You couldn’t have missed it. The reports about a ‘supermodel granny drug’,[1] an ‘anti-aging breakthrough that could extend life’,[2] were in every newspaper and on every TV station. According to Stuart Cook, the anti-ageing professor who invented the ‘supermodel granny drug’, its effect would even be comparable to that of rapamycin – ‘but without some of rapamycin‘s adverse side effects’.[3]

The epicenter of this media fuss is a publication in the prestigious scientific journal Nature.[4] The first author is molecular biologist Anissa Widjaja, affiliated with Duke-National University of Singapore Medical School.

At first glance, the publication is an animal study, as there are many in the field of anti-ageing research. Widjaja and her colleagues gave months-old mice – if the test animals had been humans, they would have been in their fifties – a substance that disables the interleukin-11 cytokine [spatial structure below]. As a result, they lived 23-25 ​​percent longer.

Interesting of course, but not unique. However, once you delve further into the details of this research, you come to understand why the highly regarded Nature wanted to publish this research. Then you will also understand that the fuss in the media might be completely justified.

Healthier

What is striking in this animal study is that the researchers do not report any adverse effects of their treatment, but they do report positive health effects. As lab mice age, they gain weight, lose muscle mass and their fur turns gray. They are less able to move, and their hearing and vision deteriorate. The treatment counteracts all these effects.

As the C57BL/6 J mice – the strain the researchers experimented with – age, they often develop cancer. In the mice in the control group, this happened to more than sixty percent of the test animals. However, the anti-aging remedy that the researchers studied reduced that chance to less than 16 percent.

Many anti-aging substances described in the literature have adverse health effects. At best they are neutral. This also applies to perhaps the most effective anti-aging drug at this moment, rapamycin. “Rapamycin is good for lifespan, but not healthspan,” said research leader Stuart Cook in an interview with Nature.[5]

Pharmacokinetics

For their experiments, the researchers used genetically modified lab mice in which interleukin-11 no longer functioned. They lived longer than comparable and unmanipulated laboratory animals. However, the effects of the genetic intervention on the life span were less significant than the effects of administration of a pharmacological substance. We described this above.

This substance is an antibody that attaches to interleukin-11 in the body and thereby neutralizes it. The dosage the researchers needed was remarkably low. If the mice had been adult humans, that dose would have been about 120-180 milligrams.

The researchers did not administer the antibodies daily, but only once a month. They injected the antibodies into the small intestines of the mice. Many substances that are effective with that method of administration are also orally active. We dare not say whether this also applies to these antibodies.

Effective in humans?

In an interview with the Spanish daily El Pais, co-author and biochemist Jesús Gil said that he expects the proven antibodies to be effective in humans as well. “There is no reason to think that what we have seen in mice will not work in people,” Gil said.[6]

Gil’s statement conflicts with the biomedical rule of thumb that only one percent of substances that work well in animal studies also show good results in human research. But in this case, there may be reason for some optimism.

The antibody that Anissa Widjaja, Stuart Cook, Jesús Gil and their colleagues are studying is an antibody that should eliminate human interleukin-11. At amino acid level, human interleukin-11 is 88 percent identical to murine interleukin-11.[7] If this human antibody already shows hopeful effects in mice, there is a chance that it will do so in humans as well.

X203

The life-extending antibody is called X203. It was developed by Stuart Cooke’s research group by injecting laboratory animals with human interleukin-11, harvesting the antibodies from their blood, selecting the very best ones, and then reproducing them.

In 2019, Cooke’s group published an animal study in which X203 was effective against idiopathic pulmonary fibrosis.[8] In 2022, an animal study followed in which X203, in combination with an ACE inhibitor, extended the life span in laboratory animals with congenital kidney disease.[9]

Blocking interleukin-11

Cooke and his colleagues build on the accepted insight that runaway inflammation plays an important role in the aging process. As cells age, they release increasing amounts of inflammatory factors that accelerate the aging of healthy cells and can damage healthy tissues.[10]

Many strategies that reduce the signs of aging inhibit inflammation. This includes reducing psychological stress,[11] supplementing with probiotics such as Lactobacillus pentosus var. plantarum C29[12] or fish oil,[13] eliminating senescent cells with the combination of quercetin and dasatinib,[14] and administering metformin.[15]

Cooke’s research focused on eliminating one specific inflammatory factor, interleukin-11. Inflammatory factors and inflammation help to clean up damaged cells and therefore have a function, but according to Cooke, this is less true for interleukin-11. “This is something we have inherited in an evolution from fish, and it does good things in the fish,” the British newspaper Daily Mail quoted Cooke saying.[16] “’Unfortunately for us, it is an evolutionary hangover that causes harm, and it causes disease.”

Safety profile

Cooke is convinced that turning off interleukin-11 can take the sting out of a wide range of chronic diseases or aging-related conditions.[17] In animal studies, Cooke and his team were able to show that turning off interleukin-11 prevents the formation of connective tissue in overworked heart muscle,[18] a fatty liver,[19] and disease-damaged kidneys.[20]

Based on these animal studies, adverse effects are unlikely to occur. Inspired by this ‘reassuring safety profile’ and the impressively broad spectrum of positive effects, Cooke founded Enlofeon, a research company focused on the development of interleukin-11 blockers. Enlofeon has acquired patents for the use of these agents in diabetes, eye disease, kidney disease and a variety of other pro-inflammatory diseases.

In 2020, Cooke sold Enlofeon to the pharmaceutical company Boehringer Ingelheim.[21] Enlofeon was one of three research companies exploring the possibilities of disabling interleukin-11.

One of them, the American Lassen, has already conducted a phase 1 trial.[22] Lassen’s interleukin-11 blocker is an antibody. It is called LASN01. Unlike X203, LASN01 neutralizes the receptor for interleukin-11, and not the inflammatory factor itself. However, in its trial, Lassen found no adverse effects either.

However, anti-aging researcher Ilaria Bellantuono from the University of Sheffield suspects that X203, LASN01 or another interleukin-11 inhibitor that will receive attention from the longevity scene in the near future may indeed appear to have adverse effects. “Every drug has side effects,” he says.[23]

Speculating about the nature of these possible side effects is difficult, not least because science has never been able to determine the precise function of interleukin-11. Cooke assumes this means interleukin-11 has no important functions, but a more cautious stance is that science simply hasn’t looked closely enough.

We do know that interleukin-11 plays a role in skeletal health[24] and perhaps also in the production of platelets. Oncologists know oprelvekin, a recombinant version of interleukin-11, as a drug that stimulates platelet production.[25] In a few years, when the current trials are completed, we may know more.

Market availability

X203 is not yet available on the gray or black market. This may change. There are sufficient starting points in the literature that allow chemical manufacturers in countries with liberal views on intellectual property to produce their own versions of X203. But as far as we know, this is not yet the case.

Speculations are already circulating on social media about supplements that naturally suppress the activity of interleukin-11. One of these is curcumin, which, according to in vitro research, indeed reduces the release of interleukin-11.[26]

However, the concentration required for this effect is not achievable with regular curcumin supplementation. We found a study in which Indian researchers who gave nano supplements with curcumin to test subjects were able to approach the necessary concentration for three minutes.[27] For this they needed a dose of several grams of nanocurcumin per day. This implies that, just like regular curcumin, nano-curcumin is not suitable for lowering the concentration of interleukin-11. Life extensionists who want to experiment with interleukin-11 inhibitors such as X203 will have to wait until they appear somewhere on the web as a research chemical.

References

[1] Gallagher J. ‘Supermodel granny’ drug extends life in animals. BBC News, 17 July 2024.

[2] Geissler H. Anti-ageing breakthrough with miracle drug that could ‘extend life’. Express, Jul 17, 2024.

[3] Buvailo A. Accidental Breakthrough in Aging Research. BioPharmaTrend, July 19, 2024.

[4] Widjaja AA, Lim WW, Viswanathan S, Chothani S, Corden B, Dasan CM, Goh JWT, Lim R, Singh BK, Tan J, Pua CJ, Lim SY, Adami E, Schafer S, George BL, Sweeney M, Xie C, Tripathi M, Sims NA, Hübner N, Petretto E, Withers DJ, Ho L, Gil J, Carling D, Cook SA. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. Nature. 2024 Jul 17. doi: 10.1038/s41586-024-07701-9. Online ahead of print.

[5] Ledford H. Mice live longer when inflammation-boosting protein is blocked. Nature, 17 July 2024.

[6] Ansede M. A simple monthly injection allows mice to live 25% longer and free from diseases. El Pais, July 17, 2024.

[7] Biotechne R&D Systems. Recombinant Human IL-11 (CHO-expressed) Protein, CF. Catalog #: 10836-IL. Via rndsystems.com.

[8] Ng B, Dong J, D’Agostino G, Viswanathan S, Widjaja AA, Lim WW, Ko NSJ, Tan J, Chothani SP, Huang B, Xie C, Pua CJ, Chacko AM, Guimarães-Camboa N, Evans SM, Byrne AJ, Maher TM, Liang J, Jiang D, Noble PW, Schafer S, Cook SA. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Sci Transl Med. 2019 Sep 25;11(511):eaaw1237.

[9] Widjaja AA, Shekeran SG, Adami E, Ting JGW, Tan J, Viswanathan S, Lim SY, Tan PH, Hübner N, Coffman T, Cook SA. A Neutralizing IL-11 Antibody Improves Renal Function and Increases Lifespan in a Mouse Model of Alport Syndrome. J Am Soc Nephrol. 2022 Apr;33(4):718-30.

[10] Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther. 2023 Jun 8;8(1):239.

[11] Casaletto KB, Staffaroni AM, Elahi F, Fox E, Crittenden PA, You M, Neuhaus J, Glymour M, Bettcher BM, Yaffe K, Kramer JH. Perceived Stress is Associated with Accelerated Monocyte/Macrophage Aging Trajectories in Clinically Normal Adults. Am J Geriatr Psychiatry. 2018 Sep;26(9):952-63.

[12] Jeong JJ, Kim KA, Jang SE, Woo JY, Han MJ, Kim DH. Orally administrated Lactobacillus pentosus var. plantarum C29 ameliorates age-dependent colitis by inhibiting the nuclear factor-kappa B signaling pathway via the regulation of lipopolysaccharide production by gut microbiota. PLoS One. 2015 Feb 17;10(2):e0116533.

[13] Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, Hwang BS, Glaser R. Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: a randomized controlled trial. Brain Behav Immun. 2012 Aug;26(6):988-95.

[14] Saccon TD, Nagpal R, Yadav H, Cavalcante MB, Nunes ADC, Schneider A, Gesing A, Hughes B, Yousefzadeh M, Tchkonia T, Kirkland JL, Niedernhofer LJ, Robbins PD, Masternak MM. Senolytic Combination of Dasatinib and Quercetin Alleviates Intestinal Senescence and Inflammation and Modulates the Gut Microbiome in Aged Mice. J Gerontol A Biol Sci Med Sci. 2021 Oct 13;76(11):1895-905.

[15] Moiseeva O, Deschênes-Simard X, St-Germain E, Igelmann S, Huot G, Cadar AE, Bourdeau V, Pollak MN, Ferbeyre G. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell. 2013 Jun;12(3):489-98.

[16] Hunter W. Is this the anti-ageing elixir we’ve all been waiting for? Daily Mail, 18 July 2024.

[17] Cook SA. Understanding interleukin 11 as a disease gene and therapeutic target. Biochem J. 2023 Dec 13;480(23):1987-2008.

[18] Corden B, Lim WW, Song W, Chen X, Ko NSJ, Su L, Tee NGZ, Adami E, Schafer S, Cook SA. Therapeutic Targeting of Interleukin-11 Signalling Reduces Pressure Overload-Induced Cardiac Fibrosis in Mice. J Cardiovasc Transl Res. 2021 Apr;14(2):222-8.

[19] Widjaja AA, Singh BK, Adami E, Viswanathan S, Dong J, D’Agostino GA, Ng B, Lim WW, Tan J, Paleja BS, Tripathi M, Lim SY, Shekeran SG, Chothani SP, Rabes A, Sombetzki M, Bruinstroop E, Min LP, Sinha RA, Albani S, Yen PM, Schafer S, Cook SA. Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic Steatohepatitis. Gastroenterology. 2019 Sep;157(3):777-792.e14.

[20] Widjaja AA, Viswanathan S, Shekeran SG, Adami E, Lim WW, Chothani S, Tan J, Goh JWT, Chen HM, Lim SY, Boustany-Kari CM, Hawkins J, Petretto E, Hübner N, Schafer S, Coffman TM, Cook SA. Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease. Nat Commun. 2022 Dec 5;13(1):7497.

[21] Boehringer Ingelheim. Boehringer Ingelheim Partners with Enleofen to Develop First-in-Class Anti-IL-11 Therapies for a Range of Fibrotic Diseases. Press release, 01/09/2020.

[22] Lassen Therapeutics. Lassen Therapeutics Commences Dosing in Phase 1 Clinical Study of LASN01, a First-in-Class Interleukin-11 Receptor-Blocking Antibody. Press release, 28 September 2022.

[23] Science Media Centre. Expert reaction to study on the ageing effects of a pro-inflammatory protein, IL11, in mice. Via sciencemediacentre.org, July 17, 2024.

[24] Sims NA, Jenkins BJ, Nakamura A, Quinn JM, Li R, Gillespie MT, Ernst M, Robb L, Martin TJ. Interleukin-11 receptor signaling is required for normal bone remodeling. J Bone Miner Res. 2005 Jul;20(7):1093-102.

[25] Sitaraman SV, Gewirtz AT. Oprelvekin. Genetics Institute. Curr Opin Investig Drugs. 2001 Oct;2(10):1395-400.

[26] Kondo A, Mogi M, Koshihara Y, Togari A. Signal transduction system for interleukin-6 and interleukin-11 synthesis stimulated by epinephrine in human osteoblasts and human osteogenic sarcoma cells. Biochem Pharmacol. 2001 Feb 1;61(3):319-26.

[27] Mohanty C, Sahoo SK. The in vitro stability and in vivo pharmacokinetics of curcumin prepared as an aqueous nanoparticulate formulation. Biomaterials. 2010 Sep;31(25):6597-611.