Dena Dubal, MD, PhD

We investigate molecular underpinnings of brain resilience in aging and neurodegenerative disease – through study of the hormone klotho and research on sex chromosomes. Our research spans discovery at the intersection between mechanisms of aging and neurodegenerative disease. We use a wide variety of techniques to uncover cellular and molecular mechanisms using cellular models, mouse models, and human populations.

How do women live longer and sustain better brain function in aging? We discovered that sex chromosomes modulate longevity and susceptibility to aging and Alzheimer’s disease (AD). We have long known that females live longer than males in normal aging and in AD. Using transgenic mouse models, we found that female-longevity and decreased susceptibility to age-related disease are driven by genetic sex. Ongoing studies are aimed at targeting sex chromosome-related biology to further understand how the second X chromosome confers resilience through a variety of pathways including escape from X inactivation. 

What does Klotho, the daughter of Zeus, have to do with brain aging? We discovered that klotho, a longevity hormone that extends lifespan and is the eponym for the Greek fate, enhances cognition and boosts brain resilience to deficits related to aging, stress, and neurodegenerative diseases. Klotho enhancement, and suppression of the aging process, may be beneficial in preventing Alzheimer’s, Parkinson’s and related diseases. Ongoing studies are aimed at dissecting the molecular mechanisms of klotho-mediated resilience.  We are particularly curious to unravel how it organizes a synapse, counters pathogenic proteins, and sends signals from the body to the brain in a manner similar to exercise.

Ultimately, we hope our findings uncover fundamental neuroscientific mechanisms and lead us to pathways that could improve human brain health.

Current Projects

Determine how the second X chromosome confers neural resilience in aging and disease through mechanisms of escape from X inactivation – and from parent-of-origin X imprinting.

Elucidate how the longevity hormone klotho sends signals from the body to the brain to induce cognitive enhancement – and how that appears to mimic exercise.

Investigate how klotho orchestrates synaptic changes to cause cognitive enhancement and neural resilience in aging and neurodegenerative diseases.

Lab Members

Lab Website