An international study led by the Institut de Neurociències at the UAB (INc-UAB) has shown that increasing levels of the Klotho protein in mice extends lifespan and improves both physical and cognitive health when aging.

As we grow older, it is natural to lose muscle and bone mass, leading to greater frailty and a higher risk of falls and serious injuries. Cognitively, neurons progressively degenerate and lose connections, while diseases such as Alzheimer’s and Parkinson’s become more prevalent. In a society where the population is steadily aging, reducing these effects is one of the main challenges for research.

Now, in an article published in Molecular Therapy, an international research team led by Professor Miguel Chillón, ICREA researcher at the INc-UAB, has shown that increasing levels of the secreted form of the Klotho protein (s-KL) improves aging in mice. The team treated young animals with gene therapy vectors that caused their cells to secrete more s-KL. At 24 months of age, roughly equivalent to 70 years in humans, they found that the treatment had improved the animals’ muscle, bone, and cognitive health.

“We have been working with the Klotho protein for some time, due to its therapeutic potential for treating neurodegenerative diseases. In this study, we wanted to see whether s-KL could also be beneficial for healthy aging by examining a broad range of factors”, explains Miguel Chillón.

Mice treated with s-KL lived 15–20% longer, with better physical performance, larger muscle fibers, and less fibrosis, indicating better muscle health. Improvements in bone health were also observed, particularly in females, with greater preservation of the internal bone structure (trabeculae), suggesting a potential protective effect against osteoporosis. Finally, in the brain, treatment with s-KL promoted the generation of new neurons and increased immune activity in the hippocampus, suggesting possible cognitive benefits.

The viral vector treatment works by introducing copies of the gene encoding the desired protein into the body’s cells, so that they can start producing it on their own. In the mice, these vectors were administered intravenously and directly into the brain to ensure that brain cells also produced s-KL. “We now have viral vectors that can reach the brain after being administered intravenously, which would make it easier to safely transfer this therapy to humans. Another option would be to administer the protein directly as a drug instead of using viral vectors, but we still need to find an efficient way to deliver it and ensure it reaches the target organs,” explains Joan Roig-Soriano, INc-UAB researcher and first author of the article.

The research group had already patented the use of Klotho to treat cognitive deficits, and following this study, three new patents were filed. These patents protect the use of Klotho for treating bone and muscle deficits, as well as for developing therapies aimed at increasing longevity.

“If we can find a viable delivery method, s-KL could make a significant contribution to improving people’s quality of life and helping to build the healthiest society possible,” the researchers conclude.