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May 27, 2024 • 2hr 5min
#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.
The Peter Attia Drive
Dr. Dena Dubal is a physician-scientist and professor of neurology at UCSF whose work focuses on mechanisms of longevity and brain resilience. In this episode, she discusses her research on klotho, a longevity factor that enhances cognitive function and brain health. Dr. Dubal provides insights into klotho's formation, distribution, and effects in the body, as well as its potential as a therapy for neurodegenerative diseases.
#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.
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Key Takeaways
- Klotho is a longevity factor that enhances cognitive function and brain health across species, from mice to monkeys to humans
- Klotho levels decline with age, but can be increased through exercise and potentially supplementation
- Klotho enhances cognition by increasing synaptic plasticity and NMDA receptor function, particularly through the GluN2B subunit
- Klotho does not cross the blood-brain barrier, but acts through peripheral factors like platelet factor 4 to enhance brain function
- A single injection of klotho can enhance cognition for 2-4 weeks in monkeys, suggesting long-lasting effects
- The KL-VS genetic variant of klotho is associated with higher klotho levels and better cognitive function in humans
- KL-VS may protect against Alzheimer's disease risk from APOE4, potentially negating its effects
- Lower klotho levels are associated with increased mortality risk from cancer and cardiovascular disease
- Klotho shows promise as a potential therapy for neurodegenerative diseases like Alzheimer's and Parkinson's
Introduction
Dr. Dena Dubal is a physician-scientist and professor of neurology at UCSF whose work focuses on mechanisms of longevity and brain resilience. In this episode, she discusses her research on klotho, a longevity factor that enhances cognitive function and brain health. Dr. Dubal provides insights into klotho's formation, distribution, and effects in the body, as well as its potential as a therapy for neurodegenerative diseases.
Topics Discussed
Discovery and Properties of Klotho (8:57)
Dr. Dubal explains how klotho was accidentally discovered in 1997 by Japanese scientist Makoto Kuro-o:
- Kuro-o was studying hypertension and engineered mice to insert a sodium-proton channel gene
- One line of mice showed premature aging, living only 3 months instead of 30 months
- Mapping revealed a mutation in what was named the klotho gene
- Overexpressing klotho extended mouse lifespan by 30%
Key properties of klotho:
- Large protein (~1000 amino acids, 130 kDa)
- Type 1 transmembrane protein with extracellular domain
- Primarily produced in kidney and choroid plexus of brain
- Cleaved to produce soluble "hormonal" form in blood/CSF
Klotho Levels and Regulation (14:41)
Dr. Dubal discusses factors affecting klotho levels:
- Age: Levels decline with age, starting around age 40
- Circadian rhythm: Highest in morning, declines ~40% by midnight
- Stress: Chronic stress associated with lower levels
- Exercise: Increases levels by ~30% after 12 weeks of regular exercise
"Exercise increases klotho levels by about 30% and maybe even increase in a study with preliminary data in mice, they can even double acutely after a 45 minutes treadmill run." - Dr. Dena Dubal
Cognitive Benefits of Klotho (27:53)
Dr. Dubal explains her research showing klotho enhances cognition:
- Mice overexpressing klotho showed improved learning and memory
- Effects seen in young, aging, and Alzheimer's model mice
- Klotho acts through NMDA receptors, particularly GluN2B subunit
- Increases synaptic plasticity and efficiency of neural connections
"The mice that overexpressed klotho that live longer were smarter. So you put them in a maze, they could map the room better, escape quicker, not because they were swimming faster, not because they could see better, but because they were remembering and learning more efficiently and better." - Dr. Dena Dubal
Mechanism of Action (37:45)
Key findings on how klotho enhances cognition:
- Klotho does not cross the blood-brain barrier
- Acts through peripheral factors like platelet factor 4 (PF4)
- PF4 crosses into brain and enhances NMDA receptor function
- Multiple factors likely involved beyond just PF4
Effects in Primate Studies (1:08:00)
Dr. Dubal discusses promising results in monkey studies:
- Single injection enhanced cognition within 4 hours
- Effects lasted 2-4 weeks
- Improved performance on spatial memory tasks
- Low physiological dose was effective, high doses less so
"It was remarkable that one sub Q dose, like a shot of ozempic, would be given a sub Q dose that was low physiologic, had an immediate effect on cognitive enhancement that lasted for a very long time." - Dr. Dena Dubal
KL-VS Genetic Variant in Humans (1:30:53)
Dr. Dubal explains the significance of the KL-VS genetic variant:
- Present in 20-25% of population (heterozygotes)
- Associated with ~15-20% higher klotho levels
- Linked to better cognitive function in normal aging
- May protect against Alzheimer's risk from APOE4
"If an individual carried KL-VS, the APOE4 didn't matter. So let me break down what that actually meant in their experiment. That meant that in those people that carry APOE4, if they were also heterozygote for KL-VS, they had a decreased risk for developing Alzheimer's disease that was pretty close to the normal population." - Dr. Dena Dubal
Klotho Levels and Mortality Risk (1:47:15)
Recent large studies have linked lower klotho levels to increased mortality:
- 30% lower levels associated with 30% higher 5-year mortality risk
- Primarily from cancer and cardiovascular disease
- Suggests klotho's effects go beyond just brain health
Measuring Klotho Levels (1:52:15)
Dr. Dubal discusses considerations for measuring klotho:
- Best measured in morning, fasting
- Levels vary throughout day
- Need for standardized assay
- Potential as future biomarker of aging/health
Potential as Alzheimer's Therapy (1:58:00)
Dr. Dubal expresses optimism about klotho as a potential Alzheimer's treatment:
- Could complement anti-amyloid therapies
- Provides "resilience" to neurons against multiple toxicities
- Long-lasting effects could allow infrequent dosing
- Human trials needed to confirm effects
"I just have this dream that people might be able someday to benefit from klotho. This factor that naturally circulates in our body, that helps with longevity, that helps with other organ systems and enhances the brain, as we know from our monkey studies, for weeks at a time, at least a couple of weeks, if not more." - Dr. Dena Dubal
Conclusion
Dr. Dubal's research on klotho reveals its potential as a powerful enhancer of cognitive function and brain health. From mice to monkeys to humans, klotho shows promise in protecting against age-related cognitive decline and neurodegenerative diseases like Alzheimer's. While more research is needed, particularly human clinical trials, the consistent positive effects across species and the long-lasting cognitive enhancement seen in primates are cause for optimism. Klotho may represent a new approach to treating Alzheimer's disease and other age-related cognitive disorders by enhancing the brain's resilience to multiple toxicities. As the global population ages, klotho could become an important tool in addressing the growing challenge of neurodegenerative diseases.