A team at the University of Barcelona employs adeno-associated virus serotype 9 to deliver the Klotho gene in adult mice. The single-dose treatment elevates s-KL protein levels systemically and in the brain, yielding nearly 20% longer lifespans alongside preserved muscle function, bone volume and cognitive resilience. Their findings illustrate a multi-organ anti-aging approach targeting fundamental longevity processes rather than individual diseases.
Key points
AAV9-mediated delivery of s-KL via intravenous and intracerebroventricular injections in mice
19.7% lifespan extension with preserved muscle, bone and cognitive functions
Enhanced muscle regeneration, improved trabecular bone architecture and increased hippocampal neurogenesis
Why it matters:
Targeting Klotho offers a unified, multi-tissue anti-aging approach that could transform longevity medicine beyond single-disease treatments.
Q&A
What is Klotho protein?
How does AAV9 delivery work in gene therapy?
Why use both intravenous and intracerebral injections?
What are potential risks of Klotho gene therapy?
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Academy
Klotho Protein in Aging
Klotho is a protein that exists in both membrane-bound and soluble forms. It was first discovered in mice and named after the Greek Fate who spins the thread of life. In mammals, Klotho plays a crucial role in regulating cellular pathways that underlie aging-related processes. The soluble form, often referred to as s-Klotho, circulates in blood and interstitial fluids, where it acts as a hormone to influence distant tissues.
Klotho modulates several molecular pathways:
- Insulin/IGF-1 Signaling: Klotho downregulates this pathway, which is associated with extended lifespan in multiple species.
- Oxidative Stress Response: It enhances antioxidant defenses, reducing damage from reactive oxygen species (ROS).
- Calcium and Phosphate Homeostasis: Klotho works with FGF23 to maintain proper mineral balance, protecting bone health.
Because it influences fundamental aging hallmarks such as stem cell function, metabolic regulation and inflammation control, Klotho is a target for longevity research.
Gene Therapy Vectors for Longevity Research
Adeno-associated viruses (AAV) are among the most widely used vectors for delivering therapeutic genes. They are preferred because they elicit minimal immune response and can infect both dividing and non-dividing cells. The AAV genome is small, which limits the size of the gene payload but ensures efficient packaging.
- Vector Design: Scientists engineer AAV particles by replacing viral genes with a therapeutic cassette containing the gene of interest, regulatory elements like promoters and any necessary enhancers.
- Serotype Selection: There are multiple AAV serotypes, each with different tissue tropism. AAV9 is often chosen for its ability to cross the blood-brain barrier and target muscle, heart and neural tissues.
- Delivery Methods: Intravenous injection distributes the vector through the bloodstream, reaching peripheral organs. Intracerebroventricular injection administers the vector directly into the cerebrospinal fluid, ensuring central nervous system transduction.
By leveraging AAV9 to deliver the Klotho gene, researchers can achieve long-lasting expression of the protein in multiple tissues, making it a powerful tool for studying and potentially intervening in aging processes.
Key Considerations for Long-Life Gene Therapy:
- Ensuring stable expression without integration into the host genome.
- Minimizing immune reactions to the viral vector.
- Balancing systemic and central nervous system delivery to address multi-organ aging.
This foundational knowledge helps longevity enthusiasts understand how gene therapy is shaping the future of aging research and why proteins like Klotho are at the forefront of anti-aging strategies.