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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 i