Summary: Raising levels of the Klotho protein, specifically its secreted form (s-KL), slows multiple aspects of aging and improves overall health in mice. In controlled experiments, animals engineered to produce more s-KL showed stronger muscles, denser bone structure, better cognitive markers, and lived approximately 15–20% longer than untreated controls.
Researchers observed that s-KL treatment promoted the generation of new neurons, reduced muscle fibrosis, and protected bone microstructure—effects that were especially notable in female mice. While clinical applications for humans remain under development, these results identify s-KL as a promising target for future therapies aimed at extending healthy lifespan and reducing age-related frailty.
Key Findings
- Extended Lifespan: Mice receiving s-KL treatment lived about 15–20% longer than controls.
- Improved Physical Health: Treated animals showed better muscle strength, larger muscle fibers, reduced fibrosis, and improved bone microarchitecture.
- Brain Benefits: s-KL increased markers of adult neurogenesis and immune activity in the hippocampus, suggesting enhanced neurological resilience.
- Therapeutic Potential: The study supports further development of Klotho-based therapies for aging-related muscle, bone, and cognitive decline.
Source: UAB
Background: As people age, common declines include loss of muscle mass (sarcopenia), decreased bone density (osteoporosis), and progressive cognitive deterioration. These changes raise the risk of falls, disability, and neurodegenerative disease, creating high personal and societal costs. Finding interventions that preserve function across multiple tissues is a major goal in aging research.
In a study published in Molecular Therapy, an international team led by Professor Miguel Chillón (ICREA researcher at the INc-UAB) tested whether elevating the secreted isoform of Klotho (s-KL) can slow normal, non-pathological aging. The investigators used gene delivery to raise circulating s-KL levels in young, healthy mice and followed the animals long-term.
The research employed adeno-associated virus serotype 9 (AAV9) vectors encoding s-KL delivered intravenously and directly into the brain to ensure broad tissue expression, including central nervous system cells. This approach increased serum s-KL concentrations and produced measurable health benefits later in life.
By two years of age—about 70 human-equivalent years—treated mice displayed improved physical performance and tissue preservation. Muscle tissue analysis revealed larger fiber size and reduced fibrotic scarring, consistent with greater regenerative capacity. Bone assessments showed better-preserved trabecular architecture, particularly in female mice, indicating a potential protective effect against age-related bone loss.
In the hippocampus, s-KL treatment was associated with increased markers of adult neurogenesis and heightened immune activity. Transcriptomic analyses of aged hippocampal tissue pointed to upregulated phagocytosis and immune cell function, which may contribute to improved tissue maintenance and cognitive resilience.
Overall, s-KL-treated mice not only lived longer but also maintained higher levels of physical fitness and neurological markers associated with health span. These pleiotropic effects are consistent with Klotho’s known regulation of pathways such as insulin/IGF-1 and Wnt signaling, along with reductions in inflammation and oxidative stress.
The team notes two potential translational routes: using viral vectors to deliver the s-KL gene or developing s-KL protein formulations that can be administered as drugs. Advances in vector design that allow systemic administration to reach the brain could simplify clinical translation; alternatively, optimized protein delivery methods would avoid gene therapy altogether. Both approaches require further development to ensure safety, efficient organ targeting, and sustained therapeutic benefit.
The research group has existing intellectual property covering Klotho-based interventions for cognitive deficits and has filed additional patents to protect applications targeting bone and muscle degeneration and therapies aimed at promoting longevity.
About this genetics and aging research news
Author: Maria Jesus Delgado
Source: UAB
Contact: Maria Jesus Delgado – UAB
Image credit: Neuroscience News
Original Research (open access): Long-term effects of s-KL treatment in wild-type mice: Enhancing longevity, physical well-being, and neurological resilience — Miguel Chillón et al., Molecular Therapy. DOI: 10.1016/j.ymthe.2025.02.030
Abstract
Long-term effects of s-KL treatment in wild-type mice: Enhancing longevity, physical well-being, and neurological resilience
Aging increases risk for sarcopenia, osteoporosis, and cognitive decline, producing significant personal and social burdens. The Klotho protein has emerged as a multi-functional anti-aging factor through its modulation of insulin and IGF-1 pathways, Wnt signaling, and its capacity to reduce inflammation and oxidative stress. This study evaluated whether boosting the secreted form of Klotho (s-KL) slows non-pathological aging in wild-type mice.
Delivery of an AAV9 vector encoding s-KL raised serum s-KL concentrations and was associated with roughly a 15–20% extension in lifespan, along with improved physical fitness, reduced muscle fibrosis, enhanced muscle regeneration, and improved bone microstructural parameters linked to osteoporosis. In the aged hippocampus, s-KL treatment increased cellular markers of neurogenesis and immune response, with transcriptomic changes indicating enhanced phagocytosis and immune cell activity. These findings support the potential of elevating s-KL expression to simultaneously reduce age-related degeneration in multiple organs, thereby extending both life span and health span.