A study in Nature in July 2024[1], raised the idea that blocking the interleukin 11 (IL-11) by using an IL-11 antibody could be a proposition for a healthy increase in lifespan, based on the outcomes in their experimental mouse subjects.
As you would expect, IL-11 has a role in the induction and promotion of inflammation an underlying defensive mechanism that is amplified as we age and release more damaged proteins and other molecules in what is known as sterile inflammation. This soup of cellular debris is partly responsible for the state of being known as inflammaging[2]. Other triggers include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, chronic infections, environmental pollutants, stress, trauma etc.[3]
Nutrients, as a modifier of the inflammatory cascades, already have a significant body of evidence supporting their role in the mitigation of persistent inflammatory responses. The balance between pro-inflammation and anti-inflammation is essential for the health-generative result of inflammation; a similar concept is observed for inflammaging and anti-inflammaging processes and is affected by a wide variety of lifestyle mediators[4].
Cytokines impact on aging
Interleukin 11, a cytokine in the IL-6 family, based on this recent paper and a few others, has undergone a significant revaluation in the scientific community. Previously believed to be anti-fibrotic, anti-inflammatory, and pro-regenerative, new studies have shown that IL-11 is actually pro-fibrotic, pro-inflammatory, and anti-regenerative[5]. This shift in understanding marks a major paradigm shift in IL-11 biology, challenging long-held beliefs and opening new avenues for research and potential treatments, in effect the notion of preventing the triggering consequences of IL-11 presents clinical opportunities. Related unintended consequences are yet to be researched, but the involvement of IL-11 in age-related diseases and its detrimental effects when chronically elevated may represent an evolutionary remnant of its original regenerative function, now maladaptive in the context of complex mammalian physiology.
The role of chronic sterile inflammation in aging-related diseases is increasingly recognised[6]. Inflammation is a key hallmark of aging, with a dysfunctional adaptive immune system marked by immunosenescence and thymic involution, along with the inappropriate activation of innate immune genes such as IL-6 and IL-11. Pro-inflammatory signalling factors NF-κB and JAK–STAT3 are particularly implicated in aging, and JAK-STAT3 inhibitors can help alleviate age-related dysfunction[7].
The JAK-STAT3 pathway is a critical signalling mechanism in cells, involving Janus Kinases (JAKs) and Signal Transducers and Activators of Transcription (STAT3). It plays a crucial role in processes such as cell growth, immune function, and inflammation. IL11 is implicated in the process as it is a recognised promoter of ERK–mTORC1 and/or JAK–STAT3 and is upregulated in humans during aging[8].
The Nature paper discusses the benefits in mice of the inhibition of IL11, which demonstrated a reversal or prevention of age-related body mass changes, muscle strength, metabolic markers and fur quality, expanding lifespan (around a 20% gain) and functionality. Whilst for the mouse population this might be an exciting proposition, what can be translated for humans?
Inflammation, Aging and Nutrients
There have been multiple research papers looking at the intersection of food, lifestyle and mobility on the induction or suppression of persistent unwanted low-grade inflammation. With the the premise that improved cellular health, the related reduced production of alarmin-type response to age-related pathogenic factors include cytokines, proteotoxic stress, oxidative species and DNA damage, among others are therapeutic longevity targets of value[9].
Cellular alarmins are endogenous molecules released by stressed or damaged cells to signal danger and activate the immune response. These molecules, including HMGB1, S100 proteins, and heat shock proteins, act as early warning signals, alerting the immune system to injury or infection. Alarmins play a critical role in initiating inflammation, recruiting immune cells to the site of damage, and facilitating tissue repair. However, their prolonged release can contribute to chronic inflammation and pathological conditions.
In 2021, the journal Nutrients published a review on the role of nutrients in targeting inflammaging, the same proposition as the mice were targeted with, but without IL11 specificity[10]. Two well-studied nutrients included:
Resveratrol: A polyphenolic compound found in grapes, red wine, and other plant-based foods, has been shown to possess anti-inflammatory properties via various mechanisms[11].
Mechanisms of Action: Resveratrol exerts its anti-inflammatory effects through various mechanisms, including protecting the intestinal barrier, regulating the gut microbiome, and inhibiting intestinal inflammation.
Quercetin: A natural flavanol antioxidant found in various plant sources and food samples, known for its notable curative effects on treating ophthalmic diseases due to its antioxidant, anti-inflammatory, and anti-fibrosis activities[12].
Mechanism of Action: It has a potent antioxidant capacity, capturing reactive oxygen species, reactive nitrogen species, and reactive chlorine species[13].
Many other studies have also examined various plant groups for their ability to inhibit the JAK-STAT pathway and inhibit IL-11 activation. Phenols like resveratrol, curcumin, and apigenin are understood to inhibit JAK1/2 and STAT3. Steroids such as diosgenin and guggulsterone inhibit JAK1/2, DNA binding activity, and STAT3. Terpenoids including cucurbitacin and andrographolide inhibit JAK1/2 and STAT3/5. These plant compounds and others show potential in targeting inflammation and other diseases linked to the JAK-STAT pathway, and by association will reduce IL-11 activation and binding, as well as many other inflammatory genes and proteins[14].
Blueberries
The benefits of blueberries, rich in anthocyanins, have garnered significant attention as functional foods. Malvidin, in part responsible for their deep blue colour is a key component, and disrupts the JAK/STAT3 pathway, and has been shown to reduce cell proliferation and induce mitochondrial-mediated apoptosis in a hamster model of oral cancer. Resveratrol, also found in blueberries, inhibits cell growth, induces apoptosis, causes G0/G1-phase cell cycle arrest, and blocks STAT3/JAK2 signalling, indicating that a daily intake may help reduce the progress of inflammaging[15]. A safe easy to consume anthocyanidin rich berry that carries specialised molecular mechanistic possibilities.
Dietary choices
Nature Microbiology published a review paper in July 2024, called The interplay between diet and the gut microbiome: implications for health and disease. In part this was to explore the relationship between mechanisms by which dietary selection (Mediterranean, High Fibre, Plant-Based, High Protein, Ketogenic and the Western Diet) influence the gut microbiome. The relevance of this work is to understand how whole food, refined food, and specific dietary preferences adversely or beneficially change the microbiome and the induction and control of gastrointestinal and mucosal immune-induced inflammation[16]. Confirming that, the effectiveness of dietary interventions in treating diseases promoted by the microbiota composition, depends substantially on the individual host and their unique gut microbiome composition at the time any precision dietary changes are introduced.
Summary
Diet and nutrient composition and concentration play a crucial role in human health, significantly impacting the development of metabolic diseases like obesity, diabetes, and hypertension as well as many chronic life-shortening and morbidity-inducing diseases. Poor dietary habits can lead to underlying inflammation, a regulated immune process where immune and non-immune cells release inflammatory mediators in response to pathogens or tissue damage. This cascade recruits leukocytes to fight infection and initiate healing. However, if the inflammation persists, it can become chronic, leading to various metabolic and immune diseases due to a defective inflammatory response[17],[18]. This notion that diet drives health outside of caloric supply is still a challenge for many who seek autonomy, the absence of behavioural tax in food selection, and expect others to ultimately fund their long term clinical needs.
The Guardian published a commentary piece discussing the huge benefits of preventative care. “The NHS still operates according to its traditional, founding principles of 75 years ago, which is disease care. But we need to move to a system of upstream, preventative health intervention,” stated Prof John Deanfield, the first-ever government champion for personalised prevention. Whilst he has set out a very modest range of preventative approaches, it is hoped that the recognition of investing in health generation, also recognises that the NHS is unable to provide this service – it will be interesting to see who he determines can!
References
[1] Widjaja, A.A., Lim, WW., Viswanathan, S. et al. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. Nature (2024).
[2] Fulop T, Larbi A, Pawelec G, Khalil A, Cohen AA, Hirokawa K, Witkowski JM, Franceschi C. Immunology of Aging: the Birth of Inflammaging. Clin Rev Allergy Immunol. 2023 Apr;64(2):109-122
[3] Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018 Sep;15(9):505-522.
[4] Szarc vel Szic K, Declerck K, Vidaković M, Vanden Berghe W. From inflammaging to healthy aging by dietary lifestyle choices: is epigenetics the key to personalized nutrition? Clin Epigenetics. 2015 Mar 25;7(1):33.
[5] Ng, B., Cook, S.A. and Schafer, S. (2020) Interleukin-11 signaling underlies fibrosis, parenchymal dysfunction, and chronic inflammation of the airway. Exp. Mol. Med. 52, 1871–1878
[6] Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW, Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ, Rando TA, Effros RB, Lucia A, Kleinstreuer N, Slavich GM. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019 Dec;25(12):1822-1832.
[7] Fabian DK, Fuentealba M, Dönertaş HM, Partridge L, Thornton JM. Functional conservation in genes and pathways linking ageing and immunity. Immun Ageing. 2021 May 14;18(1):23.
[8] Cook SA. Understanding interleukin 11 as a disease gene and therapeutic target. Biochem J. 2023 Dec 13;480(23):1987-2008
[9] Li, X., Li, C., Zhang, W. et al. Inflammation and aging: signaling pathways and intervention therapies. Sig Transduct Target Ther 8, 239 (2023).
[10] Koppula S, Akther M, Haque ME, Kopalli SR. Potential Nutrients from Natural and Synthetic Sources Targeting Inflammaging-A Review of Literature, Clinical Data and Patents. Nutrients. 2021 Nov 13;13(11):4058.
[11] Chen X, Zhang J, Yin N, Wele P, Li F, Dave S, Lin J, Xiao H, Wu X. Resveratrol in disease prevention and health promotion: A role of the gut microbiome. Crit Rev Food Sci Nutr. 2024;64(17):5878-5895.
[12] Zhao L, Wang H, Du X. The therapeutic use of quercetin in ophthalmology: recent applications. Biomed Pharmacother. 2021 May;137:111371.
[13] Carrillo-Martinez EJ, Flores-Hernández FY, Salazar-Montes AM, Nario-Chaidez HF, Hernández-Ortega LD. Quercetin, a Flavonoid with Great Pharmacological Capacity. Molecules. 2024 Feb 25;29(5):1000.
[14] Fahmideh H, Shapourian H, Moltafeti R, Tavakol C, Forghaniesfidvajani R, Zalpoor H, Nabi-Afjadi M. The Role of Natural Products as Inhibitors of JAK/STAT Signaling Pathways in Glioblastoma Treatment. Oxid Med Cell Longev. 2022 Sep 19;2022:7838583.
[15] Fahmideh H, Shapourian H, Moltafeti R, Tavakol C, Forghaniesfidvajani R, Zalpoor H, Nabi-Afjadi M. The Role of Natural Products as Inhibitors of JAK/STAT Signaling Pathways in Glioblastoma Treatment. Oxid Med Cell Longev. 2022 Sep 19;2022:7838583.
[16] Ross, F.C., Patangia, D., Grimaud, G. et al. The interplay between diet and the gut microbiome: implications for health and disease. Nat Rev Microbiol (2024). https://doi.org/10.1038/s41579-024-01068-4
[17] Nigam M, Devi K, Coutinho HDM, Mishra AP. Exploration of gut microbiome and inflammation: A review on key signalling pathways. Cell Signal. 2024 Jun;118:111140.
[18] Gill PA, Inniss S, Kumagai T, Rahman FZ and Smith AM (2022) The Role of Diet and Gut Microbiota in Regulating Gastrointestinal and Inflammatory Disease. Front. Immunol. 13:866059.
