An international study led by the Institut de Neurociències at the Universitat Autònoma de Barcelona (INc-UAB) has provided compelling evidence that increasing levels of the Klotho protein in mice can extend lifespan and significantly improve both physical and cognitive health during ageing. Published in the journal Molecular Therapy, this research represents a crucial step towards understanding how to counteract the physical decline and neurological deterioration associated with old age. The study was spearheaded by Professor Miguel Chillón, an ICREA researcher at the INc-UAB, and focused on the secreted form of the Klotho protein (s-KL), known for its potential to promote healthy ageing.
As we age, the body naturally undergoes physical and cognitive changes. Muscle and bone mass gradually decline, leading to frailty and a heightened risk of falls and fractures, while neurons in the brain progressively degenerate, losing vital connections. This neurological decay underlies the increased prevalence of diseases like Alzheimer’s and Parkinson’s. Addressing these changes in a world where populations live longer is challenging for medical science. Researchers are therefore keen to explore therapies that can extend lifespan and preserve the quality of life in later years.
The INc-UAB team approached this challenge by treating young mice with gene therapy vectors designed to increase s-KL production. These vectors introduced copies of the gene encoding s-KL into the mice’s cells, prompting them to produce the beneficial protein. The treatment was delivered intravenously and directly into the brain, ensuring that central nervous system tissues received sufficient s-KL. By the time the mice reached 24 months of age, roughly equivalent to 70 human years, the treated animals exhibited significant improvements in muscle, bone, and cognitive health compared to their untreated peers. This indicates that enhancing s-KL levels can effectively mitigate some of the most debilitating aspects of ageing.
The physical benefits were particularly striking. Mice that received the s-KL treatment lived 15 to 20 per cent longer and demonstrated superior physical performance, with larger muscle fibres and less fibrosis, pointing to improved muscle health. Bone health also improved, especially in female mice, where the treatment preserved the internal bone structure (trabeculae), potentially reducing the risk of osteoporosis. These findings suggest that s-KL may offer broad protective effects against the musculoskeletal decline associated with ageing.
The cognitive improvements were equally promising. In the brain, s-KL treatment stimulated the growth of new neurons and enhanced immune activity in the hippocampus, a critical region for learning and memory. These findings are particularly encouraging given the high burden of neurodegenerative diseases in older populations. “We have been exploring the therapeutic potential of Klotho for some time, particularly in the context of neurodegenerative disorders,” explains Professor Chillón. “This study expands on that work, demonstrating that s-KL may promote broader aspects of healthy ageing.”
With these promising results, the research team has moved to protect their findings through three new patents covering the use of Klotho for treating muscle, bone, and cognitive deficits and increasing lifespan. The researchers hope to refine the delivery methods for s-KL, potentially enabling safe and effective human applications. “If we can develop a viable delivery system, s-KL could significantly enhance quality of life as people age, helping to build a healthier society overall,” they conclude, underscoring the transformative potential of their work.
More information: Joan Roig-Soriano et al, Long-term effects of s-KL treatment in wild-type mice: Enhancing longevity, physical well-being, and neurological resilience, Molecular Therapy. DOI: 10.1016/j.ymthe.2025.02.030
Journal information: Molecular Therapy Provided by Universitat Autonoma de Barcelona
