IL-11 and Extending Healthspan and Lifespan

New study out showing 25% increased lifespan in mice when targeting IL-11

There’s a new study out in Nature that shows an impressive increase in lifespan in a mouse study. More importantly, it points to targeting a known inflammatory pathway, IL-11, that makes a lot of sense as a driver of aging. This specific inflammatory cytokine is involved in several of the known pathways causing aging — inflammation, cellular senescence, mTOR, and fibrosis.

Here’s the study if you want to read it in full: “Inhibition of IL-11 signalling extends mammalian healthspan and lifespan” Widjaja, A. et al. I’ll hit the highlights here and then go into some of the prior research on IL-11 (interleukin 11) and natural inhibitors.

IL-11 upregulated in aging and associated with senescence:
The researchers found that IL-11, which is a proinflammatory cytokine in the IL-6 family, is upregulated in aging across cell types. IL-11 plays a role in regulating known aging pathways — mTORC1-AMPK-ERK - and cellular senescence. In human cell lines, the researchers found that IL-11 stimulated fibrosis and cellular senescence.

Metabolism:
The researchers found that deleting either the IL11 gene or IL11 receptor (IL11RA1) protected against metabolic problems in old age. The mice with IL11 knocked out had decreased fat mass and increased lean mass in old age. They also had higher core body temperatures.

Importantly, the researcher found that liver function was improved along with glucose metabolism. Rapamycin has drawbacks as an mTOR inhibitor for long-term use, so the researchers wanted to make sure that inhibiting or knocking out IL11 didn’t also cause problems.

Telomeres:
Telomeres are the ends of the DNA that are reduced in aging, eventually leading to cellular senescence. One interesting effect of knocking out the IL11 gene in mice is that it attenuated the age-related decrease in telomere length.

Blocking IL-11 later in life:
In addition to looking at the effects of knocking out the IL11 gene (something that we can’t do in humans), the researchers used a drug that could block IL11, starting in late middle age. The results were decreased metabolic dysfunction, decreased muscle loss, and decreased inflammation. The drug used was an IL11 neutralizing antibody.

Reversal of fibrosis:
IL-11 is linked to causing fibrosis in tissue, which is a huge problem in aging. I’ll go into more detail on this below, but I was impressed that the mice given the IL11 neutralizing antibody later in life showed a reversal of fibrosis.

Lifespan extension:
The researchers also carried out a parallel study to the healthspan study to see if lifespan was also extended in mice given the IL11 antibody in late middle age. The lifespan extension was 22.5% in males and 25% in females. Importantly, there were fewer tumors in mice with the IL11 gene knocked out (lab mice are prone to cancer).

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Background science on IL-11 (interleukin 11):

That Nature study seems to have covered a lot of bases, but I still want to know more about IL-11 and what human studies show…

What are Interleukins?
Interleukins are a family of cytokines that have diverse functions in inflammation, cell-to-cell communication, and immune cell differentiation.

IL-11 (interleukin 11) is part of the IL-6 family of inflammatory cytokines. IL-6 is a key inflammatory mediator that is produced in response to infections and injury and it helps with the immediate response to a wound or to a virus or bacterial infection. It promotes B cell differentiation (white blood cells that produce antibodies) and promotes Th17 cells, which are involved in autoimmune response.

IL-11 is less well-studied than IL-6. It is involved in promoting fibrosis, which is a problem in the lungs, blood vessels, and heart in aging. A 2017 study identified IL-11 and the IL-11 receptor (IL11RA) as key in heart and kidney fibrosis and organ failure. IL-11 has also been identified as a key promoter of lung fibrosis.[ref][ref]

Fibrosis is promoted by TGF-beta, which stimulates fibroblasts to proliferate and essentially form something like scar tissue that is stiff and doesn’t function well. IL-11 is upregulated by TGF-beta and is one of the key signals to fibroblasts for fibrosis. IL-11 also interacts with and upregulates IL-33, which is also involved in the initiation of fibrosis.[ref]

Fibroblasts are important for tissue repair, and they can secrete collagen to promote scar formation and fibrosis. Restriction of oxygen and glucose (such as in ischemic disease) increases IL-11 secretion and fibrosis. [ref] Fibrosis in the heart and in the lungs is a real problem in aging. Fibrosis in the heart reduces function, and in the lungs can reduce oxygen exchange — and it seems that this would then exacerbate the issue with more IL-11 and more fibrosis.

Pros and Cons:
Keep in mind though that while excess fibrosis in the heart and lungs is a negative, wound repair still needs to occur. There is a lot of contradiction in research studies on the positives vs. the negatives of IL-11, with older studies from a decade ago categorizing IL-11 as anti-inflammatory and some studies explaining it as both anti-inflammatory and pro-inflammatory. Whether blocking IL-11 is a positive or negative may depend on what else is going on in the body.

For example, many studies show that IL-11 promotes tumorigenesis (tumor growth) in cancer.[ref][ref] And IL-11 plays a proinflammatory role in kidney disease.[ref] However, in animal models of multiple sclerosis, knocking out the IL-11 receptor worsened neuronal loss and demyelination. Adding extra IL-11 resulted in a milder condition.[ref] It also helps some cancer patients with producing more platelets in clinical trials for thrombocytopenia.[ref][ref] Thus, IL-11 may play a protective role in autoimmune diseases (at least in mice) and thrombocytopenia.

Natural compounds that interact with IL-11:

A cell study showed that resveratrol reduces IL-1B but increases IL-11 production.[ref]

Lutein is a carotenoid found in bell peppers, kale, corn, spinach, pumpkin, pistachios, and pastured eggs. A study in animals showed that lutein significantly reduced fibrosis and reduced IL-11 expression in heart muscle cells.[ref] Another study also showed that lutein significantly reduced cardiac fibrosis.[ref]

Lutein supplement options on Amazon
*affiliate link, I’ll get a small percentage of any purchase, which I’ll then use to buy supplements… feedback loop?

Curcumin as nanocurcumin has also been down to downregulate IL-11 during acute inflammation. Curcumin also tamps down the overactivation of TGF-beta.[ref]

Nanocurcumin on Amazon

Omega-3s (DHA/EPA) have been shown in a mouse study to inhibit IL-11 in a study on liver damage.[ref] I think the key to supplementing with DHA and EPA is to find a high-quality supplement that hasn’t been exposed to extreme conditions in storage or shipping —which is why I don’t order fish oil from Amazon or other online stores. Algal oil or krill oil may be better options.

What is in the works for IL11 drugs?

There is an interesting 2022 study showing an inhalable siRNA nanoparticle targeting IL-11. The nanoparticle was able to penetrate the mucous in the lungs, and blocking IL-11 in the lungs reversed pulmonary fibrosis (in mice).[ref]

Neutralizing antibodies, such as in the longevity study, seem to be used only in animal research (as far as I can find).[ref] siRNA is also being used in multiple ways in animal studies to target IL-11.

Most of the clinical trials for IL-11, though, are a couple of decades old and investigated recombinant IL-11 (increasing IL-11) to increase platelet production in chemo patients or von Willebrand disease.

Concluding thoughts:

The longevity and healthspan study in mice is exciting, with a clear mechanism and significant health effects. Will it carry over to humans? I don’t know, but targeting IL-11 to reduce fibrosis seems like it will benefit a lot of older people with lung or heart problems.