Key Takeaways:
- IL-11, a pro-inflammatory cytokine, negatively impacts healthspan and lifespan by modulating critical ageing pathways such as ERK, AMPK, and mTORC1.
- Deletion or inhibition of IL-11 in mice improves metabolic function, reduces biomarkers of ageing, and significantly extends lifespan.
- Anti-IL-11 therapies, currently in early-stage clinical trials, hold promise for mitigating ageing-related diseases and enhancing longevity in humans.
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In the intricate landscape of ageing research, cytokines have emerged as pivotal regulators of longevity and health. Among them, Interleukin-11 (IL-11) stands out for its profound, albeit less recognised, impact on healthspan and lifespan. While IL-11 is part of the well-studied IL-6 family, its unique role in modulating inflammation and ageing makes it a critical target for new therapeutic interventions.
IL-11 and the Ageing Pathways: ERK, AMPK, and mTORC1
IL-11 has been identified as a significant influencer of key signalling pathways that govern ageing: ERK, AMPK, and mTORC1. These pathways are crucial in maintaining cellular homeostasis, metabolic regulation, and the overall ageing process.
As organisms age, IL-11 levels increase across various cell types and tissues. This upregulation leads to a modulation of the ERK–AMPK–mTORC1 axis, contributing to cellular and tissue ageing. The ERK pathway is involved in cell proliferation and survival, AMPK regulates energy balance, and mTORC1 is a central controller of cell growth and metabolism. Dysregulation in these pathways is a hallmark of ageing and age-associated diseases (R).
The Protective Effects of IL-11 Deletion
Groundbreaking research has demonstrated that deleting IL-11 or its receptor (Il11ra1) in mice provides substantial protective benefits against age-related decline. In these genetically modified mice, there was a marked reduction in metabolic deterioration, multimorbidity, and frailty, common characteristics of ageing. These findings underscore IL-11’s role in exacerbating ageing processes and highlight the potential benefits of targeting this cytokine (R, R).
Therapeutic Potential of Anti-IL-11 Treatments
Further supporting these findings, administering anti-IL-11 antibodies to aged mice yielded remarkable improvements. Mice treated with anti-IL-11 from 75 weeks of age for 25 weeks exhibited better metabolic function, enhanced muscle performance, and reduced biomarkers of ageing. Both male and female mice showed reduced frailty, suggesting that anti-IL-11 therapy can robustly enhance healthspan across sexes (R).
Extending Lifespan Through IL-11 Inhibition
One of the most striking outcomes of IL-11 inhibition is its impact on lifespan. Genetic deletion of Il11 extended the lifespan of both male and female mice by an average of 24.9%. Treatment with anti-IL-11 from 75 weeks of age until death extended the median lifespan by 22.5% in male mice and 25% in female mice. These results are compelling, demonstrating that IL-11 not only affects healthspan but also has a significant influence on overall lifespan (R).
Bridging Research to Human Application
Currently, anti-IL-11 therapies are in early-stage clinical trials for fibrotic lung disease. These therapies offer a promising translational opportunity to explore their effects on ageing in humans. By targeting IL-11, it may be possible to mitigate multiple ageing-related pathologies, improve quality of life, and extend healthy years (R).
Conclusion
IL-11’s role in modulating ageing through critical pathways like ERK, AMPK, and mTORC1 positions it as a crucial target for extending healthspan and lifespan. The promising results from mouse models pave the way for further research and potential therapeutic applications in humans. As we continue to unravel the complexities of ageing, targeting IL-11 offers a hopeful avenue for enhancing longevity and combating age-associated diseases.
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