During the 55th European Renal Association–European Dialysis and Transplant Association (ERA–EDTA) Congress from 24th–27th May 2018 in Copenhagen, Denmark, the EMJ team were delighted to spend time with Prof Peter Stenvinkel, senior lecturer at Karolinska University Hospital and Professor of Nephrology at the renowned Karolinska Institutet, Karolinska, Sweden. In a fascinating dialogue, Prof Stenvinkel informed us about the work his research team are undertaking to try to understand the mechanisms behind accelerated ageing in chronic diseases, especially chronic kidney disease (CKD), and novel therapy methods being developed from this. We then moved on to the topic of biomimetics, which Prof Stenvinkel holds a special interest in. This is the observation of nature and evolution and using this information to contribute toward human medicine. With increasing interest in this area, the Karolinska Institutet are involved in the setting up of a unique event in 2019, which will bring together prominent experts from a number of disciplines, such as zoologists, biologists, ecologists, and botanists.
Accelerated Ageing in Chronic Disease
For many years, Prof Stenvinkel’s team at Karolinska have been using chronic disease as a model of accelerated ageing. In a presentation he gave at the ERA–EDTA Congress, entitled ‘Inflammation as a driver of premature aging in CKD’, literature was outlined relating to inflammation and accelerated biological ageing in CKD patients. In CKD, it has been shown that patients with advanced kidney disease can have a biological age 30–40 years older than their chronological age.1 This type of accelerated ageing is also a feature of many other chronic diseases related to burden of lifestyle, including diabetes, heart disease, and osteoporosis. Therefore, targeting and modulating the fundamental mechanisms of biological ageing is of particular interest for finding solutions to such conditions. “The idea is that you should die young but at an old age,” he explained. “We are very interested in finding markers of biological ageing, which is probably much more relevant to use than chronological age.”
“All Diseases Begin in the Gut”
There are many markers of chronic inflammation, also known as inflammaging, that lead to premature ageing; for example, mitochondrial dysfunction and telomere dysfunction. An area the Swedish professor is particularly interested in is the role of diet in promoting subclinical inflammation, and he recounted the famous Hippocrates quote: “Everything in excess is opposed to nature. All diseases begin in the gut.” He believes more research efforts need to go into understanding the effect of modern diet, such as junk food, on premature ageing in kidney disease. However, he does see good prospects on the horizon regarding the anti-inflammatory food types that patients with conditions like CKD are now able to consume. “We usually advise our patients not to eat the food items that eliminate inflammation because they are very rich in potassium and that, of course, is a major problem because potassium can be life-threatening when you have kidney disease,” he elucidated. “But now, with more effective potassium-binding drugs, we may be able to start to ask our patients to have a diet that consists of these items that are more inflammation friendly and may even eliminate inflammation.”
NRF2 Transcription Factor
A particularly important area of study in regard to epigenetic age is the NRF2 transcription factor. It has been observed, for instance, that in children with the rare Hutchinson–Gilford progeria syndrome, which is characterised by extreme accelerated biological ageing, and often leads to patients dying due to conditions such as stroke and heart attack in their childhood years, NRF2 is markedly downregulated. Prof Stenvinkel compared Hutchinson–Gilford progeria patients to the naked mole rat, native to Eastern Africa, which can live for an extraordinarily long time for a rodent: in excess of 30 years. A key reason for this longevity is that this rat does not appear to undergo any signs of vascular ageing whatsoever. In comparison to laboratory mice, the naked mole rat has a very high expression of NRF2.
“Almost all these diseases that are related to high lifestyle burden premature ageing, such as inflammatory diseases and CKD, which have low expression of this transcription factor NRF2,” he commented. It therefore appears that modulating or increasing NFR2 levels could be a means of combatting these chronic conditions. He believes that this can be achieved through lifestyle factors, especially diet; for example, a high fructose diet has been shown to lower NFR2 expression. Additionally, there are a number of naturally occurring NRF2 agonists becoming available that can also increase expression, such as sulforaphane.2
In the second part of our discussion, Prof Stenvinkel told us about his substantial work and interest in the field of biomimetics. “This, I think, is a very interesting and novel concept of conducting research, and actually means learning from nature,” he elucidated. “We use nature as models and then imitate and take inspiration from nature for the benefit of humans; so that is solutions that have been created in nature during evolution.” This inspiration comes from a variety of sources, from plants to wild animals and even humans. Prof Stenvinkel then went through some particularly interesting examples of where anomalies have been identified.
In regard to CKD, animal species that are predisposed to the condition have been compared to others that appear to have developed evolutionary defences despite having lifestyle factors that should increase their risk of disease onset. Lions and tigers, for instance, have a very high risk of developing CKD. Yet seals, despite regularly diving in the sea for periods of up to 2 hours and to a depth of up to 2,000 metres, a time in which there is no circulation through their kidneys, are able to avoid acute kidney injury. Another good example is that of the vampire bat, which consumes vast quantities of blood and protein levels equivalent to a human eating 80 big steaks per day; however, no problems seems to ensue.
Scandinavian Brown Bears
Prof Stenvinkel has been in collaboration with the Scandinavian Brown Bear Project3 studying Scandinavian brown bears in their natural habitat, and how they appear to be protected from chronic diseases despite spending a large portion of the year hibernating. For example, they may not urinate for up to 6 months during hibernation yet not develop complications often observed in humans with kidney problems. Additionally, immobilisation for such a long period would lead to loss of muscle mass and resulting conditions like osteoporosis in humans, but in these bears no such problems present; indeed, muscle strength is preserved and fatigue resistance maintained. Prof Stenvinkel explained that the team had conducted chemical analyses and taken computed tomography (CT) scanners to examine bone structure of bears in Scandinavia to obtain this vital information. Interestingly, the bears had stronger bones in the winter during hibernation than in the summer months.
Some promising findings are now emerging. A major one is in regard to diet. “We believe one of the secrets may be the enormous amounts of berries they eat, because the berries have lots of potential beneficial effects,” Prof Stenvinkel elucidated. The findings therefore emphasise that a similar diet would be highly beneficial for humans. Blueberries for instance have been shown to have numerous health benefits to humans, including improving blood pressure and arterial stiffness4 and reducing the risk of cardiovascular disease.5
Red Meat Consumption
In collaboration with Prof Paul Shiels at Glasgow University, differences in longevity have also been studied in humans. In the city of Glasgow, UK, there are drastic variations in male life expectancy, with those residing in the area of Calton having an average lifespan of just 54 years. This compares to the Lenzie area of Glasgow, just 14 km away, where the male life expectancy is 82 years.6 One of the team’s findings, in collaboration with Glasgow-based researchers, is that red meat and processed meat consumption in Calton is one of the key drivers of the early mortality rates.7 This is comparable to red meat consumption in lions and tigers, whom have a high risk of CKD.
As may be surmised, Prof Stenvinkel believes that lifestyle, especially diet, plays a fundamental role in the risk of onset of chronic conditions, and he re-emphasised the adage of the gut being at the core of many diseases. “We know there are toxins generated in the gut when you have a meat-rich diet that contributes to cardiovascular and CKD,” he said. “I believe that lifestyle and nutrients have a big impact here; that our sedentary, meat-eating, and junk-food eating society increases the risk of not only CKD but all those lifestyle-burden diseases.”
With biomimetics clearly shedding light on potential solutions to human disease, Prof Stenvinkel and the Karolinska Institutet are involved in planning a unique event in this field in Stockholm in 2019, of which further information will shortly be available. The aim is to share expertise from numerous fields and use this knowledge to create novel solutions in human healthcare. It is a principle that Prof Stenvinkel’s team have followed in their own research, such as collaborating with wildlife veterinarians to study wild animals. “The idea is that we should invite not only medical doctors but also people from completely different disciplines such as biologists, veterinarians, botanists, ecologists, anthropologists, zoologists, and chemists to meet in the intersection and this is where good ideas can be generated when you talk to people with completely different knowledge,” he outlined.
It was a pleasure to speak to Prof Stenvinkel about some of the work he is involved in regarding accelerated ageing and chronic diseases. Seeking ideas for solutions to human disease by using nature as a model is an area that is be growing in interest. Chronic conditions such as CKD have increased in prevalence substantially in recent years, for example, an astonishing 10% of the world’s population is estimated to have CKD in some form,7 and novel approaches such as these could provide much needed solutions. The conference next year is one that the EMJ team are very much looking forward to hearing all about.
For insights into other topics like this, a full review of this year’s ERA-EDTA Congress, including coverage of research in CKD in addition to many other nephrological conditions, will be available in the next edition of the EMJ Nephrology eJournal. This journal, which will be published on our website in early July, will also provide abstract reviews from the event, interviews with members of the EMJ Nephrology Editorial Board, and a range of peer-reviewed papers. Click here to subscribe for free to ensure you don’t miss out on all of this content!
- Koetsier M et al. Reference values of skin autofluorescence. Diabetes Technol Ther. 2010;12(5). [Epub ahead of print].
- Stenvinkel P et al. Novel treatment strategies for chronic kidney disease: insights from the animal kingdom. Nat Rev Nephrol. 2018;14:265-84.
- Skandinaviska Björnprojektet. Welcome. Available at: http://bearproject.info/. Last accessed: 11 June 2018.
- Johnson SA et al. Daily blueberry consumption improves blood pressure and arterial stiffness in postmenopausal women with pre- and stage 1-hypertension: A randomized, double-blind, placebo-controlled clinical trial. J Acad Nutr Diet. 2015;115(3):369-77.
- Basu A et al. Blueberries decrease cardiovascular risk factors in obese men and women with metabolic syndrome. J Nutr. 2010;140(9):1582-7.
- World Health Organization. Closing the gap in a generation. 2008. Available at: http://www.who.int/social_determinants/final_report/csdh_finalreport_2008.pdf. Last accessed: 8 June 2018.
- Johnston I. Cheap red meat helps to kill off Glasgow’s poorest men 30 years early. April 2016. Available at: https://www.independent.co.uk/news/science/red-meat-processed-life-expectancy-cancer-glasgow-diet-a7004266.html. Last accessed: 8 June 2018.
- ISN. Global Kidney Health Atlas. 2017. Available at: https://www.theisn.org/images/ISN_Biennial_Report_2011-2013/GKHAtlas_Linked_Compressed1.pdf. Last accessed: 8 June 2018.