The growing link between inflammation and cancer, heart disease and Alzheimer'sby Nicky Pellegrino
Inflammation, the body’s natural response to injury or infection, is increasingly implicated in a host of ailments from heart disease to dementia, but there are significant breakthroughs.
“Without inflammation we’d have serious problems,” says Madhav Bhatia, a professor in the department of pathology and biomedical science at the University of Otago’s Christchurch campus. “It’s a normal protective response to any infection or injury.”
But as Grandma always said, you can have too much of a good thing. Chronic or systemic inflammation means trouble. When Bhatia first began research into inflammation 23 years ago, it was already implicated in a variety of conditions.
“Arthritis, pancreatitis, gastritis … anything that ends with ‘-itis’,” he says. “Today, it’s appreciated that inflammation is associated with most of the diseases: cardiovascular, Alzheimer’s, diabetes, cancer.”
Bhatia’s work as leader of the university’s inflammation research group has focused on acute pancreatitis, sepsis and rheumatoid arthritis – conditions that the inflammatory response, once triggered, substantially aggravates.
The group have made some significant discoveries. Working with a compound called crambene, found in broccoli and brussels sprouts, they managed to induce an anti-inflammatory response in mice that protected them from acute pancreatitis.
They have also found that hydrogen sulfide plays a clear role in several inflammatory conditions. A toxic gas with the smell of rotten eggs – anyone who has visited Rotorua has smelt it – it occurs naturally in small amounts in the body. But Bhatia’s team discovered that in acute pancreatitis, it was being formed in the pancreas. Further work found it was present in cases of sepsis – a condition that arises when the body’s response to infection causes injury to its own tissues and organs – and rheumatoid arthritis. When an inflammatory inhibitor was used, it conferred protection against inflammation in all the conditions being treated.
Block the progress
Scores of researchers around the world are looking at inflammation in relation to other diseases and trying to do much the same thing: if we can block the processes that lead to excess inflammation without suppressing the immune system or otherwise throwing the body out of balance, we might have the secret to warding off a host of serious diseases.
Perhaps the greatest strides have been made in the field of cardiovascular medicine. It’s an area that Paul Ridker of Brigham and Women’s Hospital in Boston has been working in for more than two decades. In the 1990s, he wanted to know why half of heart attacks were occurring in people with normal cholesterol levels. Suspecting some sort of inflammatory reaction was at play, he began testing for a blood marker called CRP (C-reactive protein), which is produced by the liver in response to inflammation. He discovered that healthy middle-aged men with high levels of CRP were three times as likely to suffer a heart attack in the next three years as those with the lowest levels. Ridker needed a medication that would control the inflammation to see if it changed the outcome.
Last August, he announced the results of a trial evaluating the effects of an anti-inflammatory drug called canakinumab in patients with a history of heart attacks and elevated CRP levels. The study, named Cantos (short for Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) was sponsored by the drug company Novartis, which manufactures canakinumab, a so-called monoclonal antibody that fights systemic inflammation and is approved to treat a type of juvenile rheumatoid arthritis.
The 10,000 participants were randomly assigned to receive either a placebo or regular doses, at varying levels, of the anti-inflammatory, in addition to their usual drugs, and followed up for four years. For those taking the higher doses of canakinumab, there was a 15% reduction in cardiovascular events.
This has been heralded as a major milestone. “In my lifetime, I’ve seen three broad eras of preventative cardiology,” Ridker was reported as saying. “In the first, we recognised the importance of diet, exercise and smoking cessation. In the second, we saw the tremendous value of lipid-lowering drugs such as statins. Now, we’re cracking the door open on the third era. This is very exciting.”
Canakinumab was also seen to dramatically cut rates of death from cancer, in particular lung cancer. But there are catches: it is expensive, and because it suppresses a part of the immune system, it increases the risk of potentially fatal infections. It’s possible that heart-disease patients will be treated specifically for their inflammatory risk, but that exciting third era of medicine isn’t quite here yet.
Ridker is involved in a trial to see whether a cheaper drug, methotrexate, which is widely used to treat rheumatoid arthritis, can be used in low doses to reduce cardiovascular risk. And other drugs are being used to target inflammation.
The most popular is aspirin, which is widely taken to reduce the risk of heart attack, stroke and cancer. Aspirin helps trigger the production of molecules called resolvins that are naturally made by the body from omega-3 fatty acids. These shut off the inflammation that underlies conditions such as heart disease.
Aspirin does have some side effects. It increases the risk of bleeding in the gut and brain – and the older you are, the more that risk increases. But it seems that it may have a beneficial role to play in preventing the cognitive decline that accompanies old age.
Dr Simon O’Carroll of the University of Auckland’s Centre for Brain Research is exploring whether aspirin and the common cholesterol-lowering medications called statins have the potential to strengthen the blood-brain barrier, the shield that prevents anything harmful reaching the brain but maintains the organ’s supply of glucose.
O’Carroll says we know there is a connection between a leaky blood-brain barrier and dementia, “and there is evidence, although it’s not all that conclusive, that if you’re on aspirin or statins, you’re less likely to develop dementia”.
He was interested in the link between cognitive decline and conditions such as diabetes and obesity, which are known to produce cytokines, molecules that cause inflammation and can act on the cells of the blood-brain barrier, weakening it and making it leaky. The theory is that this leaves the brain vulnerable to substances in the body that have the potential to cause cell death, which can then lead to dementia.
O’Carroll has spent a lot of time in the lab looking into the biology of this by growing the endothelial cells that form the blood-brain barrier and seeing how they can be weakened or killed and, by contrast, how they can be protected. It’s all still happening in a test tube, but he is starting to understand how statins and aspirin will need to be used for maximum benefit.
“If you take people with mild cognitive impairment and give them statins, it’s probably not going to do much,” he says. “But if you have people taking them before that develops, it may make a difference. That’s what we’re trying to understand: how long before you [injure] the blood vessels do you have to pre-treat them with aspirin or statins? And we’re seeing some evidence that the longer you do it, the more effective it is.”
O’Carroll believes the blood-brain barrier plays a role in dementia and that maintaining its strength by protecting it from the ravages of inflammation will be of benefit.
The role of inflammation in cognitive decline was highlighted this week when an esteemed Vancouver-based research team announced it had successfully carried out studies suggesting that, if started early enough, a daily regimen of the non-prescription nonsteroidal anti-inflammatory drug ibuprofen can prevent the onset of Alzheimer’s disease. The team, led by Dr Patrick McGeer, reported in 2016 that they had developed a simple saliva test that can diagnose Alzheimer’s disease as well as predict its future onset. The test detected levels of a protein that is made everywhere in the body but deposited only in the brain, causing neuroinflammation, which destroys neurons.
“The test can indicate if a person is fated to develop Alzheimer’s disease long before it begins to develop,” McGeer said. “Individuals can prevent that from happening through a simple solution that requires no prescription or visit to a doctor.”
Defence goes rogue
But why exactly does inflammation, one of our best lines of defence, go rogue and turn on the body? The evidence increasingly suggests that our modern lifestyles may be contributing.
What we eat and drink certainly has a role to play. Thinking of pulling the tab on a nice cold can of diet soft drink? Recent research from Mexico has linked consumption of artificially sweetened fizzy drinks with a significant rise in CRP levels – it was 50% higher in those who drank the most.
The relative levels of omega-3 and omega-6 fatty acids in our diets have also been under scrutiny. We evolved eating equal amounts of both, but the Western diet has skewed the ratio towards the pro-inflammatory omega-6 – largely because of the widespread use of processed vegetable oils – and away from the anti-inflammatory omega-3, found in oily fish.
In 2014, epidemiologists from the University of South Carolina reviewed research into the relationship between nutrition and inflammation and produced the dietary inflammatory index (DII) as a tool to assess various eating plans. It won’t come as a huge surprise that, by this measure, fast food has been shown to have strong pro-inflammatory potential or that the Mediterranean-style diet – rich in fresh vegetables, fruit, wholegrains and fish – produces high anti-inflammatory scores.
Other studies have shown that some foods are particularly good at reducing inflammation. The spice turmeric, for instance, contains a compound called curcumin that has been shown to lower the levels of enzymes in the body that cause inflammation. Ginger has also been shown to influence inflammatory processes.
Foods high in antioxidants and polyphenols – blueberries, apples, leafy greens, fatty fish, nuts, olive oil, tomatoes and green tea – are all touted as inflammation beaters. Coffee may have a friendly role to play, as may dark chocolate. Meanwhile, refined carbohydrates, processed meats, red meat and sugary and high-fat foods are all associated with excess inflammation.
The experts, including Bhatia and Ridker, avoid advising people to mega-dose on any one nutrient. Instead, they recommend the Mediterranean-type diet – or variations of it, such as the Mind or Dash diets. Bhatia promotes “a balanced diet, rich in fibre and good fats like fish and olive oil. Most fruits and vegetables have anti-inflammatory properties. But excessive alcohol is definitely bad, as is too much sugar or salt.”
Diet is not the only lifestyle factor at play. Low physical fitness, poor oral hygiene, smoking and obesity are all linked to higher levels of inflammation. Chronic stress has also been seen to act at a cellular level and have lasting effects.
Adam Moeser, the director of the gastrointestinal stress biology laboratory of Michigan State University, has been investigating how long-term stress may be making us sick. Brief moments of acute stress are not unhealthy, but when stress goes on and on, and keeps activating our immune and nervous systems, never allowing the body to return to its natural balance, problems arise.
“I’m interested in understanding the in-depth biology of the stress response,” says Moeser. “It’s such a common thing for us to be stressed and anxious. We know it’s linked to lots of diseases – allergies, cancers, even pain disorders – but we don’t really understand the mechanism of this important environmental factor.”
Moeser says when we’re under stress, our central nervous system sends out signals to activate the immune cells. Those cells kick in with the inflammatory response that is part of our defence system.
If the stress continues and there is an excessive inflammatory response, the body tries to adapt by shutting down the immune system and we become more susceptible to diseases and viruses.
In a recent study, he focused on mast cells, which play an important role in the immune response and are found in certain parts of the body, such as the skin and the linings of the lungs and stomach.
“These become activated early in the stress response,” says Moeser. “In many stress responses, they’re found to be chronically activated and increased in number. They’re known to release substances that activate a slew of immune cells that cause inflammation. That’s important if you have an infection and need to establish immunity against a pathogen. But if they are over-activated, they become harmful to our body and can lead to inflammatory and allergic diseases, such as irritable bowel syndrome, asthma, life-threatening food allergies and autoimmune disorders such as lupus.”
In asthmatics, stress “feeds the fire”, bringing on severe attacks more quickly, says Moeser. He isolated a particular receptor, CRF1, and found that when it is blocked, the stress response is reduced, which leads to a significant reduction in the disease.
Moeser, who is based in Michigan State’s school of animal science, works with animal models such as mice and pigs. He is particularly interested in the effects of stress during life’s important developmental stages.
Early-life stressors can permanently affect the immune system. How we respond depends on gender: in women, activation of the mast cells in the gut causes gastrointestinal problems, such as leaky gut; men typically become immune-suppressed.
In the future, there may be drugs targeted at specific cell types that will prevent over-activation of the stress response and control inflammation. For now, all we can do is try to find ways of controlling the effect that stress is having on us and calm our central nervous systems.
The ageing risk
But the biggest risk factor for chronic low-grade inflammation is age. As our cells get older, they become less efficient at turning off inflammation when its job is done. As our brains shrink, as our heart function fails, as the incidence increases of age-related diseases, including diabetes and cancer, and as our bodies become stiffer and frailer, inflammation becomes harder to control. Indeed, its role in the ageing process has led to the coining of a new word – inflammaging.
How much we can influence it with lifestyle factors is a question that’s still wide open, but at the University of Auckland, a longitudinal study called LiLACS NZ (for Life and Living in Advanced Age Cohort Study) may go some way to answering it. Starting in 2010, it has been following a group of octogenarians, measuring and recording diet, lifestyle, cognition, activity levels, health status and common blood markers of inflammation. It is early days yet in terms of analysing the data that the study has gathered, but the aim is to discover the main factors that contribute to successful ageing.
Researcher Ruth Teh of the school of population health says part of the problem in older age is that, just as you reach a point when a healthy lifestyle is really crucial, a cascade of events makes it more difficult. For instance, we know that a balanced diet is good, but someone who has lost a partner will be eating alone more frequently and this may mean they don’t get a sufficiently varied diet or even enough food – older people eat 40% more when they eat with others, Teh says.
Elderly people are often unable to exercise or make social connections. They may take many different drugs. Often they don’t sleep well. All of this will contribute in some way to inflammaging.
The LiLACS NZ study measured three markers of inflammation – IL-6 (interleukin 6), TNF-alpha (tumour necrosis factor alpha) and CRP. What to do with the information gained so far is the challenge. There is no point passing it on to the GPs of participants, because there’s no treatment available. And even for researchers, interpreting results poses problems. “We’re not quite sure what they mean and what we can measure from them yet,” says Teh.
Not enough is understood about the whole picture yet. For example, the pro-inflammatory marker IL-6 is produced by the contraction of our muscles when we exercise, but it induces an anti-inflammatory response, so when in balance, it’s beneficial.
Teh is researching community programmes that could help reduce the risk of frailty in the elderly. She is the principal investigator for the Staying UPright and Eating Well Research (Super) study, in which a chef provides cooking and nutrition classes, and Steady As You Go (Saygo), which involves strength and resistance exercises. Rather than addressing inflammation, Teh is sticking with more straightforward measures – grip strength, gait speed, blood pressure, heart rate – that give a clearer picture of health status.
Scientists know for sure that inflammation plays a key role in frailty and a host of age-related conditions. But the more they learn, the more complexity they uncover. So it may be some time before they can tell us exactly what to do about it.
“It’s kind of like solving the Da Vinci code for us,” says Teh.
This article was first published in the April 7, 2018 issue of the New Zealand Listener.
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