#303 - A breakthrough in Alzheimer's disease: the promising potential of klotho for brain health, cognitive decline, and as a therapeutic tool for Alzheimer's disease | Dena Dubal, M.D., Ph.D.
Dr. Dena Dubal, a UCSF neurologist and neuroscientist, discusses klotho, a longevity factor linked to brain resilience. She details its decline with age, its increase with exercise, and its profound impact on cognitive function in animal models, including potential for Alzheimer's and Parkinson's treatment.
Deep Dive Analysis
16 Topic Outline
Introduction to Dr. Dina Dubal and Klotho
Dr. Dubal's Path to Studying Brain Aging and Klotho
Serendipitous Discovery and Early Findings of Klotho
Biological Structure and Forms of Klotho Protein
Factors Influencing Klotho Levels and Their Daily/Lifespan Variation
Klotho's Unexpected Cognitive Benefits in Healthy and Alzheimer's Mouse Models
Investigating How Peripheral Klotho Impacts Brain Function
The Role of Platelet Factor 4 (PF4) as a Klotho Messenger
PF4's Sufficiency but Not Necessity for Klotho's Cognitive Effects
Klotho's Impact on Cognitive Deficits in Parkinson's Mouse Models
Cognitive Enhancement in Aging Non-Human Primates with Klotho
Human Genetic Variant KL-VS and Its Impact on Klotho Levels and Cognition
KL-VS Interaction with APOE4 and Broader Health Implications
Association of Low Klotho Levels with Increased Mortality and Organ Health
Challenges and Future of Measuring Klotho Levels
Future Therapeutic Potential and Funding for Klotho Research
6 Key Concepts
Klotho (protein/gene)
Klotho is a longevity factor accidentally discovered in 1997. Its disruption in mice causes premature aging and a shortened lifespan, while its overexpression can extend lifespan by about 30%. It is a large transmembrane protein predominantly made in the kidney and choroid plexus.
Soluble Klotho (Klotho hormone)
This is the majority of the Klotho protein that is cleaved from the cell membrane by enzymes (ADAM10, ADAM17) and released into the blood or cerebrospinal fluid (CSF). It acts as a hormonal factor, circulating throughout the body and influencing various organs, including the brain.
BDNF (Brain-Derived Neurotrophic Factor)
BDNF is a trophic factor in the brain that is strongly associated with positive brain health. It is known to improve neuronal function and is increased by interventions like exercise and intermittent fasting.
Brain Resilience
Brain resilience refers to the ability of the brain to maintain normal cognitive function despite the presence of age-related or disease-related pathologies, such as amyloid beta and tau in Alzheimer's disease. Klotho appears to confer this resilience by preserving synaptic connections.
Platelet Factor 4 (PF4)
PF4 is a chemokine released by activated platelets, which can cross the blood-brain barrier and enhance cognition by acting on GluN2B subunits of NMDA receptors. It is increased by Klotho, exercise, and factors found in young blood, suggesting it acts as a messenger for brain health.
KL-VS (Klotho genetic variant)
KL-VS is a genetic variant (two single nucleotide polymorphisms) in the Klotho gene. Carrying one copy (heterozygous) leads to approximately 15-20% higher circulating Klotho levels and is associated with better cognition and protection against Alzheimer's disease risk, especially in APOE4 carriers. Homozygosity for KL-VS is rare and associated with lower Klotho levels and shorter lifespans.
13 Questions Answered
Klotho is a longevity factor accidentally discovered in 1997 by Makoto Kuroo while studying hypertension in mice. He found that disrupting the Klotho gene led to premature aging, while overexpressing it extended lifespan.
Klotho is primarily produced in the kidney and choroid plexus, and its extracellular portion is cleaved to form a soluble, hormonal version that circulates in the blood and CSF. Levels are highest at birth, decline with age, show a diurnal rhythm (highest in the morning), and are influenced by factors like chronic stress (decreasing levels) and exercise (increasing levels).
Klotho enhances cognition by increasing the presence of the GluN2B subunit at neuronal synapses, which is a key component of NMDA receptors. This leads to more efficient connections between neurons and improved memory formation, or synaptic plasticity.
No, Klotho does not cross the blood-brain barrier. Despite this, peripheral injections of Klotho still lead to cognitive enhancement, suggesting it acts through a messenger system in the blood that then enters the brain.
Platelet Factor 4 (PF4) is a chemokine released by activated platelets. Research suggests Klotho modestly activates platelets to release PF4, which then travels to the brain and enhances cognition, acting as a messenger for Klotho's effects.
While PF4 is sufficient to recapitulate Klotho-mediated cognitive enhancement, experiments in PF4 knockout mice showed that Klotho still enhanced cognition to the same extent in their absence, indicating that PF4 is not necessary and other messengers likely exist.
In mouse models of Parkinson's disease, Klotho treatment significantly improved cognitive abilities (nearly normalized them) but did not show any effect on motor dysfunctions. This suggests a potential role for Klotho in addressing the cognitive deficits associated with Parkinson's.
Studies in aging Rhesus macaques showed that a single, low, physiologic dose of Klotho enhanced cognition within four hours, and this improvement lasted for at least three weeks. The effect was particularly pronounced in tasks requiring high memory load, while supraphysiologic doses did not provide additional benefit.
The KL-VS genetic variant involves two single nucleotide polymorphisms in the Klotho gene. Individuals carrying one copy (heterozygotes) have about 15-20% higher circulating Klotho levels and are associated with better cognitive performance in normal aging.
A large meta-analysis found that KL-VS heterozygosity appears to abrogate the toxicity of APOE4. APOE4 carriers who also carry the KL-VS variant have a decreased risk for developing Alzheimer's disease, reduced conversion from MCI to AD, and lower Alzheimer's biomarkers, regardless of whether they have one or two copies of APOE4.
While KL-VS heterozygosity is generally associated with protection against stroke, cardiovascular, and metabolic risks, it has been linked to a poorer prognosis in BRCA1 carriers with breast cancer, indicating it is not universally beneficial.
Large-scale human studies, such as the NHANES study, have shown a strong association between lower circulating Klotho levels and increased all-cause mortality. Individuals with Klotho levels below a certain threshold (e.g., <666 pg/mL) had a 30% higher mortality risk over five years, primarily due to cancer and cardiovascular disease.
Due to Klotho's diurnal rhythm, it is recommended to measure levels in the morning, in a fasting state, similar to cholesterol tests, to obtain the most accurate and consistent results. A standardized clinical assay for Klotho is currently needed.
7 Actionable Insights
1. Engage in Chronic Exercise
Regularly engage in chronic exercise, as it is a robust intervention shown to increase clotho levels by about 30% after 12 weeks, potentially enhancing brain health and longevity.
2. Manage Chronic Stress
Actively manage chronic stress, as high levels of stress are associated with lower clotho levels and shorter telomeres, suggesting a negative impact on aging markers.
3. Consider Rapamycin
Consider rapamycin as a potential intervention, as studies in mice show it can increase clotho levels, contributing to the convergence of biology for longevity factors.
4. Monitor Clotho Levels
Consider getting your clotho levels checked as a potential diagnostic biomarker, as lower levels are associated with increased mortality risk from diseases like cancer and cardiovascular disease.
5. Standardize Clotho Measurement
If getting clotho levels checked, ensure the blood draw is done in a morning fasting state to minimize diurnal variation and provide a more accurate and consistent measurement.
6. Pursue Big, Important Science
When conducting scientific research, aim for projects that are ‘big and important, and not incremental or mediocre,’ because both types of work will take the same amount of time.
7. Fund Risky, High-Upside Science
Philanthropists should fund scientific endeavors that are too risky for traditional funding but possess significant biologic plausibility and potential for transformative, game-changing impact.
4 Key Quotes
Sometimes experiments will show you those differences. And then the next time you do it, they don't. Someone who runs the water maze is wearing a new cologne and the mice get stressed out. They don't always repeat and are not always replicable. This is a case that it was amazing, but was it going to replicate? Was it going to be true in different cognitive tasks? What would happen in an aging mouse? All of these questions opened up and we iterated and we did experiment after experiment and the data held strong in mice that clotho overexpression really enhanced their cognition in young mice, in aging mice, in mice that modeled Alzheimer's disease, and also in mice in a publication that's in peer review now, but also in mice that model Parkinson's disease, that overexpression of clotho enhanced cognition. It is really a remarkable finding. I think it's maybe one of the most important findings in my professional career.
Dina Dubal
I would go one step further. I feel like it's one of the most important findings in brain health, period. I mean, on some levels, it's a bit of a mystery to me why this isn't known by everyone.
Peter Attia
In other words, their brains are still riddled with the Alzheimer's toxins, but they've been able to really thwart the effects of those toxins because they show normal cognition.
Dina Dubal
If it doesn't work, it's going to kill your research program. And I would say, let it die then. I don't want to spend my career on something that's not important.
Dina Dubal