#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.

I have this dream that people might be able someday to benefit from klotho, this factor that naturally circulates in our body, that helps with longevity, that helps with other organ systems and enhances the brain.” —Dena Dubal

Read Time 47 minutes

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.


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}

Would you like access to extensive show notes and references for this podcast (and more)?

Check out this post to see an example of what the substantial show notes look like. Become a member today to get access.

Become a Member

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

Disclaimer: This blog is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this blog or materials linked from this blog is at the user's own risk. The content of this blog is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions.


  1. Wondering I’d Peter et al have investigated “RESPeRATE” breathing exercise apparatus in regard to claims of hypertension relief.

  2. As an academic and practicing internist, I have been following research on Klotho, and have presented this fascinating topic to my multi specialty journal club- so glad to hear this wonderful in depth interview here. It would be great to have an additional in depth discussion on local myokine effects of Klotho with exercise that may be insufficiently captured with serum assays. Have you looked at the studies of Kuro-o on bound Klotho and the atherogenic/pathogenic effects of secondary calciprotein particles- also a fascinating under appreciated story…

  3. Your interview with Dr. Dena Dubal was one of the best in your series. There have been so many great and informative interviews on The Drive, but today was exceptional.
    FYI, I do not have a medical or scientific background, but enough of a background and interest in health and longevity to have benefited from the info. Thank you for all that you do and all that you share!😊

  4. I found out I had the APOE4 gene from both parents about five years ago. I watched my mother deteriorate from the age of 76 – 89. She died a week before her 89th birthday. I am about to turn 76.

    I have researched and read everything I was able to find about AZ and came across an article on the Klotho gene 2 or 3 years ago. I pulled the info out of my 23andme raw data and found this on chromosome 13: Klotho rs9536314 genotype G/T.

    I am not a scientist or doctor, so I cannot extrapolate all the details about a-Klotho or b-Klotho. I understand it’s the protein that provides possible protection. I’m just trying to find some information about whether the Klotho gene I found in my data is meaningless or hopeful.

    • From Listening to the podcast your Klotho G/T allele should negate your E4/E4 and act as if you are a E3/E3. Sounds very hopeful to me.
      Do you have your mothers SNPs? would be very interesting to see what she had. E4/E4 with a Klotho T/T perhaps.

  5. Loved this episode! My husband is a 4/4 and through genetic testing, we unfortunately only have data for one of the KL-VS variants rs9536314, but no data for rs9527025. Would love to know how we can obtain this information. I would also be interested in understanding if this promising data supports improvement in humans with 4/4 and homozygous KL-VS. This episode left me with a lot of hope!

  6. Any drugs on the market that can be repurposed that elevate klotho or PF4?

  7. Can Klotho be reproduced synthetically?
    Can Klotho be administered to patients at present ? Is it FDA approved?
    Does the Blood/Brain barrier pose a problem in getting Klotho to the brain?
    Has alcohol consumption shown some correlation to loss of Klotho over time?

    • Your fourth question is answered, I believe, in the episode. It was suggested somewhere after hour one and before 1 hour and 40 minutes in (I was out walking with the dog) that subcutaneous injections in mice in the body cause a change in the Klotho in the brain, although it doesn’t cross the brain barrier. If I recall, there is evidence that platelets release many different factors that act as signaling mechanisms and I think they mentioned PF4 as this particular factor. It signals, in some manner I don’t know, to the brain to release the Klotho there. So nothing, and this is surprising, has to cross the barrier. Inject in the body to cause signaling and a change occurs in the brain with the impact described by Dr. Dubal.

  8. Another thing that is wonderful about Dr. Dubal’s research is that her papers are Open Access (i.e. not paywalled) so we can download them and read for ourselves.

    My question is about Rapamycin increasing Klotho. Is there a reference for that? The show notes mention it in passing, and I haven’t read the papers yet, but these comments may close before I do, so I want to ask now.

  9. Thank you Peter and Dena for this most interesting and informative podcast. I enjoyed every minute of it and look forward to learning more.

Facebook icon Twitter icon Instagram icon Pinterest icon Google+ icon YouTube icon LinkedIn icon Contact icon