Why This Matters to Us
As longevity enthusiasts, discovering therapies that extend lifespan and improve health is core to our goals. Klotho, a protein known for its anti-ageing properties, appears to influence multiple body systems, from muscle regeneration to cognition. This study showcases a novel gene therapy that can extend life and improve health in male mice while revealing challenges for female mice. It also opens the door to further exploration of how age-related therapies can be personalised to genetic makeup and sex. These results offer hope for therapies that could one day slow ageing in humans.
The Detail
Understanding Klotho
Klotho is a protein that plays a role in regulating ageing and metabolism. It exists in various forms:
- Membrane-bound Klotho (m-KL) – This full form is attached to cell membranes and regulates functions like mineral metabolism. However, artificially increasing m-KL can interfere with certain proteins, causing potential harm.
- Processed Klotho (p-KL) – A cleaved version of m-KL, which includes smaller protein fragments.
- Secreted Klotho (s-KL) – A form released into the bloodstream that has shown promise in promoting longevity without the risks associated with m-KL.
In this study, researchers used a gene therapy to boost s-KL with the help of an adeno-associated virus (AAV), a delivery system for gene editing. By increasing s-KL levels in mice, researchers aimed to explore its potential for extending lifespan and improving health. You can find the full study here.
Lifespan Results
A total of 96 Black 6 mice were involved in the study. These groups were divided as follows:
- Mice treated with s-KL AAV at 6 months of age.
- Mice treated with s-KL AAV at 12 months.
- A control group that received an inactive AAV at 6 months.
The outcomes highlighted stark differences between males and females:
- Male Mice: s-KL treatment significantly increased lifespan, particularly when given at 12 months. These mice also avoided any negative health effects, despite showing substantially higher levels of s-KL.
- Female Mice: While lifespan extension was minimal, serious health complications were observed. Female mice developed issues such as skin ulcers and bleeding, which raised concerns about the therapy’s safety for females.
These results suggest that male mice benefit more from increased s-KL levels than females, but the reasons behind this remain unclear.
Muscle Performance and Regeneration
The therapy also boosted physical performance:
- Mice treated with s-KL at 12 months outperformed their peers in grip strength tests. However, female mice showed this improvement only during initial trials, while males performed strongly across all attempts.
- Another test measured balance and coordination (the rotarod test). At 24 months, female mice scored higher than their male counterparts, even though males benefitted more in lifespan outcomes.
To evaluate muscle regeneration, old muscle tissue was transplanted into younger mice. The results revealed:
- Larger muscle fibres in animals treated with s-KL.
- A broader range of muscle fibre sizes in mice treated at 6 months compared to those treated at 12.
- Increased markers of stem cell activity geared towards muscle repair.
Bone and Cognitive Improvements
Bone quality also improved slightly:
- Female mice treated at 6 months showed significant improvements in bone structure, while males recorded non-significant changes.
Interestingly, the benefits extended beyond physical health:
- Treated mice exhibited thicker brain cell layers and more functional neurons.
- Analyses of gene expression revealed fewer age-related changes in the treated mice.
These findings suggest that s-KL positively influences brain ageing and cognitive function, although behavioural testing wasn’t included in this study.
Why Were There Sex Differences?
The study raised an intriguing observation: the therapy increased levels of a protein called fibroblast growth factor 23 (FGF23) in male mice but decreased it in females. Age-related rises in FGF23 are linked to osteoporosis, meaning its reduction might have protective effects for females. However, this difference likely plays a role in the varying outcomes seen between sexes.
Final Thoughts
This research marks the first time a secreted Klotho AAV gene therapy has demonstrated lifespan extension in wild-type mice (mice without genetic modifications). While the results are promising, particularly for male mice, they also highlight the importance of exploring the therapy's safety and efficacy across different genetic backgrounds and sexes.
The study underlines the potential of Klotho-based treatments as tools to combat ageing but underscores the necessity of future research to refine and personalise these therapies for humans.