DeepSummary
The podcast features Dr. Dena Dubal, a physician-scientist at UCSF, discussing her research on the longevity factor klotho and its potential as a therapeutic for Alzheimer's disease. She explains how klotho is formed, its regulation in the body, and how factors like stress and exercise influence its levels. Dubal shares insights from her studies in animal models, where increasing klotho levels enhanced cognitive function, protected against neurodegenerative diseases like Alzheimer's and Parkinson's, and had broader impacts on organ health.
Dubal delves into the mechanisms by which klotho may promote cognitive enhancement, including its interaction with NMDA receptors and the role of platelet factors like PF4. She discusses promising results from primate studies, where a single injection of klotho improved cognition for several weeks, and the importance of finding an appropriate therapeutic dose before human trials.
The episode also explores the significance of the KL-VS genetic variant, which is associated with higher klotho levels and decreased risk of Alzheimer's disease, particularly in APOE4 carriers. Dubal highlights the need for standardized klotho level testing and the potential for klotho as a biomarker and therapeutic for various age-related diseases.
Key Episodes Takeaways
- Klotho is a longevity factor that appears to enhance cognitive function, protect against neurodegenerative diseases like Alzheimer's and Parkinson's, and have broader impacts on organ health.
- Studies in animal models and primates have shown promising results for klotho's cognitive-enhancing effects, with a single injection improving cognition for several weeks in primates.
- The KL-VS genetic variant is associated with higher klotho levels and decreased risk of Alzheimer's disease, particularly in APOE4 carriers.
- Klotho levels decline with age and chronic stress, but can be increased through exercise, suggesting potential for lifestyle interventions.
- Standardized testing for klotho levels and determining an individual's KL-VS status could have important implications for disease risk assessment and personalized treatment.
- Identifying the appropriate therapeutic dose of klotho is crucial before moving to human clinical trials for Alzheimer's disease and other age-related conditions.
- Klotho's potential extends beyond brain health, with associations between low klotho levels and increased mortality from cancer and cardiovascular disease.
- Philanthropic funding for high-risk, high-reward research like Dubal's work on klotho is essential for advancing scientific understanding and developing novel therapies.
Top Episodes Quotes
- “I really want to be doing something that I have a lot of faith in and that potentially has meaning for the human condition to improve human health.“ by Dena Dubal
- “If it's done well, we'll know. This collaboration between biotech, me and Yale was one in which a lot of thought, a lot of money went into the design and the execution.“ by Dena Dubal
- “It's really remarkable, isn't it? It's particularly remarkable as we imagine therapeutics in that maybe this is the type of treatment of rejuvenation that could be administered maybe once a month, once every three months as a shot in the arm, for example.“ by Dena Dubal
- “Alzheimer's disease is one of our biggest biomedical challenges. Our entire world is aging. It used to be the US, Japan, Sweden, but it's the entire world. China, India, Africa, all continents are aging. We're aging rapidly again. This is one of our biggest biomedical problems. We really do not have effective therapies, and I'm hopeful that with multiple shots on goal right now, something will come to market that provides that resilience.“ by Dena Dubal
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Episode Information
The Peter Attia Drive
Peter Attia, MD
5/27/24
View the Show Notes Page for This Episode
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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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