Sun May 26 2024

Klotho Protein and Brain Health:

• Klotho, a protein associated with longevity, decreases by half during aging, with levels peaking upon waking due to a circadian rhythm.
• Chronic stress is linked to lower klotho levels, while exercise significantly boosts klotho levels by about 30% after 12 weeks.
• Methylation around the clotho promoter inhibits its transcription and translation as individuals age, impacting klotho production.
• Studies show a direct correlation between shorter telomeres and lower klotho levels, suggesting an interplay in aging processes.
• Klotho enhances cognition in mice across different ages and disease models like Alzheimer's and Parkinson's diseases.

Discovery of Clotho Gene:

• The clotho gene was serendipitously discovered in 1997 by Makoto Kuroo during hypertension studies in mice.
• Clotho codes for a transmembrane protein primarily produced in the kidney before being released as soluble clotho into the blood or cerebrospinal fluid.

Mechanism of Action - GluN2B Receptors:

• Clotho enhances cognition through NMDA receptors' subunit GluN2B at synapses, promoting memory formation and synaptic plasticity.
• Overexpression of GluN2B improves neural connections and memory efficiency, indicating their role in brain function.
• Blocking GluN2B inhibits clotho's ability to enhance cognition, highlighting their interplay in brain health.

Peripheral Administration of Clothoprotein:

• Despite not crossing the blood-brain barrier, peripheral administration of clothoprotein results in cognitive enhancement within hours lasting for weeks.
• Studies suggest that clothoprotein may act through messengers sent from the blood into the brain to enhance cognitive functions.

Klotho's Impact on Brain Health in Mice:

• Klotho was found to enhance cognition in mice, with a single klotho injection leading to long-lasting effects.
• The study showed that platelet factor four (PF4) released by activated platelets enhanced cognition in both young and aging mice.
• Clotho stimulated platelets to release PF4, which improved cognitive function in mouse models of Parkinson's and Alzheimer's diseases.
• In the experiments conducted, clotho demonstrated the ability to activate platelets, leading to the release of PF4, ultimately enhancing brain health and cognitive functions in mice.

Clotho's Cognitive Enhancement in Primates:

• Rhesus macaques were used as a model system due to their genetic diversity and anatomical complexity similar to humans.
• Monkeys treated with klotho demonstrated better performance than those receiving a placebo in spatial memory tasks.
• A low physiologic dose of clotho immediately enhanced cognition in monkeys, lasting for at least three weeks.
• The study design involved rigorous testing methodologies such as spatial delayed response tasks to assess cognitive improvements accurately.

Dosing Strategies and Efficacy Across Species:

• In mice, very low doses of clotho significantly enhanced cognition, even more so than higher supraphysiologic doses.
• Dosing strategies aimed to stay within physiological levels while also testing higher doses up to 10-20 times the natural level.
• The minimum effective dose in mice was more than five times less than the peak physiologic dose.
• Researchers carefully considered dosing regimens across species, ensuring that the dosages remained within physiological ranges while exploring potential therapeutic benefits.

Longevity Factor Klotho's Potential Therapeutic Role:

• Clotho treatment extended lifespan and normalized cognition across the lifespan of APP mutant mice overexpressing clotho.
• Clotho provided resilience against Alzheimer's toxins without reducing amyloid beta or tau levels in the brain.
• The potential use of clotho as a therapeutic agent for neurodegenerative diseases like Alzheimer’s and Parkinson’s is being explored.
• Studies have shown promising results indicating that clotho could potentially serve as a protective agent against neurodegenerative conditions through its positive impact on neural circuits associated with memory and cognitive functions.

Implications for Human Clinical Trials:

• There is interest in moving towards human clinical trials with clotho as a potential therapy for cognitive decline associated with neurodegenerative diseases like Alzheimer’s disease.
• Clotho may offer protective benefits by enhancing brain health through its impact on neural circuits involved in memory and cognitive functions.

Klotho Protein and Cognitive Function:

• Klotho, a protein associated with longevity, plays a vital role in brain health and cognitive function, offering protection against neurodegenerative diseases like Alzheimer's and Parkinson's.
• Testing different doses of klotho in monkeys showed that high doses did not harm cognition but also did not enhance it compared to low doses.
• In mice, continuous cognitive improvement was observed with klotho, indicating the necessity of determining the optimal therapeutic dose before human trials.

Potential Longevity Effects of Klotho Injection:

• The long-lasting effects of a single klotho injection are intriguing due to its potential organizational impact on synaptic plasticity and cognitive function over time rather than just immediate enhancements.
• Speculation exists around the idea that klotho may have an extended effect beyond acute improvements seen with interventions like exercise boosts.

Genetic Variant KLVS Associated with Cloth O Gene:

• KLVS refers to two specific genetic variations affecting clotho protein levels in individuals.
• Heterozygotes carrying one copy of KLVS exhibit better cognition across aging studies compared to non-carriers or homozygotes.

Association Between KLVS and APOE4 Genes:

• Individuals carrying both KLVS and APOE4 genes demonstrated decreased risk for developing Alzheimer's disease and lower amyloid beta deposition.
• The protective effect of KLVS seemed consistent regardless of APOE4 status, potentially mitigating the negative impact of APOE4 on Alzheimer's risk.

Impact of Homozygosity for KLVS:

• Homozygotes for KLVS produce lower levels of clotho compared to non-carriers or heterozygotes, showing about a 30% decrease in clotho levels.
• Studies indicate that homozygosity leads to decreased clotho levels by approximately 30% compared to non-carriers.