#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.

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.

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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.

Dena’s fascination with aging and how she came to study klotho [3:30]

Tell me a little about your clinical work, your research work, what you did during your PhD and how that carried forward during your tenure 

• Dena is a neurologist and a neuroscientist
• She directs a group that is deeply involved in the discovery around klotho

Thinking back to when her interest in aging actually began 

• She thought back to her undergraduate days at UC Berkeley when she was a 19-year-old that was oddly interested in aging (kind of obsessed)
• She worked with a medical anthropologist at Berkeley (Lawrence Cohen) on what it meant to experience dementia in different cultures (India versus the United States)
• Simultaneously she took a class on the physiology of aging ‒ she was at the edge of her seat learning about cellular senescence
  • It’s amazing that this is happening to us day by day, yet we don’t know much about it
  • We don’t know much about brain aging 

As an undergraduate, she was committed to learning more about brain aging and possibly to do something about it, and that led her to do a MD PhD at the University of Kentucky 

• She trained with Phyllis Wise, a neuroendocrinologist who studied brain aging, who was an amazing PhD
• She learned so much, fell in love with the discovery process of science
• Fast-forward, she then trained as a neurologist at UCSF where she is now
  • And that was over 20 years ago, 2003

Her work at UCSF 

• She’s on the wards, it’s a regular day of patient rounding, and the former chair of UCSF neurology (Stephen Hauser) turned to her and he said, “Dena, when you go back to the lab, do things that are big and important and not incremental or mediocre because they’ll take you the same amount of time.”
  • That really clicked with her, and it became her mantra
• After an Alzheimer’s fellowship, in both clinical and basic science, she had the chance to build a group and really start her own scientific discovery
• They focused on klotho, the subject of what we’ll talk about today
  • Named after the Greek fate who spins the thread of life

The idea of studying klotho is to understand whether factors that help us to live longer could help us to live better 

• Whether this longevity factor could actually help the brain
• Could help it stave off Alzheimer’s disease?

The first time klotho crossed her radar 

• She was a junior faculty thinking about what to focus on, “What was going to be our chance to do something big and important?”
• She was intrigued by a few decades of work showing that aging itself was malleable
  • Cynthia Kenyon demonstrated that tweaking genetics in worms could dramatically increase their lifespan
    • Her work knocked-out an analog of one of the IGF genes, DAF-16 
• Dena wanted to know if that could have effects in the brain
• Klotho had emerged as a longevity factor, and it was a chance to understand: could klotho do something in the brain? 
• Very little was known about klotho when she started
• A colleague had observed that the levels decrease in the white matter of monkey brains, that a variant of klotho that we can talk about in a bit was associated with decreased stroke risk
• The person who discovered klotho had noted that mice without klotho moved slowly and they were cognitively a little slow
• Dena was the right person at the right time, and had the chance to really dig in

It was risky to start with something that not much was known about in the brain, but it was a chance to do something maybe big and important 

The discovery of klotho is such a story of serendipity 

• It was in 1997, Makoto Kuro-o, a Japanese scientist accidentally discovered klotho
• He was studying hypertension and he engineered a mouse to insert a gene, and then he noticed that in a few lines of these mice, maybe it was just one line of these mice, there was this premature aging phenotype
  • The mice lived to about 3 months instead of about 30 months
  • They developed normally, but around 2 weeks of age they became progeroid: they looked like they were rapidly aging with osteoporosis, atherosclerosis, emphysema, and they moved slow
  • They looked really old
• So, he went back to that mouse and he mapped out what had been disrupted, and that was klotho
• That was the first time klotho was found, and he named it after the Greek fate (Clotho) who spins the thread of life, daughter of Zeus
  • He named it K-L-O-T-H-O in homage to his discovery
  • His name is Kuro-o
• And a longevity factor isn’t something that just causes premature aging if disrupted
  • So, it was very important for him to then go back and see what would happen if he overexpressed it
• He engineered mice to overexpress klotho, and those mice lived 30% longer

That showed that klotho is a longevity factor ‒ disruption caused premature aging and overexpression extended lifespan 

• Peter adds, “It’s a great story for people especially maybe who don’t do or haven’t done science because it illustrates the role of curiosity and serendipity.”
• There are some people who maybe wouldn’t have even gone back and done the experiments that he did to understand what turned out to be the most relevant thing

“He followed the science, he opened the field. He looked into the mistake, the oops of science. And here we are, maybe on the cusp of a new therapy.”‒ Dena Dubal  

Biological properties of klotho: production, regulation, decline with age, and factors influencing its levels [11:45]

• Klotho itself is a pretty big protein: it’s about a 1,000 amino acids, by weight maybe 130 kilodaltons 
• It codes for a type I transmembrane protein
  • Which means that its N-terminus will sit in the extracellular space, it has one pass through the membrane, and its C-terminus is inside the cell

{end of show notes preview}

Dena B. Dubal M.D., Ph.D.

Dena B. Dubal MD, PhD is a physician-scientist and Professor in the Dept of Neurology and Weill Institute of Neurosciences at the University of California, San Francisco (UCSF). She holds the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease and is an Investigator with the Simons Foundation and Bakar Aging Research Institute. Dr. Dubal received her MD and PhD degrees from the University of Kentucky College of Medicine. She completed a medical internship and neurology specialty training at UCSF, where she served as chief resident.

Dr. Dubal trained at UCSF for a Behavioral Neurology Fellowship at the Memory and Aging Center. She now directs a laboratory focused on mechanisms of longevity and brain resilience that integrates genetic and molecular approaches to investigate aging, Alzheimer’s and Parkinson’s disease – in animal models and human populations at UCSF.

Her discoveries have been profiled in high-impact media such as The New York Times and The Economist. Her work is recognized for its potential toward therapies to live longer and better. Among her honors, Dr. Dubal received the NIA/AFAR Paul Beeson Award for Aging Research, Glenn Award in Biologic Mechanisms of Aging, Grass Award in Neuroscience, and the Neuroendocrine Research Award from the American Academy of Neurology. She served on the Board of the American Neurological Association and currently serves in the leadership of JAMA Neurology, the Weill Institute Neurohub, and the Glenn Foundation for Medical Research.

Conflict of Interest Disclosures: Dr. Dubal has consulted for Unity Biotechnology and S.V. Health and reports funding for her research from the National Institutes of Health, the Simons Foundation, the American Federation for Aging Research, the Glenn Medical Foundation, Unity Biotechnology, and philanthropy; in addition, Dr. Dubal holds a patent for Methods for Improving Cognition, focused on klotho, filed by the Regents of the University of California and issued.

Lab website: Dubal Lab

X: @DenaDubal