Welcome to Science with Shrike! This week we’re going to dive deeper into aging, and what happens to your body. In order to do that, I’ll give a high-level overview of inflammation and cellular function. I’m going to simplify immunology, and try to build from here. Since immunology is complex, there’s almost always an exception. As I build out the framework, though, you will see why certain exceptions are exceptions rather than rules.
Please remember that this commentary is not medical advice and that Shrike is a scientist, not a physician. Now let’s talk about inflammatory mechanisms.
Intro to Immunology
The immune system is one aspect of our body that we simultaneously can live without, but also can’t live without. People with severe immune defects can live normal lifespans… …as long as other organisms and pathogens don’t kill and eat them first. So-called “Bubble babies” are one example of immunodeficient people. Usually they lack “adaptive” immunity (= T and B cells) so they have problems getting rid of pathogens. People with other diseases, like Chronic Granulomatous Disease, lack working parts of “innate” immunity (in this case neutrophil function), so lots of other organisms (not just pathogens) can colonize and grow in them.
Broadly, the immune system divides into two parts: adaptive and innate. The innate system is your hard-wired defenses against pathogens. Bacteria and fungi look and act differently than human cells, so your innate immune system has learned how to recognize and target those differences. To catch pathogens that can hide, your innate system also monitors your body for danger signs. Danger signs are cellular signals that there’s a problem. For example, DNA is restricted to nuclei and mitochondria in normally growing cells. DNA buildup in your blood is a sign something is wrong, so your immune system attacks. DNA in the cytoplasm is a sign of bacteria or viruses growing, so your immune system attacks. DNA in circulation and in the cytoplasm is a danger sign—even if the immune system can’t find the pathogen, it knows there is a problem and responds. So the innate system is ‘innate’ because it targets specific signs of infection or danger.
The adaptive system helps coordinate the innate response and finish off the pathogen. While the innate system (and physical and chemical barriers in your body) clears out the vast majority of unwanted bacteria and pathogens, pathogens have come up with ways to get around the innate system. This is where the adaptive immune system comes in. The adaptive system specifically targets each pathogen (or in some cases toxic substances) and tries to destroy it utterly. To do so, it does three things differently from the innate system: target one specific, custom aspect of the pathogen (called an antigen), raise an army of clone warriors that all recognize the same antigen, and remember that antigen long after the original pathogen is gone (‘memory’). Without the adaptive system, pathogens are able to evade innate immunity, and then it’s game over for the host.
The innate and adaptive immune systems work together in 3 broad steps: “Recognize, Respond, Resolve”. Recognition is the stage where pathogens (or danger) is sensed. Innate immune cells use a variety of receptors for this. Most relevant to this discussion is the fact that these receptors will sense “danger” and other problems just as easily as they recognize pathogens. Adaptive cells recognize pathogens by matching their custom antigen-targeting receptor to pathogen parts shown to them by other cells.
Response will be one main focus for today. This is the inflammation. Not all inflammation is equal, both in terms of type and in terms of duration. In the short term, inflammation is vital for survival and prolongs life. In the long-term, inflammation kills. This long-term, chronic inflammation is one of the main enemies for aging. Inflammation comes in many different flavors and forms, and is often triggered by small immune defense proteins called ‘cytokines’. These help the body determine what kind of inflammatory response to mount. ‘Is there inflammation’ is step one, but ‘what kind of inflammation’ is step two. Along with inflammation, the response stage includes immune cells murdering infected cells, eating pathogens, destroying connective tissue, triggering mucus clearance (think coughing, runny nose, diarrhea), activating adaptive cells, recruiting blood vessels, and promoting cell division/regrowth. These are all focused on removing the danger.
Resolution is the other key focus for today. This is the body returning to homeostasis. Successful resolution, along with successfully clearing the pathogen, are two key differences between chronic inflammation and acute inflammation. The following tasks need to be completed: shut down the immune response, eliminate the clone army of adaptive cells, remember the pathogen for next time, and repair all of the collateral damage. Promoting resolution is one area with a lot of promise for dealing with chronic inflammation. However, this stage is the enemy when it comes to cancer. The trade-offs are apparent with Yervoy (ipilimumab). Yervoy targets one shut-off for the adaptive immune system. It’s approved for melanoma, but a subset of patients die from the subsequent autoimmunity that can be unleashed. The lesson from Yervoy is that broad-strokes aimed at response or resolution carry significant side-effects, so a more nuanced approach to treating diseases will be necessary.
When recognizing and responding to pathogens, the immune system uses three threat response modes, based on the type of threat the body faces. Pathogens fall into 3 broad categories: pathogens (viruses/bacteria/fungi/protozoa) that invade cells and live/replicate inside of them, smaller pathogens (bacteria/fungi/protozoa) that prefer to live outside of cells and never go in, and finally large pathogens (worms) that damage our tissue as they adventure through our tissues. Each of these threats requires a different immune response to eliminate the pathogen. For example, hunting intracellular pathogens and destroying host cells isn’t going to help against pathogens that avoid entering host cells. Conversely, stimulating tissue repair and mucus clearance will not help remove pathogens living inside cells. What this means is that the immune system has to decide what kind of threat it is facing, engage the appropriate module and shut off the other modules. These modules are primarily defined by the type of adaptive (T cell) response engaged, and are named by the T helper (Th) cell subset engaged. Intracellular immunity is driven by a Th1 response, anti-worm immunity is driven by a Th2 response, extracellular bacteria driven by a Th17 response and resolution is driven by a Treg response. Each threat response module marshals different sets of immune cells while telling some common ones how to act. For example, Th17 cells work closely with neutrophils, and Th2 cells work with basophils and mast cells. However, all T helper cells tell macrophages what to do. Excessive activation of any module causes problems: too much Th1/Th17 drives autoimmunity, too much Th2 causes allergy/asthma, and too much Treg enables cancers/pathogen spread.
This schematic of T cell polarization shows the cytokines (IL, TGF, IFN) used to polarize T cells to the correct threat module after they are turned on (ie polarized) by “antigen-presenting cells”, show what cytokines they make, and what threats they target.
To connect back to last week’s post, your lungs are programmed to promote a Th2 response, which clears worms. Viruses need a Th1 response (target intracellular pathogens) to clear. When your lungs mistakenly promote an immune response to dust mites or pollen, you are developing an aberrant Th2 response, which you feel as mucus clearance and swelling.
As the lung example shows, the immune system changes depending on the tissue in which it is responding. Your gut contains more microbes than the rest of your body contains human cells. Most of these are beneficial, so the immune system needs to keep an eye on them, but not overreact. Your gut, skin, and muscle all regenerate way, way better than neurons in your central nervous system. As a result, it is really important to limit collateral damage in certain parts of the body, especially the brain, the eyes, the gonads, and the fetus during pregnancy. The need to avoid collateral damage is called “immune privilege". This means when a pathogen invades these areas, it is harder to clear, which can lead to chronic inflammation.
To summarize so far:
Two arms of the immune response: innate and adaptive immunity
Innate immune cells broadly recognize problems (pathogens or danger)
Adaptive immune cells target one specific aspect of a pathogen, raise a clone army and remember that aspect
Immunity can be broken down into 3 stages: Recognize, Respond and Resolve
The immune system uses different threat modules to counter different pathogens
The immune system limits responses in in high value parts of the body to avoid collateral damage
When the immune system screws up, anything from chronic inflammation to death can result
The immune system in the elderly
Now that we know the broad strokes of the immune responses, we can consider the long-term problems that develop with aging. There are two main issues: loss of immune function with age, and build-up of chronic inflammation. As you age, your immune system becomes less effective. You lose immunologic memory, and you mount poorer adaptive immune responses to threats. Two examples highlight this: first, fatal brain infections that are more prevalent in the elderly. The brain is immune privileged to begin with, and the weaker immune response gives pathogens like Listeria time to invade the brain. Second, vaccine efficacy is often reduced in the elderly (usually defined here as 60+). This is best studied with flu shots, where it can be ~60% ineffective even when the flu strain is correctly matched.
The immune system does not fail all at once. Certain parts become less effective, so other parts of the immune system step up their game to try keeping you alive. However, this can lead to excessive inflammation, and illustrates one paradox of chronic inflammation: sometimes chronic inflammation is due to an inadequate immune response rather than too vigorous of a response. Inflammation tries to clear the problem, calls in inadequate adaptive help, fails to clear the problem, and then more inflammation is tried and the process is repeated. This leads to a vicious feedback loop that drives chronic inflammation.
Aside from research into new ways to stimulate the elderly immune system, this suggests you should be more responsible when you are elderly. Aggressively deal with ills and problems while they are small so that they do not become larger problems. Know your body, and recognize when things are out of sorts. Assuming it will ‘just go away’ carries higher risk as you age.
The other big immune health risk in the elderly is “inflammageing”. Inflammageing was a term coined in 2000 to describe and underscore the long-term, low grade, chronic inflammation that leads to several aging phenotypes. Older people accumulate more pro-inflammatory markers in their blood. There are many ways this can happen, and some of these methods are still controversial.
First, there are some genetic predispositions, especially in pro-inflammatory cytokine genes. There’s not much you can do about these. We also have associations, but it’s unclear if these are markers or actually causative.
Second, obesity drives inflammation in many ways. You can fix this one. Exercise and diet. A poor diet also changes your gut bacteria, while calorie restriction is associated with beneficial changes in your gut bacteria.
Third, chronic viral diseases can become problematic. While HIV is one culprit, the one with more potential to cause you problems is cytomegalovirus (CMV). There is ~50% chance that you had CMV, because this is a normally-harmless herpesvirus that you don’t notice, and is spread in bodily fluids including saliva and urine. In AIDS patients and newborns, CMV is debilitating and potentially lethal. This is why your blood is tested for CMV after you donate—if it is negative, it can be given to newborns. If positive, it only goes to immunocompetent people. The hypothesis (this is still controversial) is that CMV drives “cell senescence”. Cell senescence is when cells become old and useless instead of becoming cancerous. On the plus side, no cancer. On the downside, these cells also secrete pro-inflammatory cytokines which can get into your circulation. Cells can become senescent for reasons other than viral infection, so senescence is another potentially contributor to inflammageing.
The continual inflammation is associated with many of the killers we discussed last week. Alzheimer’s, dementia, and even depression, are associated with chronic inflammation. Inflammation can drive insulin resistance, and cardiovascular diseases. Frailty is also associated with chronic inflammation.
Cancer, too, is associated with inflammation. Sometimes it is called “the wound that will not heal” due to similarities between cancer and wound repair. The chronic inflammation in cancer is incredibly immunosuppressive, which is one reason immunotherapies still have had limited success. This also suggests that chronic inflammation includes immune dysfunction, and improving immune function may help clear inflammation. On the other hand, unrestricted cell growth is cancer, and it’s no accident certain cell types are more prone to cancer than others.
Overall, these associations suggest that managing inflammation is one major aspect of dealing with aging. Some drugs, like metformin, aspirin and rapamycin, improve lifespan in animal models (but note that mice—the most common mammalian model—live up to 2 years, not 100+). Metformin and aspirin show a lot of promise in human trials for many of these diseases of old age. However, other attempts to block inflammation, like blocking the pro-inflammatory cytokine TNFα—worsened heart failure. This suggests that pro-inflammatory cytokines help immune cells respond, but also help lay the foundation for resolution. Other drugs may specifically promote immune resolution, like the resolvins. Resolvins are derived from Omega-3 fatty acids, and help reduce inflammation by promoting a return to homeostasis. Killing old and lazy senescent cells reduces inflammatory phenotypes in some models, suggesting removing these cells may be one approach to reducing aging impacts.
The main takeaway is to manage chronic inflammation early. The best way to do this is “calorie restriction and physical activity” aka diet and exercise. However, to progress beyond these approaches, we still need to figure out which immune responses and resolution steps we need to improve, and how to hedge against cancer.