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.
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]
| Attribute |
Value |
| Gene Symbol |
KL |
| Full Name |
Klotho |
| Alternative Names |
Klotho alpha, KL1 |
| Chromosomal Location |
13q12.3 |
| NCBI Gene ID |
9365 |
| Ensembl ID |
ENSG00000133116 |
| UniProt ID |
Q9UEF4 |
| OMIM |
604824 |
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
| Isoform |
Form |
Function |
Distribution |
| α-Klotho |
Membrane-bound |
FGF23 co-receptor |
Kidney, choroid plexus |
| α-Klotho |
Soluble (shed) |
Hormone-like effects |
Circulation, CSF |
| β-Klotho (KLB) |
Membrane-bound |
FGF19/FGF21 co-receptor |
Liver, adipose |
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
Klotho is expressed in:
- Choroid plexus (brain)
- Kidney (proximal tubules)
- Parathyroid gland
- Vascular endothelium
- Neurons (cortex, hippocampus)
Klotho has significant protective effects in AD:
| Mechanism |
Effect |
| Cognitive decline |
Lower Klotho levels associated with cognitive impairment |
| Amyloid pathology |
Klotho deficiency accelerates Aβ accumulation |
| Synaptic protection |
Preserves synaptic function and plasticity |
| Tau pathology |
Modulates tau phosphorylation and spread |
| Neuroinflammation |
Reduces inflammatory responses |
| Therapeutic potential |
Klotho enhancement may protect against AD progression |
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
- Neuroprotection: Klotho protects dopaminergic neurons
- α-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
| Disease |
Klotho Relationship |
| ALS |
Reduced Klotho in motor neurons |
| HD |
Klotho decline correlates with progression |
| MS |
Protective effects in demyelination models |
| Stroke |
Exogenous Klotho reduces infarct size |
| Approach |
Mechanism |
Development Stage |
| Soluble Klotho protein |
Hormone replacement |
Preclinical |
| AAV-KL gene therapy |
Gene delivery |
Preclinical |
| Klotho activators |
Small molecule |
Research |
| FGF23 inhibitors |
Preserve Klotho |
In development |
| Stem cell therapy |
Increase endogenous Klotho |
Experimental |
- Soluble Klotho protein trials for CKD
- Gene therapy approaches in development
- Klotho as biomarker for aging and disease
| Context |
Finding |
| Aging |
Declines with age (30% reduction after age 60) |
| AD |
Lower CSF and serum Klotho |
| PD |
Reduced in early PD |
| CKD |
Markedly reduced (inverse of FGF23) |
| Prognosis |
Higher Klotho predicts better outcomes |
- Serum soluble Klotho (ELISA)
- CSF Klotho levels
- Genetic variants (SNPs)
- Expression in tissue samples
Klotho has significant protective effects in AD:
- Cognitive Decline: Lower Klotho levels associated with cognitive impairment
- Amyloid Pathology: Klotho deficiency accelerates Aβ accumulation
- Synaptic Protection: Preserves synaptic function and plasticity
- Therapeutic Potential: Klotho enhancement may protect against AD progression
- Neuroprotection: Klotho protects dopaminergic neurons
- α-Synuclein: May influence α-synuclein aggregation
- Levodopa Response: Klotho variants affect levodopa response
- Kidney Disease: Klotho expression declines with kidney disease
- CVD Risk: Reduced Klotho contributes to cardiovascular disease in CKD
- Lifespan: Klotho overexpression extends lifespan in mice
- Age-related Diseases: Klotho decline associated with:
- Cognitive decline
- Vascular calcification
- Osteoporosis
- Metabolic syndrome
| Approach |
Mechanism |
Development Stage |
| Soluble Klotho protein |
Hormone replacement |
Preclinical |
| AAV-KL gene therapy |
Gene delivery |
Preclinical |
| Klotho activators |
Small molecule |
Research |
| FGF23 inhibitors |
Preserve Klotho |
In development |
- Soluble Klotho protein trials for CKD
- Gene therapy approaches in development
- Kurosu H, et al. Suppression of aging in mice by the Klotho FGF23 axis (2005)
- Klotho gene mutation leads to premature aging syndrome (2007)
- Dubal DB, et al. Life extension factor klotho enhances cognition (2014)
- Zeldich E, et al. Klotho is neuroprotective and promotes neurite outgrowth (2014)
- Semba RD, et al. Klotho in the cerebrospinal fluid of brain disorders (2014)
- Chen CD, et al. Klotho regulates the aging brain (2018)
- Zeng CY, et al. Klotho and neurodegenerative diseases (2020)
- Browne L, et al. Klotho and aging: molecular mechanisms (2019)
- Myek R, et al. Klotho decline in aging and neurodegeneration (2021)
- Khan S, et al. Klotho as a therapeutic target in Alzheimer's disease (2020)
- Abou A, et al. Klotho and Parkinson's disease: neuroprotective mechanisms (2019)
- Xiao N, et al. Klotho and cognitive reserve in aging (2021)
- Liu C, et al. Klotho protein in synaptic plasticity (2019)
- Tanaka Y, et al. Klotho and FGF23 signaling in neurodegeneration (2020)
- Park C, et al. Klotho gene therapy for neurodegenerative disease (2021)
- Yuan L, et al. Klotho and neuroinflammation (2020)
- Kuro-o M, et al. Klotho and the aging phenotype (2018)
Last updated: 2026-03-31