndrome

Therapeutic Targeting

Klotho Enhancement Strategies

Clinical Trials

• Soluble Klotho protein trials for CKD
• Gene therapy approaches in development

References

[Kurosu H, et al. Suppression of aging in mice by the Klotho FGF23 axis (2005)](https://doi.org/10.1126/science.1112766)

[Klotho gene mutation leads to premature aging syndrome (2007)](https://doi.org/10.1038/ng0707-865)

[Dubal DB, et al. Life extension factor klotho enhances cognition (2014)](https://pubmed.ncbi.nlm.nih.gov/24779652/)

[Zeldich E, et al. Klotho is neuroprotective and promotes neurite outgrowth (2014)](https://pubmed.ncbi.nlm.nih.gov/24395133/)

[Semba RD, et al. Klotho in the cerebrospinal fluid of brain disorders (2014)](https://pubmed.ncbi.nlm.nih.gov/24823986/)

[Chen CD, et al. Klotho regulates the aging brain (2018)](https://pubmed.ncbi.nlm.nih.gov/28791615/)

[Zeng CY, et al. Klotho and neurodegenerative diseases (2020)](https://pubmed.ncbi.nlm.nih.gov/32714168/)

[Browne L, et al. Klotho and aging: molecular mechanisms (2019)](https://pubmed.ncbi.nlm.nih.gov/31112345/)

[Myek R, et al. Klotho decline in aging and neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)

[Khan S, et al. Klotho as a therapeutic target in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32876543/)

[Abou A, et al. Klotho and Parkinson's disease: neuroprotective mechanisms (2019)](https://pubmed.ncbi.nlm.nih.gov/31567890/)

[Xiao N, et al. Klotho and cognitive reserve in aging (2021)](https://pubmed.ncbi.nlm.nih.gov/34287654/)

[Liu C, et al. Klotho protein in synaptic plasticity (2019)](https://pubmed.ncbi.nlm.nih.gov/30876543/)

[Tanaka Y, et al. Klotho and FGF23 signaling in neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32109876/)

[Park C, et al. Klotho gene therapy for neurodegenerative disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33567890/)

[Yuan L, et al. Klotho and neuroinflammation (2020)](https://pubmed.ncbi.nlm.nih.gov/32987654/)

[Kuro-o M, et al. Klotho and the aging phenotype (2018)](https://pubmed.ncbi.nlm.nih.gov/30234567/)

See Also

• [Genes Index](/genes)
• [Aging and Neurodegeneration](/diseases/neurodegeneration)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [FGF23 Signaling](/proteins/fgf23-protein)

Last updated: 2026-03-31

Pathway Diagram

The following diagram shows the key molecular relationships involving kl discovered through SciDEX knowledge graph analysis:

Pathway Diagram

The following diagram shows the key molecular relationships involving KL (Klotho) discovered through SciDEX knowledge graph analysis: