Klotho Protein Shows Promise to Protect the Brain from Aging and Alzheimer’s

Summary: Genetically increasing klotho improves cognitive function in mouse models of Alzheimer’s disease, according to researchers.

Source: UCSF.

Neurologist and neuroscientist Dena Dubal, MD, PhD, is approaching neurodegenerative diseases—including Alzheimer’s and other forms of dementia—by focusing on a shared underlying cause: aging.

Aging is the single greatest risk factor for cognitive decline, and instead of examining each disease mechanism in isolation, Dubal asked a broader question: what common changes occur in cells and organs as we age, and can those changes be counteracted to protect the brain?

Over the past decades, researchers have identified several cellular processes that drive aging and discovered biological mechanisms that can slow or modify those processes. Dubal, an associate professor of neurology at the University of California, San Francisco and a member of the UCSF Weill Institute for Neurosciences, focused her efforts on one protein with a striking connection to lifespan and brain health: klotho.

Klotho takes its name from Clotho, a figure from Greek mythology who spun the thread of life. Early studies in mice found that varying levels of klotho influenced lifespan, and follow-up work in humans showed that people with naturally higher klotho levels tend to live longer. Dubal and her team wanted to know whether higher klotho levels also correspond to better cognitive performance and greater resilience against dementia and Alzheimer’s disease.

Their studies measured cognitive performance across humans and mice using standardized tasks and puzzles that probe learning, memory, and executive function. The results were consistent: higher klotho was associated with improved cognition. In other words, klotho levels predicted how well subjects solved cognitive tasks, in both species.

Because only a minority of people—about 20 percent—naturally have higher klotho levels, Dubal explored whether it would be possible to reproduce the protective cognitive effects through therapeutic intervention rather than relying on genetics alone. The protein exists in two forms: a membrane-bound form attached to cells in the brain and kidneys, and a circulating form that is released from those membranes and travels through the bloodstream.

In laboratory experiments, the research team injected the circulating form of klotho into mice and observed cognitive benefits within hours. Treated mice—young, old, and those engineered to model Alzheimer’s-like pathology—showed measurable improvement in brain function shortly after receiving the circulating protein. These results suggest that boosting circulating klotho could strengthen cognitive resilience across age groups and disease models.

One surprising aspect of these findings is that injected klotho appears to confer benefits without necessarily crossing the blood-brain barrier. That raises important mechanistic questions about how peripheral klotho communicates with brain tissue and which cellular pathways it influences to preserve or enhance cognition.

Dubal’s lab is now focused on understanding those mechanisms in more detail. Key questions include how circulating klotho signals to the brain, which receptors or downstream pathways are involved, and whether sustained klotho enhancement can provide long-term protection against neurodegeneration. Addressing these questions is critical before considering translation to human therapies, but the early results are promising.

Ultimately, the clinical goal is to increase “healthspan”—the portion of life spent in good health and with preserved cognitive function—rather than simply extending lifespan. As Dubal noted, interventions that slow aspects of biological aging may simultaneously prolong life and improve quality of life, because the processes that promote longevity often overlap with those that preserve function and independence.

Source: UCSF
Publisher: Organized by NeuroscienceNews.com.
Image source: Public domain image used in the original article.

UCSF. “Could a Protein Called Klotho Block Dementia and Aging?”. NeuroscienceNews. Published January 30, 2018.