#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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May 27, 2024

Dena Dubal, a physician-scientist and neurology professor at UCSF, shares her groundbreaking insights on klotho, a longevity protein that promotes brain health and combats cognitive decline. She discusses how factors like stress and exercise influence klotho levels, and presents exciting research showing its potential in treating neurodegenerative diseases, including Alzheimer's. Dena emphasizes the promise of klotho as a therapeutic tool, while highlighting the importance of innovative research and philanthropy in advancing treatments for cognitive health.

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INSIGHT

Klotho's Indirect Effect on the Brain

Klotho enhances cognition but doesn't cross the blood-brain barrier.
This suggests an indirect mechanism, possibly involving messengers in the blood that communicate with the brain.

INSIGHT

Platelets as Messengers of Brain Health

Clotho appears to activate platelets, leading to the release of platelet factor 4 (PF4).
PF4, also increased by young blood and exercise, crosses the blood-brain barrier and enhances cognition.

INSIGHT

PF4 and GluN2B Receptors

PF4 works through the GluN2B subunit of NMDA receptors, much like klotho itself.
However, PF4 is not required for klotho's cognitive benefits, suggesting other messengers are involved.

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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, Dena delves into the intricacies of the longevity factor klotho: its formation and distribution in the body, the factors such as stress and exercise that impact its levels, and its profound impact on cognitive function and overall brain health. Dena shares insights from exciting research in animal models showing the potential of klotho in treating neurodegenerative diseases as well as its broader implications for organ health and disease prevention. She concludes with an optimistic outlook for future research in humans and the potential of klotho for the prevention and treatment of Alzheimer's disease.

Disclosure: Peter is an investor in Jocasta Neuroscience, a company working to develop klotho as a therapy for people with Alzheimer's disease.

We discuss:

Dena's fascination with aging and how she came to study klotho [3:30];
Biological properties of klotho: production, regulation, decline with age, and factors influencing its levels [11:45];
Potential benefits of klotho on brain health [22:00];
The relationship between soluble klotho protein, platelet factors, and cognitive enhancement [33:45];
The role of platelet factor 4 (PF4) and it's interaction with GluN2B in mediating cognitive enhancement [46:45];
Benefits of klotho observed in a mouse model of Parkinson's disease [55:45];
Benefits of klotho observed in a mouse model of Alzheimer's disease [1:03:00];
Promising results of klotho in primate models, and the importance of finding an appropriate therapeutic dose before moving to human trials [1:08:00];
Speculating why a single klotho injection has such long-lasting effects [1:25:30];
Potential cognitive benefits of klotho in humans, the impact of the KL-VS genetic variant on klotho levels, and the need for human trials to confirm these effects [1:27:45];
The interaction between the KL-VS genetic variant and APOE4 and how it impacts risk of Alzheimer's disease [1:34:45];
The significance of klotho levels: studies linking lower levels to increased mortality and the broader implications for organ health and disease prevention [1:47:15];
Measuring klotho levels and determining an individual's KL-VS status [1:52:15];
The promising potential of klotho for Alzheimer's disease treatment, and the importance of philanthropy for funding research [1:58:00]; and
More.

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