Interleukin-11 in the treatment of aging, 25% Lifespan Increase

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A drug that inhibits inflammation helped mice live longer and reduced the animals’ incidence of cancer and age-related health problems

Scientists at the Medical Research Council Laboratory of Medical Science and Imperial College London have discovered that ‘switching off’ a protein called IL-11 can significantly increase the healthy lifespan of mice by almost 25%.

The scientists, working with colleagues at Duke-NUS Medical School in Singapore, tested the effects of IL-11 by creating mice that had the gene producing IL-11 (interleukin 11) deleted. This extended the lives of the mice by over 20% on average.

They also treated 75-week-old mice – equivalent to the age of about 55 years in humans – with an injection of an anti-IL-11 antibody, a drug which stops the effects of the IL-11 in the body.

The results, published in Nature, were dramatic, with mice given the anti-IL-11 drug from 75 weeks of age until death having their median lifespan extended by 22.4% in males and 25% in females. The mice lived for an average of 155 weeks, compared with 120 weeks in untreated mice.

Previously, scientists have posited that IL-11 is an evolutionary hangover in humans, as while it is vital for limb regeneration in some animal species, it is thought to be largely redundant in humans.

However, after about the age of 55 in humans, more IL-11 is produced and past research has linked this to chronic inflammation, fibrosis in organs, disorders of metabolism, muscle wasting (sarcopaenia), frailty, and cardiac fibrosis. These conditions are many of the signs we associate with ageing.

While small doses of inflammation can protect us from disease or injury, excessive amounts damage cells, which is believed to accelerate ageing.

The drug used in this study not only increased lifespan but also reduced cholesterol levels, frailty and body weight in the treated animals, and it improved their muscle strength and metabolism. Together, these findings suggest that blocking IL-11 may minimize age-related health declines in mice as well as improving lifespan.

Few approaches have been shown to robustly increase life span in mice by more than 20%, and now IL-11 inhibition adds to that small selection of interventions. As reported, IL-11 inhibition may work through essentially the same pathways as mTOR inhibition. The degree of life extension is similar to that achieved via mTOR inhibitors such as rapamycin. (from “Fighting Aging”)

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Study - Inhibition of IL-11 Signaling Extends Mamillian Lifespan and Healthspan
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Interleukin-11 looks promising and of course both metformin and rapamycin, as longevity drugs, would be taken for the rest of your life, too.

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#3

It looks promising and certainly shows the role of IL-11 in aging, however, the drug is an antibody (anti-IL 11) and so not very practical and very $$ to take for the rest of one’s life. Perhaps a small molecule will be developed that can work via this mechanism.

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#4

“Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%.”

https://www.nature.com/articles/s41586-024-07701-9

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#6

What supplements inhibit interleukin 2?
I think frankincense does (Boswellia Serrata). There must be others

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#7

Just started my investigation of IL-6 but for others that don’t know much about it, here are some links, starting with basic info.
https://omega3innovations.com/blog/interleukin-6-the-inflammation-marker-you-need-to-know/

It’s important for the body to generate enough IL-6 for the right occasions. After exercise, for instance, the body typically produces more IL-6 to help maintain energy and repair any skeletal muscle damage. This is generally a positive thing (23).

The key thing to remember is that, while acute spikes in IL-6 is normal, having chronically high levels becomes problematic. Research shows that those who are less physically active have higher IL-6 levels than disciplined exercisers (16). In addition, researchers have also found that regular exercise, combined with eating a low calorie diet, significantly decreases IL-6 levels.

A sizable body of research has separately documented that melatonin supplementation can reduce IL-6 (likely because of melatonin’s anti-inflammatory effect) (10, 11, 12, 13). Indeed, some researchers found that IL-6 levels dropped with as much as 34% after high dose melatonin supplementation (14)

https://en.wikipedia.org/wiki/Interleukin_6

Like mTORC1 and it’s function as a nutrient/energy/redox sensor, IL-6 is related to inflamation but also has both positive and negative effects. So inhibitors
likely would need to be cycled.

Like in humans, there seems to be an increase in IL-6 expression in working muscle and plasma IL-6 concentration during exercise in rodents.[29][30] Studies in mice with IL-6 gene knockout indicate that lack of IL-6 in mice affect exercise function.[9]

It has been shown that the reduction of abdominal obesity by exercise in human adults can be reversed by the IL-6 receptor blocking antibody tocilizumab. Together with the findings that IL-6 prevents obesity, stimulates lipolysis and is released from skeletal muscle during exercise, the tocilizumab finding indicates that IL-6 is required for exercise to reduce visceral adipose tissue mass.[31] Bone may be another organ affected by exercise induced IL-6, given that muscle-derived interleukin 6 has been reported to increase exercise capacity by signaling in osteoblasts.[32]

IL-6 has extensive anti-inflammatory functions in its role as a myokine. IL-6 was the first myokine that was found to be secreted into the blood stream in response to muscle contractions.[33] Aerobic exercise provokes a systemic cytokine response, including, for example, IL-6.

Aging

IL-6 is commonly found in the senescence-associated secretory phenotype (SASP) factors secreted by senescent cells (a toxic cell-type that increases with aging).[88][89] Cancer (a disease that increases with age) invasiveness is promoted primarily though the actions of the SASP factors metalloproteinase, chemokine, IL-6, and interleukin 8 (IL-8).[90][88] IL-6 and IL-8 are the most conserved and robust features of SASP.

https://en.wikipedia.org/wiki/Tocilizumab

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome, COVID‑19, and systemic sclerosis-associated interstitial lung disease (SSc-ILD). It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.[

https://reliefweb.int/report/world/tocilizumab-second-drug-ever-recommended-who-covid-19-will-remain-unaffordable-and

As the World Health Organization (WHO) recommended tocilizumab today for people with severe COVID-19, Médecins Sans Frontières/Doctors Without Borders (MSF) called on the Swiss pharmaceutical corporation Roche, the world’s sole producer of the drug, to lower the price of the drug to make it affordable and accessible for everyone who needs it, everywhere. Roche must end its monopoly and urgently share the know-how, master cell lines and technology needed to produce this drug with other manufacturers across the world to ensure supply and improved access.

Tocilizumab is the second drug ever recommended by the WHO for COVID-19 treatment after recommending dexamethasone in September 2020. It belongs to the class of drugs called monoclonal antibodies (mAbs), that are used in the treatment of various diseases including cancers. However, most of the existing mAbs have been priced extremely high, and are hence virtually impossible to access in low- and middle-income countries.

[Translating IL-6 biology into effective treatments | Nature Reviews Rheumatology](https://www.nature.com/articles/
s41584-020-0419-z)

Translating IL-6 biology into effective treatments

Unravelling the therapeutic potential of IL-6 pathway inhibition for indications other than those discussed above is a matter of ongoing basic and clinical research spanning various therapeutic areas4,5. Several investigator-initiated studies are either planned or ongoing or have already been published as proof-of-concept studies. A detailed representation of all of these studies is beyond the scope of this article, but briefly, they encompass conditions such as uveitis, thyroid eye disease, neuromyelitis optica, graft-versus-host disease, erosive hand osteoarthritis, various oncological indications, depression, schizophrenia, Schnitzler syndrome, myocardial infarction, familial Mediterranean fever and COVID-19 pneumonia.

Several questions relating to IL-6 biology remain unanswered. For example, why does IL-6 over-production occur and why does IL-6 signal inhibition lead to clinically meaningful benefits for patients with some diseases associated with IL-6 over-production (such as RA), but not all (such as AS)? Answering these questions would help to further progress our understanding of how various autoimmune diseases are regulated in the context of IL-6 pathway biology and would help in developing additional, personalized treatment options for individual patients or patient subgroups. It seems that the journey of realizing the therapeutic potential of IL-6 pathway inhibition is far from over.

Edit: Interleukin 11 and Interleukin 6 are both in the IL-6 family and have many similarities. IL-6 is better studied.

Interleukin-6 and interleukin-11: same same but different

https://pubmed.ncbi.nlm.nih.gov/23740659/

“IL11 is often thought of as similar to IL6 and redundancy has been inferred. However, recent studies reveal that IL6R and IL11RA are expressed on dissimilar cell types and these cytokines actually have very different roles in biology and pathology.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644218/

“Amongst these is interleukin (IL)-6, the first and prototypical member of the IL-6 family of cytokines, nearly all of which utilize the common signaling receptor, gp130. In the last decade, there have been numerous advances in our understanding of the structural mechanisms of IL-6 family signaling, particularly for IL-6 itself. However, our understanding of the detailed structural mechanisms underlying signaling by most IL-6 family members remains limited. With the emergence of new roles for IL-6 family cytokines in disease and, in particular, roles of IL-11 in cardiovascular disease, lung disease, and cancer, there is an emerging need to develop therapeutics that can progress to clinical use.”
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01424/full

" In this review, we examine the roles IL6 and IL11 in the liver and discuss the therapeutic opportunities these cytokines may provide for liver disease. While the older literature proposed these two cytokines have overlapping and redundant roles in the liver, we discuss recent data that challenges long-held assumptions.

IL6 and IL11 – different children from the same family

Since the discovery and cloning of IL6 in 1986,12 more than 30 y of extensive research has been carried out on this key cytokine. Analysis of the published literature shows that IL6 is the 6th most studied gene of all time.13 The same cannot be said for IL11, which was first cloned not long after IL6 in 199014 (Figure 1). IL11 remains poorly studied and based on some recent data, it appears that some of the assumed IL11 functions may have been misinterpreted."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644218/

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#8

One way to reduce IL-11 is to reduce the senescent cell population. As a component of SASP it is also a recruiting cytokine.

Reducing SASP also reduces other IL cytokines like IL6 and IL8

Many reasons to reduce senescent cell burden as it is a significant Hallmark of the 12 Hallmarks

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#9

It looks like they took 25 mg/day Melatonin for 6 months to reduce IL-6 by 34%. This seems like a good deal. I’ve been taking that much before bed for a couple years, since my daughter got cancer and I read about the miracle of melatonin. Good Stuff!

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#10

IL-6 isn’t the same thing as IL-11.
The best way to measure IL-6 is by measuring CRP and a powerful way to lower CRP is to use statins.

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#12

Snarky Iowegian farmer. Hahaha.

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#13

Nature News piece (with generally good science but some unfortunate incorrect trash-talking rapamycin!)

Mice live longer when inflammation-boosting protein is blocked

Humans also have the protein, called IL-11, offering hope for a future longevity treatment

https://www.nature.com/articles/d41586-024-02298-5

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#14

The Company being founded from this research:

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#15

If I understand it right. Rapamycin has probably an indirect effect on IL-11. This is through Rapamycin’s anti-inflammatory effects and slows down senescent cells build up.

In the study they also used Rapamycin but they did not say much about it. When I look at this picture it seems like Rapamycin inhibits IL-11. Or am I interpreting things wrong?

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Source: https://www.nature.com/articles/s41586-024-07701-9/figures/8

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#16

A scientist has the same view:

The data from the Cook team’s research looked “solid” but the techniques suggested did not necessarily seem superior to senolytics, said Ilaria Bellantuono, professor of musculoskeletal ageing at Sheffield university.

https://www.sciencemediacentre.org/expert-reaction-to-study-on-the-ageing-effects-of-a-pro-inflammatory-protein-il11-in-mice/

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#17

I agree a small molecule is preferable, but long term Monoclonal antibodies are not necessary cost prohibitive. Some MABS for autoimmune disease are taken every month and others every week.

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#18

One thing that researchers should do is to start looking at gene therapy for knocking out or inhibiting the IL-11 receptor. It would be very nice to be able to do a single gene therapy treatment for example late in life and thereby skip regular IL-11 inhibitor injections which most people probably are not so keen towards to do. One very interesting thing is that those people with knockout mutations of the IL-11 receptor seem to do well with that mutation. It seems therefore that there are very small risks with doing this. I think there may be a huge company potential here for the person who grabs this opportunity.

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#19

Yeah…
‘But rapamycin has been linked to unwanted side effects, says Cook, who co-founded a Singapore-based company called Enleofen that is developing drugs against fibrosis. “Rapamycin is good for lifespan, but not healthspan,” he says.’

Of course he’s gonna knock something that can maybe work better than his product - because he’s selling his product. Hahaha.

I am waiting for the unwanted side effects. :upside_down_face:

So far memory, strength, weight control, skin quality, immunity, sinus, blood panel… etc. off the charts.

But we are all hopefully experiencing similar benefits.

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#20

There is variation in reported fertility phenotypes associated with LOF mutations in the IL11 pathway in mice and humans (Table 2). Female mice lacking Il11RA1 are infertile due to defective decidualization in response to embryo implantation5, 13. In contrast, women with homozygous IL11RA variants appear able to reproduce9, which could be explained by species differences in decidualization.>
In conclusion, loss of IL11 signaling due to mutation in either Il11 or Il11RA1 is protective against lung fibrosis that relates to reduced autocrine IL11 activity in myofibroblasts14, 30. However, the craniosynostosis and bone phenotypes seen in Il11RA1 deficient mice are not seen in Il11 −*/− mice, suggesting that developmental, STAT3-related bone effects are not due to defective IL11 signaling per se and instead, specific to Il11RA1 LOF. This is in agreement with a recent study that, apart from the fertility issue we describe here, reported no other phenotype in Il11 −/*− mice27. This is important, as therapeutic targeting of IL11 signaling for fibrotic lung and liver diseases is being considered and it may be that targeting the ligand has potential advantages over the receptor.

https://www.nature.com/articles/s41598-021-93623-9

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#21

From the Nature article on the study: (linked above)

" For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK–AMPK–mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age."

on ERK https://www.nature.com/articles/s41580-020-0255-7

“By phosphorylating widely diverse substrates, ERK proteins govern a variety of evolutionarily conserved cellular processes in metazoans, the dysregulation of which contributes to the cause of distinct human diseases. The mechanisms underlying the regulation of ERK1 and ERK2, their mode of action and their impact on the development and homeostasis of various organisms have been the focus of much attention for nearly three decades.”

“We begin with a brief overview of the structure, regulation, substrate recognition and subcellular localization of ERK1 and ERK2. We then systematically discuss how ERK signalling regulates six fundamental cellular processes in response to extracellular cues. These processes are cell proliferation, cell survival, cell growth, cell metabolism, cell migration and cell differentiation.”

The AMPK signalling pathway coordinates cell growth, autophagy and metabolism

"One of the central regulators of cellular and organismal metabolism in eukaryotes is AMP-activated protein kinase (AMPK), which is activated when intracellular ATP production decreases. AMPK has critical roles in regulating growth and reprogramming metabolism, and has recently been connected to cellular processes such as autophagy and cell polarity. "

https://medicalxpress.com/news/2024-07-scientists-interleukin-key-driver-aging.html

“Unlike other drugs known to inhibit specific pathways involved in aging, such as metformin and rapamycin, anti-IL-11 therapy blocks multiple major signaling mechanisms that become dysfunctional with age, offering protection against multimorbidity from cardiometabolic diseases, age-related loss of muscle mass and strength as well as frailty.”

So, are they saying that rapamycin only affects mTORC1 but that anti-IL-11 therapy also affects ERK and AMPK pathways as well as mTORC1?

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#22

Here is a paper by Stuart which lift both mice and human data in a interesting way.

Based on the genetic studies of IL11RA mutants, IL11 signaling is thought important for a number of phenotypes. Il11ra1 -deleted female mice are infertile5 and mutation in Il11ra1 in the mouse is associated with incompletely penetrant snout displacement and tooth abnormalities: a craniosynostosis-like phenotype6. Several human studies have identified individuals with IL11RA mutations who have mild features of craniosynostosis, joint laxity, scoliosis and delayed tooth eruption, although ascertainment bias has been suggested6–8. Unlike mice, female humans with mutations in IL11RA appear fertile in some studies9.
Source: Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis - PubMed

Here is time clip from a webinar he had on one 10 month ago where he gives a very short comment on side effects in humans.

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