KLTO and Japan’s Okinawa Research Center for Longevity Science partner to assess alpha-Klotho protein levels in centenarian blood and tissues, investigating how declining expression correlates with age-related pathologies. By leveraging gene therapy to restore secreted Klotho isoform, they aim to mitigate neurological disorders and extend healthspan in humans, building on promising preclinical models.
Key points
Quantification of alpha-Klotho and s-KL levels in centenarian blood and tissue via immunoassays.
AAV-mediated s-KL gene therapy vectors designed to restore secreted Klotho expression and evaluate neuroprotective efficacy.
Correlation analysis between s-KL depletion and onset of ALS, Alzheimer’s, and Parkinson’s, highlighting biomarker and therapeutic potential.
Why it matters:
Restoring Klotho levels offers a novel therapeutic strategy to counteract age-related neurodegeneration and extend human healthspan.
Q&A
What is alpha-Klotho?
What is the secreted Klotho isoform?
How is Klotho gene therapy delivered?
Why study Okinawan centenarians?
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Academy
Alpha-Klotho and Its Role in Longevity Science
Alpha-Klotho is a protein and anti-aging factor initially identified as a regulator of phosphate and vitamin D metabolism. It exists in two forms: a membrane-bound form that acts as a co-receptor for fibroblast growth factor 23 (FGF23), and a secreted soluble form (s-KL) generated by alternative splicing. Both forms influence key signaling pathways related to cellular senescence, oxidative stress, and tissue homeostasis.
What Is Alpha-Klotho?
The alpha-Klotho gene produces a type I transmembrane protein expressed predominantly in the kidneys, brain, and parathyroid glands. The extracellular domain can be cleaved or produced directly in a truncated form to circulate as secreted Klotho (s-KL). This soluble form acts like a hormone, exerting effects on distant organs by modulating hormonal and growth factor signals.
Mechanisms of Action
- FGF23 Co-Receptor: Membrane-bound Klotho binds FGF23 in the kidney, regulating phosphate excretion and vitamin D levels.
- Insulin/IGF-1 Signaling: s-KL inhibits the insulin and IGF-1 pathways to reduce oxidative stress and extend lifespan in animal models.
- Wnt Signaling Modulation: Soluble Klotho binds Wnt ligands, preventing excessive cellular proliferation and protecting against fibrosis.
- Antioxidant Effects: Klotho enhances expression of antioxidant enzymes, reducing reactive oxygen species and cellular damage.
Why Is Klotho Important in Aging?
Studies show that Klotho levels decline with age in blood and tissues, preceding the onset of multiple age-related diseases, such as Alzheimer’s, Parkinson’s, and chronic kidney disease. Lower Klotho correlates with increased oxidative damage, inflammation, and cellular senescence. By maintaining or restoring Klotho, researchers hope to slow biological aging and prevent disease progression.
Therapeutic Approaches
- Recombinant Klotho Protein: Direct administration of s-KL protein to restore circulating levels.
- Gene Therapy: Viral vectors (e.g., AAV) deliver the Klotho gene to target tissues for sustained Klotho production.
- Small Molecule Activators: Compounds that upregulate endogenous Klotho expression through epigenetic or transcriptional mechanisms.
Research and Future Directions
Current research focuses on clinical translation of Klotho therapies. Key challenges include optimizing delivery methods, ensuring long-term safety, and understanding tissue-specific effects. Ongoing studies in centenarian cohorts from Okinawa aim to correlate natural Klotho expression patterns with exceptional healthspan, guiding next-generation interventions in human aging.
