Inflammation Is Misunderstood by the Public — And Scientists
Vishwa Deep Dixit is a professor of comparative medicine and immunobiology at Yale’s School of Medicine. Dixit and eight other students, postdoctoral fellows, and professors study the intersection between the immune system and metabolism at Dixit Lab.
We all know inflammation: the painful red swelling that happens when we are injured or a wound becomes infected. But why would a Yale scientist interested in the mechanisms of aging and age-related disease be leading a lab researching such a thing?
Turns out there’s a lot more to the condition than most people realize. “‘Inflammation’ is not just a word not understood properly by the lay public, it’s often not properly understood by scientists,” said Vishwa Deep Dixit, a professor of comparative medicine and immunobiology at Yale’s School of Medicine. Dixit and eight other students, postdoctoral fellows, and professors study the intersection between the immune system and metabolism at Dixit Lab. Their focus is not these signs of “classic” inflammation, like redness, swelling, pain, and loss of function. Instead, they believe a different, underlying condition, “low-grade chronic inflammation,” is part of a wider immune system process linked to aging and age-related diseases. By studying the connections between inflammation and other bodily systems, like metabolism and the immune system, they hope to help humans live longer. We asked Dixit about his lab’s work, the future of immunobiological research, and the potential for effective interventions in human health.
How would you describe the work your lab does to a non-scientist?
When I tell people that I work on the connection between the immune system and metabolism, they often struggle. Everyone understands that the immune system protects us against pathogens and infections. But what we are trying to understand better is that the immune system has multiple functions. Defense against viruses and pathogens is just one of those. The immune system is also critical for maintenance, and repair, for instance in specific immune cells like the macrophage, which is critical in maintaining function in every organ in the body.
And this does not happen in a vacuum. The immune system requires energy, specifically ATP, which comes from the glucose and fats we consume. That energy comes from metabolic activity in the body. So these two systems talk to each other. This communication is very important, and we’re beginning to understand that diseases that were previously thought to be metabolic diseases manifest as metabolic, but have a strong immune system component. When the communication between metabolism and the immune system does not go properly, we are prone to get several diseases, and those diseases are related to aging.
We are also interested in immunometabolic systems because, from the perspective of aging, almost every lifespan-extending intervention is metabolic in nature. Caloric restriction, for example, extends lifespan in almost every species. And lifespan extension from those metabolic interventions is intimately linked to the immune system. When the immune system is getting the right input from metabolism, immune cells are able to perform their functions in a much better way, and so that person is able to function for a longer period of time.
How is the work you do novel? Where does it fit into the context of immunometabolic research?
I think the novelty really is the surprising information we are finding these days — for example, this idea that the metabolic systems and immune systems talk to each other. We’ve found that certain metabolites that are produced depending on how your body uses its fuel have a major impact on the immune system. We’ve found that a certain ketone metabolite that fuels the brain actually also dampens inflammatory responses by blocking what’s called the macrophage pathway, and the NLRP3 inflammasome. We never thought the body could act in this way.
Our discoveries have to do with the specific pathways between inflammation and disease. The question has always been, if inflammation causes all of these age-related diseases, well, there are lots of anti-inflammatory drugs on the shelf of your local pharmacy. We ought to be able to take those and not get old, and not get diseases, which isn’t the case. The problem is inflammation is a very broad term. Within the phenomena, we’re finding very specific pathways, and within those we’ve found that there is not only an association but a causal link between specific inflammatory pathways and diseases of aging. For instance, this complex called the NLRP3 inflammasome. It’s found in every macrophage in all human organs. If we lower the activity of this inflammation-producing mechanism, at least in mice, we find they are protected from many aging disorders like bone loss and diabetes. In the elderly, we’ve found that lowering the activity of this pathway improves metabolism. These are the kind of new findings that are linking the very disparate fields of metabolism and the immune system and even the nervous system, since we recently discovered very special macrophages that hug the nerves in the periphery of the brain. Activity in those macrophages can actually impair the functioning of the nervous system.
How do you think about fundamental biology versus clinical translation, and how has your lab contributed to both?
Our first question is to understand the fundamental biology that’s going on. How is an immune cell talking to the metabolic system? If a macrophage is producing inflammation, how? What is this immune cell sensing?
That is the first goal. And while pursuing those mechanisms and studying inflammation, the implications of finding those answers are obvious. For many inflammatory diseases, we don’t have good drugs to treat them. Instead of looking directly at a particular disease, we are right now more interested in studying the basic mechanisms of how inflammation is produced in the context of aging.
Now that we have found the NLRP3 inflammasome as a major target that produces inflammation in aging, and that we can inhibit this inflammasome, there are potential approaches we can take — through diet, for example. By reducing caloric intake, or using a ketogenic diet, there is a high likelihood that you can lower the activity of the inflammasome. And right now there are drug companies in the process of making inhibitors of the NLRP3 inflammasome. Once they’re tested to see if they’re safe, and to make sure they do reduce inflammation, we’ll see whether they will be an effective treatment against certain diseases of aging.
Given your work, what do you think is possible from the standpoint of biological intervention?
I’m extremely optimistic about this, because we have things in the pipeline that are really exciting. We think there’s a good future for us as far as the biology of aging is concerned. I can’t talk about it yet, but we have results that will publish soon about targeting age-related diseases. We have discovered certain metabolites and proteins that are induced by restricting calories in humans. Participants reduced their caloric intake, and then we identified pathways that are induced by that that we could harness. We’ve studied these pathways for the past five years, and they appear to have positive health benefits. The data shows that some of them are effective in blocking inflammation, and impact lifespan by prolonging lifespan and disease-free lifespan. That being said, dietary interventions are hard to do, and not everyone can do them.
The question is, if you reduce calories, why would you live longer? What the body seems to be doing in that state is basically upregulating all the homeostatic pathways that are critical for maintenance. We are trying to harness these protective pathways that exist within us, and to understand how those pathways and molecules act on these systems, so that we can create a new generation of drugs that could be beneficial not only to aging and age-related diseases, but also in acting against acute inflammatory diseases.
In terms of your lab’s focus, what’s the most important unanswered question?
That’s a very difficult question, because there is no such thing as a single most important unanswered question. We’re dealing with multiple questions, and the important thing is to recognized the problem: that aging is a major risk factor for all chronic diseases. There must be something intrinsic in the biology of aging that disturbs the immune system in such a way that it triggers the activation of those diseases. That is really intriguing. How is the immune system so central to good health, but also to diseases? We are excited by new approaches that we think could have a future in terms of regulating the immune system in order to regulate aging.
Recent Studies from the Dixit Lab
Dixit and his team linked immune-system cells called macrophages to the NLRP3 inflammasome pathway and the sympathetic nervous system. Targeting the signalling between all three can mitigate chronic inflammation, and functional decline, in mice.
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Prolongevity hormone FGF121 protects against immune senescence by delaying age-related thymus involution.
FGF21, a hormone produced when starving, burns fats — and producing it in excess also extended the lives of mice by close to 40 percent. Dixit and collaborators at University of Texas Southwestern found that the hormone maintained the health of the immune system in particular.
Liver-derived metabolic hormone fibroblast growth factor 21 (FGF21) improves insulin sensitivity and extends lifespan…www.pnas.org
The NLRP3 pathway was found to control the type of low-grade inflammation related to aging in elderly people; Dixit and his team explored the mechanisms of the pathway.