#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.
May 27, 2024
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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.
Klotho's impact on brain health extends to cognitive improvement and resilience against neurodegenerative diseases.
Platelet factor four (PF4) plays a significant role in enhancing cognitive functions mediated by Klotho.
Peripheral administration of Klotho benefits cognition in mice and monkeys, with platelet factors potentially facilitating its effects on brain function.
Klotho shows promise in Alzheimer's treatment by protecting neurons from protein toxicities and enhancing cognitive performance against Alzheimer's toxins.
Deep dives
Importance of Clotho in Enhancing Cognitive Function
Clotho, a crucial protein discussed in the podcast, has shown significant potential in enhancing cognitive functions across different species and ages. Studies have revealed that overexpressing Clotho improved cognition in both aging mice and those modeling Alzheimer's disease. The protein's ability to increase synaptic plasticity through the GluN2B subunit suggests its role in promoting brain health and resilience against neurodegenerative diseases.
Platelet Factor Four Function as a Messenger
Platelet factor four (PF4) has emerged as a significant player in the Clotho-mediated enhancement of cognitive functions. Experiments have indicated that PF4, known for its roles in wound healing and coagulation, can enhance cognition in mice when administered both peripherally and directly to brain tissues. PF4's involvement in impacting the GluN2B subunit suggests a potential pathway through which Clotho influences cognitive processes.
Crossing the Blood-Brain Barrier
While Clotho does not directly cross the blood-brain barrier, its peripheral administration has shown cognitive benefits in both mice and monkeys. Investigations into the mechanism of action have revealed that platelet factors, particularly PF4, may act as messengers carrying the cognitive enhancement effects of Clotho into the brain. Further research is delving into the intricate interactions between Clotho, platelet factors, and brain function.
Potential Therapeutic Implications for Neurological Diseases
The podcast highlights promising therapeutic implications of Clotho, especially in conditions like Alzheimer's and Parkinson's diseases. Clotho treatment has demonstrated cognitive improvements in mouse models with Parkinson's disease, hinting at its potential for targeting cognitive deficits associated with neurodegenerative disorders. The findings pave the way for potential clinical trials to explore Clotho's efficacy in enhancing brain health and cognitive functions in human subjects.
Clotho as a Potential Treatment for Alzheimer's Disease
Clotho, a factor naturally present in the body that aids in longevity and organ function, holds promise in Alzheimer's disease treatment due to its ability to counteract multiple protein toxicities and protect neurons from various toxicities. Studies on genetically susceptible mice, namely the J20 model expressing human APP and developing cognitive deficits by three to four months, have shown that administering clotho significantly extends lifespan, normalizes cognition, and preserves synapses even in the presence of amyloid and tau proteins, demonstrating its resilience against Alzheimer's toxins.
The Impact of Clotho on Cognitive Enhancement in Non-Human Primates
Research conducted on non-human primates, which show cognitive decline paralleling that of humans, revealed that clotho treatment, particularly at a low physiologic dose, led to immediate cognitive enhancement lasting for weeks. Studies using a spatial delayed task demonstrated that clotho preferentially targeted circuits affected by aging and neurodegenerative diseases, resulting in improved cognitive performance, especially under high memory load conditions.
The Genetic Variant KLVS and its Association with Clotho Levels and Cognition
The genetic variant KLVS, found in a small percentage of individuals and associated with higher clotho levels, has been linked to improved cognition in normal aging populations. Studies have shown that KLVS carriers exhibit better cognitive performance, nearly offsetting the detrimental effects of APOE4 carriers, and may offer protection against Alzheimer's disease onset and biomarker abnormalities, showcasing its potential therapeutic benefits.
Clotho Levels as a Biomarker for Mortality and Health Outcomes
Clotho levels have emerged as a potential biomarker for mortality and health outcomes, with lower clotho levels correlating with an increased risk of all-cause mortality over time. Studies indicate that clotho plays a crucial role not only in brain health but also in mitigating risks of cancer, cardiovascular disease, and kidney dysfunction. Monitoring clotho levels, preferably in the morning fasting state, holds promise in assessing overall health and disease risk.
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
