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.

**Peter Attia** (0:11)
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My guest this week is Dr. Dena Dubal. Dena is a physician, scientist, and professor of neurology at the University of California, San Francisco, and holds the David Coulter Endowed Chair in Aging and Neurodegenerative Disease. She is also an investigator with the Simmons Foundation and the Baccar Aging Research Institute. Her work is recognized for its significant potential towards therapies to help people live longer and better. She directs a laboratory focused on mechanisms of longevity and brain resilience that integrate genetic and molecular approaches to investigate aging, Alzheimer's disease, and Parkinson's disease. In my conversation with Dena, we focus around something called Clotho. Now, if you've heard me talk on this podcast and other podcasts, you've probably heard me bring up Clotho, either the protein or the gene that codes for the protein. My interest in Clotho really started a couple of years ago when I became aware of some of the genetic data in humans about the relationship between Clotho and Alzheimer's disease prevention, particularly in people who are carriers of the A4 gene. This, of course, has led me deeper and deeper down the Clotho rabbit hole, and really all roads lead to Dena if you want to have this discussion. So we begin our discussion with an overview of Clotho. What is it? How is it formed? How does it get around our body? And what does it do? I talk about the mechanisms regulating Clotho in the body and in particular in the brain. We also talk about things that impact Clotho levels, such as stress and exercise and to what extent they do. From there, we look at the research that's being done in how Clotho relates to various cognitive functions, as well as its role in brain health across different species and across different ages, as well as understanding how Clotho treatment may be helpful in treating neurodegenerative disease, particularly Alzheimer's disease.
We wrap up this discussion speaking about the broader impacts of Clotho on organ health in addition to what its potential may hold for the treatment of Alzheimer's disease in the future.
Before getting to this podcast, I'd like to mention a conflict of interest, which is that I am an investor in a company called Jocasta. Jocasta is a company that is trying to bring Clotho, the protein, into human clinical trials for treatment of Alzheimer's disease. So without further delay, please enjoy my conversation with Dena Dubal.
Dena, thanks so much for joining me today. This is a topic I've been very interested in for the better part of about a year and a half to two years. And obviously there's no better person to discuss this with than you. I also suspect that this is a topic not enough people know about given its potential implications and significance vis-a-vis Alzheimer's disease, which we'll get to. But maybe before we get into this, let's give people a bit of a sense of your background. Tell me a little bit about your clinical work, your research work, what you did during your PhD and how that carried forward during your tenure.

**Dena Dubal** (4:14)
Sure, well, thanks again for the invitation. I'm delighted to join you today. By way of introduction, I'm a neurologist and I'm a neuroscientist. And I direct a group that is deeply involved in the discovery around clotho.
And I was thinking back to when my interest in aging actually began. What was this journey? And I thought back to my undergraduate days at UC Berkeley when I was a 19 year old that was oddly interested in aging, kind of obsessed with aging. I worked with a medical anthropologist at Berkeley, Lawrence Cohen, on what it meant to experience dementia in different cultures. What was it like in India versus the United States? And then simultaneously, I took a class on the physiology of aging. I remember it so clearly in Dwanell Hall, and I was at the edge of my seat learning about cellular senescence. And I remember thinking, this is amazing. This is happening to us day by day, aging, yet we don't know so much about it. And we don't know much about brain aging per se. And I was committed as an undergraduate to really learn more about brain aging and possibly to do something about it. That led me to an MD PhD at the University of Kentucky. I trained with Phyllis Wise, a neuroendocrinologist who studied brain aging, who has an amazing PhD, learned so much, fell in love with the discovery process of science.