Klotho longevity hormone helped make mice smarter

A shot of klotho, a hormone associated with longevity, seems to make mice smarter. Klotho is a naturally occurring hormone in the body. More than two decades ago, Japanese researchers discovered that this hormone plays a role in aging. People with more klotho in their body, tend to live longer and to retain more of their faculties—that is to stay sharp—well into old age.

Researchers injected three types of mice with a portion of the protein. They injected young mice, aged mice, and mice genetically altered to have brains similar to that which we would see in Alzheimer’s or Parkinson’s patients in humans.

“Within hours they showed better cognitive function,” says Dubal.

Since you can’t exactly administer a mouse an IQ test, they assessed brain power based on the mice’s ability to navigate a series of water mazes, in an experiment that sounds on par with human a trip to Wisconsin’s famed waterslide park, The Dells.

They found that mice that had daily injections and were better able to navigate the maze (as measured by the distance traveled to find a hidden platform) than their control group peers. In a classic example of work smarter, not harder, the klotho mice were just much more efficient seekers.

We tested them two weeks later in a different cognitive test and they were still smarter,” says Dubal, “which suggested that getting the klotho protein into their bodies combined with brain training and stimulation had a long-lasting effect in their brain.” Because the half-life of the protein is only seven and a half hours long, any of the protein should have been long out of their system.

Cell Reports – Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and α-Synuclein Transgenic Mice


• A klotho fragment (αKL-F) enhances cognition in young and aging mice
• αKL-F counters deficits in α-synuclein mice without altering pathogenic protein levels
• αKL-F induces GluN2B cleavage and increases NMDAR-dependent synaptic plasticity
• Selective NMDAR blockade of GluN2B subunits abolishes acute αKL-F effects


Cognitive dysfunction and decreased mobility from aging and neurodegenerative conditions, such as Parkinson and Alzheimer diseases, are major biomedical challenges in need of more effective therapies. Increasing brain resilience may represent a new treatment strategy. Klotho, a longevity factor, enhances cognition when genetically and broadly overexpressed in its full, wild-type form over the mouse lifespan. Whether acute klotho treatment can rapidly enhance cognitive and motor functions or induce resilience is a gap in our knowledge of its therapeutic potential. Here, we show that an α-klotho protein fragment (αKL-F), administered peripherally, surprisingly induced cognitive enhancement and neural resilience despite impermeability to the blood-brain barrier in young, aging, and transgenic α-synuclein mice. αKL-F treatment induced cleavage of the NMDAR subunit GluN2B and also enhanced NMDAR-dependent synaptic plasticity. GluN2B blockade abolished αKL-F-mediated effects. Peripheral αKL-F treatment is sufficient to induce neural enhancement and resilience in mice and may prove therapeutic in humans.


Cognitive dysfunction and decreased mobility from aging and age-related neurodegenerative conditions such as Alzheimer disease (AD) and Parkinson disease (PD) are major biomedical challenges. Because more effective treatments are needed, and clinical trials targeting putative pathogenic proteins have failed, it is critical to develop alternate or complimentary therapeutic strategies. In light of this urgent medical need for our rapidly aging populations, delaying aging itself or increasing the function and resilience of the brain (Bennett, 2017, McEwen and Morrison, 2013) may represent new treatment strategies.