Blocking One Protein Extends Mouse Lifespany by 25%

Blocking a single master protein has caused laboratory mice to live over 20% longer healthier lives. Recent research has revealed exciting findings regarding interleukin-11 (IL-11) and its potential impact on aging and health. This breakthrough study, conducted by scientists at the Medical Research Council Laboratory of Medical Science, Imperial College London, and Duke-NUS Medical School, has uncovered a promising avenue for extending healthspan and potentially lifespan in mammals.

The Role of IL-11 in Aging

Interleukin-11 (IL-11) is a pro-inflammatory cytokine belonging to the IL-6 family of cytokines. As organisms age, their cells accumulate damage, triggering the immune system to produce inflammatory molecules like IL-11[3]. While inflammation is a protective response, excessive amounts can damage cells and accelerate the aging process.

The researchers hypothesized that IL-11 could be involved in pathologies related to aging and lifespan reduction, based on its role in activating signaling molecules such as extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTORC1)[2].

Groundbreaking Findings

The study’s results were remarkable:

Increased Lifespan: Inhibiting IL-11 in mice extended their healthy lifespan by nearly 25%. Mice genetically modified to lack the IL-11 gene lived significantly longer, with treated mice showing a median lifespan increase from 120 weeks to an average of 155 weeks[1][3][4].

Health Improvements: Mice receiving anti-IL-11 antibody treatment exhibited:
– Fewer signs of aging and frailty
– Reduced muscle wasting
– Improved muscle strength
– Decreased cancer incidence
– Lower cholesterol levels
– Improved metabolism[1][2][4]

Cancer Reduction: The treatment significantly reduced deaths from cancer in the animals. Less than 16% of treated rodents developed tumors, compared to over 60% in the control group[3].

Metabolic Benefits: Inhibition of IL-11 improved deterministic features of aging common among vertebrates, such as frailty and metabolic decline[1].

Experimental Approach

The researchers employed various strategies to investigate IL-11’s role in aging:

1. Genetic Modification: They created mice with deleted IL-11 receptor subunit alpha 1 (Il11ra1) or IL-11 gene[2].

2. Antibody Treatment: 75-week-old mice (equivalent to about 55 years in humans) were treated with anti-IL-11 antibodies[1][3].

3. Comprehensive Analysis: The team conducted glucose and insulin tolerance tests, echo magnetic resonance imaging, grip strength assessments, and various assays to measure biomarkers and metabolic parameters[2].

Potential Mechanisms

The study suggests that IL-11 inhibition may extend lifespan and improve health through several mechanisms:

1. Reduced Inflammation: By blocking IL-11, chronic sterile inflammation associated with aging is mitigated[1].

2. Improved Metabolism: IL-11 inhibition appears to enhance metabolic function across various tissues[1][2].

3. Cancer Prevention: The significant reduction in age-related cancers suggests IL-11 plays a role in tumorigenesis and tumor immune evasion[1].

4. Cellular Rejuvenation: The treatment may promote cellular repair and regeneration, counteracting age-related damage[4].

Known IL-11 Blockers

While the study primarily focused on genetic deletion and antibody treatment, there are other potential IL-11 blockers:

1. Anti-IL-11 Antibodies: The primary method used in the study, these specifically target and neutralize IL-11[1][3]. Anti-IL-11 antibodies are designed to specifically target and neutralize IL-11, a cytokine involved in various pathological processes, including fibrosis and inflammation. By binding to IL-11, these antibodies prevent it from interacting with its receptor, thereby inhibiting downstream signaling pathways that could lead to disease progression. An example of an anti-IL-11 antibody is the humanized monoclonal antibody 9MW3811, which is noted for its potential anti-fibrotic and antineoplastic activities. This antibody is designed to specifically target IL-11, inhibiting its effects in various pathological conditions.[19] Boehringer Ingelheim has initiated clinical development of a first-in-class IL-11 inhibitor antibody aimed at treating fibrotic diseases.[20]

2. IL-11 Receptor Antagonists: IL-11 receptor antagonists are molecules that bind to the IL-11 receptor without activating it. This competitive binding prevents IL-11 from interacting with its receptor, effectively blocking the signaling cascade that would normally be triggered by IL-11. This approach can be beneficial in conditions where IL-11 signaling contributes to disease pathology. Neutralizing IL-11 receptor antibody (X209) binds to the IL-11 receptor without activating it, effectively blocking IL-11 signaling.[1]

3. Small Molecule Inhibitors: Small molecule inhibitors are compounds that can interfere with the signaling pathways activated by IL-11. These inhibitors can target various components of the signaling cascade, such as kinases or other downstream effectors, to prevent the cellular responses mediated by IL-11. The development of these inhibitors requires a detailed understanding of the IL-11 signaling pathway to identify suitable targets for intervention.[21]

Examples of small molecules that inhibit IL-6:

• LMT-28 is an oxazolidinone derivative identified as a small molecule that inhibits IL-6 signaling by targeting the gp130 receptor. This compound disrupts the association of the IL-6/IL-6Rα complex with gp130, which is crucial for IL-6 signal transduction. It has shown promising activity and binding affinity compared to other small molecule inhibitors in preclinical studies.
• Madindoline A, another small molecule, has been reported to inhibit IL-6 activity. Although it is derived from natural sources and has shown efficacy in vitro, its low yield and difficult synthesis pose challenges for broader application. It binds to the extracellular domain of gp130, similar to LMT-28
• SC144 is another small-molecule inhibitor targeting gp130. It has been noted for its potential in modulating IL-6 family cytokine signaling and may have implications for treating inflammatory diseases and cancers
• BMS-986016: This small molecule has been shown to inhibit the IL-6 signaling pathway by targeting gp130. It has been evaluated in clinical settings for its effectiveness in treating autoimmune diseases, which often involve IL-6 and potentially IL-11 signaling pathways.
• Tocilizumab: While primarily a monoclonal antibody against IL-6R, Tocilizumab influences the IL-6 signaling pathway and may have downstream effects on IL-11 signaling due to the shared receptor complex involving gp130
• Siltuximab: Similar to Tocilizumab, Siltuximab targets IL-6 directly but may also affect IL-11 signaling indirectly through its impact on the gp130 receptor complex

IL-6 and IL-11 Compared

Interleukin-11 (IL-11) is a cytokine that plays a significant role in various physiological and pathological processes, including inflammation, hematopoiesis, and tissue repair. It belongs to the IL-6 cytokine family, which is characterized by its ability to influence immune responses and cell growth. Both IL-6 and IL-11 signal through a common receptor component, the glycoprotein 130 (gp130), which forms a homodimer to initiate signaling. They utilize specific alpha receptors (IL-6Rα for IL-6 and IL-11Rα for IL-11) that do not directly transduce signals but facilitate the formation of the signaling complex with gp130. This leads to the activation of similar downstream signaling pathways, primarily the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway and the mitogen-activated protein kinase (MAPK) cascade.

IL-11 is structurally longer than IL-6, with differences in the binding sites on their respective receptors. The binding site of IL-11 is more hydrophobic compared to that of IL-6, which affects how these cytokines interact with their receptors and assemble the signaling complex.[22][23]

Natural Options

While direct IL-11 blockers are not available as natural supplements, some natural compounds are known for their anti-inflammatory and or anti-aging effects and may help modulate inflammation and potentially influence IL-11 levels:

1. Omega-3 Fatty Acids

• Primary sources: Fatty fish (salmon, mackerel, sardines), fish oil supplements, flaxseeds, chia seeds, walnuts, and fortified foods like eggs and dairy products.
• Mechanism: Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce the production of inflammatory mediators such as prostaglandins and leukotrienes by competing with arachidonic acid. They also increase the production of anti-inflammatory molecules like resolvins and protectins, inhibit transendothelial migration of neutrophils, and decrease the expression of adhesion molecules on leukocytes and endothelial cells.

2. Curcumin

• Source: Turmeric root
• Mechanism: Inhibits multiple inflammatory pathways, including nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (COX-2). It also modulates cytokine production and reduces the expression of pro-inflammatory enzymes and mediators.
• Potential IL-11 impact: Some studies suggest curcumin may modulate IL-11 expression, though more research is needed

3. Resveratrol

• Sources: Red grapes, blueberries, cranberries, peanuts
• Mechanism: Resveratrol activates sirtuin 1 (SIRT1), which has anti-inflammatory effects by deacetylating and inhibiting the activity of NF-κB, thereby reducing the expression of pro-inflammatory genes.

4. Green Tea Extract

• Primary compound: Epigallocatechin gallate (EGCG)
• Mechanism: Contains polyphenols with anti-inflammatory and antioxidant properties. Inhibits pro-inflammatory cytokine production and modulates inflammatory signaling pathways. Epigallocatechin gallate (EGCG) contains polyphenols with anti-inflammatory and antioxidant properties. It inhibits the production of pro-inflammatory cytokines and modulates inflammatory signaling pathways, including NF-κB and mitogen-activated protein kinase (MAPK) pathways.

5. Quercetin

• Sources: Onions, apples, berries, citrus fruits
• Mechanism: Inhibits inflammatory enzymes such as lipoxygenase and cyclooxygenase, reduces oxidative stress by scavenging free radicals, and modulates the expression of inflammatory cytokines.

6. Ginger

• Active compounds: Gingerols and shogaols
• Mechanism: Compounds inhibit the production of inflammatory mediators such as prostaglandins and leukotrienes and modulate NF-κB signaling, reducing the expression of pro-inflammatory cytokines and enzymes.

7. Boswellia

• Source: Boswellia serrata tree resin
• Mechanism: Inhibits 5-lipoxygenase, reducing leukotriene production, which are inflammatory mediators. This inhibition reduces leukotriene production and inflammation.

8. Alpha-lipoic acid

• Sources: Spinach, broccoli, yeast; also produced in small amounts by the body
• Mechanism: A potent antioxidant that reduces oxidative stress and inflammation by regenerating other antioxidants and inhibiting the activation of NF-κB.

9. Lutein

• Sources: Green leafy vegetables (spinach, kale), egg yolks, corn, avocados
• Mechanism:Lutein, a carotenoid, has antioxidant properties and may inhibit IL-11 expression. It also impacts IL-6, another pro-inflammatory cytokine, thereby reducing inflammation.

10. Osthole

• Sources: Some medicinal plants, including Cnidium monnieri and Angelica pubescens
• Mechanism: This natural coumarin compound may inhibit IL-11 expression and also impacts IL-6, reducing inflammation through modulation of these cytokines.

While these natural options have shown positive effects, they have not been specifically studied for their effects on IL-11 and should not be considered equivalent to the targeted therapies used in the research.

Future Implications

While these findings are currently limited to mice, they raise exciting possibilities for human health. Anti-IL-11 treatments are already undergoing clinical trials for other conditions, potentially paving the way for future studies on their effects on aging in humans[2][5].

The research underscores the connection between chronic inflammation, aging, and various age-related diseases. By targeting IL-11, there is potential not only for extending lifespan but also for enhancing the quality of life in older individuals[3][4].

As we continue to unravel the complexities of aging, IL-11 inhibition presents a promising avenue for developing therapies aimed at improving healthspan and potentially extending lifespan in humans. However, further research is needed to fully understand the long-term effects and potential applications of this approach in human aging.

Avoiding Causes

What this research has found is that by forcing the bodies of these little mammals to not react to stimuli that cause inflammtaion, they live longer. Would this same finding hold for wild mice exposed to a variety of pathogens, or would the reverse be true? In wild mice, the balance between inflammation (which can lead to tissue damage and chronic diseases) and immune defense is crucial. Therefore, while blocking IL-11 may extend lifespan in a controlled environment, the same strategy might not be effective or safe for wild mice that need to respond to a variety of environmental stressors.

Inflammation is a complex biological response that can be triggered by various factors, and while targeting specific cytokines like IL-11 may be beneficial, addressing the root causes of inflammation can lead to more effective treatments. Chronic infections, autoimmune disorders, and metabolic factors such as obesity and diabetes play significant roles in perpetuating inflammatory responses. Persistent infections from pathogens, for instance, can lead to ongoing inflammation, while conditions like rheumatoid arthritis involve the immune system attacking healthy tissues.

Environmental factors and lifestyle choices also contribute to inflammation. Exposure to some electromagnetic radiation, pollutants and harmful chemicals can provoke inflammatory responses, while a diet high in processed foods and sugars can exacerbate the issue. Conversely, adopting an anti-inflammatory diet rich in fruits, vegetables, and omega-3 fatty acids can help mitigate inflammation. Additionally, regular physical activity and effective stress management are crucial for maintaining a balanced inflammatory response.

Gut health is another critical aspect, as dysbiosis and food sensitivities can lead to increased intestinal permeability and systemic inflammation. By focusing on these root causes—such as improving gut microbiota, managing stress, and promoting healthy lifestyle choices—we can develop comprehensive strategies that not only target inflammation more effectively but also enhance overall health and well-being.

Keeping Perspective

While exiting information in many regards, these longer lived lab mice do not change the basic equation for human health and lifespan, not yet. We still need to each take responsibility to avoid causes of inflammation in our lives. One of the hardest things to do, but something that is humany possible, is to break the stranglehold of the trillion dollar telecommunications industry in silencing research on EMF-caused inflammation. This effort must include freeing industry captured agencies like the FCC and FDA, and allowing the research to tell the story, for example, to admit that decades of research makes clear that certain types of electromagnetic radiation provokes inflammatory responses in the body. This is true, but it is forbidden, non-funded science.

We are awash in inflammation causes, and the situation is getting worse. Research indicates that certain types of electromagnetic radiation (EMR) can provoke inflammatory responses in the body, particularly through their effects on the immune system.

Effects of Electromagnetic Fields on Inflammation

1. Immune System Disturbance: Electromagnetic fields have been shown to disturb immune function by stimulating various allergic and inflammatory responses. This disturbance can lead to increased risks for diseases, including cancer, as electromagnetic fields (EMFs) affect tissue repair processes and other biological functions at exposure levels below current safety limits[24][26].

2. Extremely Low-Frequency Electromagnetic Fields (ELF-EMF): Studies specifically focusing on ELF-EMF exposure have demonstrated that it enhances inflammatory responses in macrophage cell lines. For instance, exposure to 60 Hz ELF-EMF resulted in increased production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. This indicates that ELF-EMF can amplify inflammatory responses by activating macrophages and altering the effectiveness of antioxidants[25].

3. Mechanisms of Action: The mechanisms through which EMR influences inflammation include the activation of signaling pathways such as NF-κB and the influx of calcium ions, which are critical in mediating inflammatory responses. The translocation of NF-κB to the nucleus under ELF-EMF exposure conditions further supports the idea that EMR can modulate inflammatory processes at the cellular level[25][27].

Conclusion

Citations
^{[1] https://www.nature.com/articles/s41586-024-07701-9
[2] https://www.news-medical.net/news/20240718/Breakthrough-in-aging-research-Blocking-IL-11-extends-lifespan-and-improves-health-in-mice.aspx
[3] https://www.newscientist.com/article/2439800-anti-inflammatory-drug-extended-the-lifespan-of-mice-by-20-per-cent/
[4] https://www.sciencedaily.com/releases/2024/07/240717120907.htm
[5] https://www.imperial.ac.uk/news/254933/turning-inflammatory-protein-extends-healthy-lifespan/
[6] https://lms.mrc.ac.uk/scientists-find-master-switch-which-could-hold-the-key-to-longer-healthier-lives/
[7] https://www.bioworld.com/articles/710754-stop-interleukin-11-to-age-better-and-live-longer?v=preview
[8] https://www.nature.com/articles/d41586-024-02298-5
[9] https://www.ncbi.nlm.nih.gov/books/NBK564314/
[10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174995/
[11] https://go.drugbank.com/drugs/DB11133
[12] https://www.sciencedirect.com/topics/nursing-and-health-professions/omega-3-fatty-acid
[18] https://my.clevelandclinic.org/health/articles/17290-omega-3-fatty-acids
[19] https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-il-11-monoclonal-antibody-9mw3811
[20] https://www.boehringer-ingelheim.com/science-innovation/human-health-innovation/il-11-inhibitor-antibody-clinical-development-launched
[21] https://journals.aai.org/jimmunol/article/195/1/237/104516/A-Novel-Small-Molecule-Inhibitor-Targeting-the-IL
[22] https://www.nature.com/articles/s41467-024-46235-6
[23] https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01424/full
[24] https://pubmed.ncbi.nlm.nih.gov/19398310/
[25] https://pubmed.ncbi.nlm.nih.gov/28370033/
[26] https://www.sciencedirect.com/science/article/abs/pii/S0928468009000352
[27] https://ieeexplore.ieee.org/document/10229142
[28] https://mmrjournal.biomedcentral.com/articles/10.1186/s40779-018-0156-7}