Do you have problems with low energy and feeling winded any time you get up off the couch?
Can you feel your heart beat through your chest any time you make the slightest attempt to do anything physically active?
If you notice these things coupled with poor detoxification, easy bruising, and slow wound healing you may be experiencing the anemia of chronic disease. And if you’re waiting around in bed hoping for it to go away you’re going to be very disappointed. In my estimation, physical activity is a critical component of getting your health back.
Physical activity is an underappreciated way to improve health. There are many reasons why physical activity is important for attaining optimal health. There are also mechanisms that show how lack of physical activity can cause poor health. For the most part, most of these mechanisms are due to dysregulation of normal biological processes.
At least three of these processes appear to be dependent on one another:
- Proper bile flow
- Iron homeostasis
- Regulation of inflammation
These processes are linked together through 2 inducible proteins that play a major role in the response to oxidative stress: heme oxygenase-1(HO-1) and inducible nitric oxide synthase(INOS).
In this blog I’ll go over how HO-1 and INOS work together to maintain homeostasis. We’ll also dig in to how physical activity and exercise help regulate their effects.
The heme oxygenases are enzymes that break down free heme in to bilirubin, iron, and carbon monoxide(CO). When red blood cells burst or are catabolized by macrophages in the spleen, heme is released from them.
Free heme is highly toxic to cells so it must be taken care of quickly before it can cause oxidative stress. But the breakdown of heme leaves free iron which can also become toxic. Fortunately, inducing HO-1 also calls upon ferritin to safely shuttle iron to where it’s needed.
There are 3 types of heme oxygenase. Two of them are expressed constitutively meaning they’re always on while the other is inducible. Heme oxygenase 1 is the inducible kind and is induced by many things including free heme, oxidative stress, and nitric oxide(NO).
The heme oxygenases play a role in reducing systemic inflammation via a few routes. Bilirubin, once thought of as a toxic byproduct of heme catabolism, actually functions as a powerful lipid soluble antioxidant if maintained at the appropriate level. Given that bilirubin is sent to the liver where it’s conjugated and released in to bile, it may play an important role in shaping gut health.
The cells that form the intestinal barrier, like all cells, have cell membranes that are entirely composed of lipids. Bilirubin is a fat soluble antioxidant that can repair damage caused to these cell membranes. Through this effect, bilirubin may play a big role in reducing inflammation in the gut.
Staying in the gut, carbon monoxide also has a role in regulating inflammation by increasing bile flow. CO increases bile flow via inhibition of cysteine beta synthase(CBS) activity(1, 2). Proper bile flow is a must for a healthy gut and general health. However, this can be good or bad for certain individuals as it can cause an elevation in homocysteine in those with CBS mutations and polymorphisms along the methylation and choline pathways.
Note: Exercise as well as taurine induce HO-1 and can therefore be problematic for people who don’t take the time to make sure these pathways are working properly. Taurine also directly inhibits CBS activity.
From a gut healing perspective, good bile flow is critically important but other factors need to be addressed before increasing bile flow. If inhibition of CBS is a necessary step in bile flow, people with a CBS mutation may be prone to poor bile flow. In my opinion, the solution is fixing the problem by modifying other factors, not avoiding physical activity which is the more common approach.
CO also has powerful anti-inflammatory effects. Interleukin 10(IL-10) is a known anti-inflammatory cytokine that works by inducing HO-1. The release of CO during heme degradation mediates this process(3).
Heme oxygenase-1 also plays a role in iron regulation. Mice without HO-1 have defective iron homeostasis. Specifically, they experience low blood levels of iron but iron overload in the liver and kidneys(4) due to poor iron recycling. This may be caused, in part, by low ferritin due to deficient HO-1 activation.
Another effect seen in HO-1 deficient mice is chronic inflammation. It certainly makes sense given the above mentioned anti-inflammatory effects of bilirubin and CO. But it actually runs deeper than that, which brings us to INOS.
Inducible nitric oxide synthase
Just like the heme oxygenases, there are 3 forms of the enzyme nitric oxide synthase. And just like the heme oxygenases, there are 2 constitutively expressed forms and an inducible form. For the purposes of this blog, we’ll only be dealing with inducible nitric oxide synthase(INOS).
INOS plays an important role in the immune system by generating nitric oxide(NO). The NO created by INOS is used as an antimicrobial agent to rid the body of pathogenic bacteria(5). As it accumulates, NO induces HO-1 which functions as a brake for INOS. In this way, HO-1 regulates INOS and prevents it from getting out of control.
There’s also a complex interplay between HO-1 and INOS during inflammation that can disrupt iron homeostasis. Most of this comes down to the dependency on both enzymes for heme iron. Ultimately, this interplay can result in something referred to as the anemia of chronic disease.
Iron, Heme oxygenase-1, and inducible nitric oxide synthase
As red blood cells(RBCs) wear out, macrophages begin gobbling them up like Ms. Pac Man. The RBCs are broken down in to globin and free heme which activates HO-1. HO-1 breaks heme in to free iron, bilirubin, and carbon monoxide within the macrophage. Induction of HO-1 also brings ferritin to sequester and shuttle free iron away before it can damage tissues.
When an invader enters the body, macrophages gobble them up as well which triggers the induction of INOS. This creates NO to use as firepower against the bad guy, but it also causes the macrophage to shed its stored iron(6). Since pathogens are dependent on iron for growth, this helps weaken the bad guy for removal.
As NO accumulates, it induces HO-1 which shuts off INOS. This helps prevent excessive collateral damage from too much nitric oxide. However, during chronic inflammation, this process doesn’t work well. This causes something called the anemia of chronic disease.
In the anemia of chronic disease, blood levels of iron are low while tissues concentrations are either normal or high, just like the HO-1 deficient mouse. Since heme requires iron for synthesis, it’s not unreasonable to think that the anemia of chronic disease could eventually cause poor induction of HO-1.
HO-1, INOS, and the anemia of chronic disease
Recall that HO-1 is induced by free heme from the break down of red blood cells. During the course of chronic inflammation, red blood cell production decreases while white blood cell production increases. This is because both are formed from the same stem cells in bone marrow and the invader needs to be dealt with more than you need more red blood cells.
This decrease in red blood cells has a negative effect on both HO-1 activity and iron levels. Fewer red blood cells floating around the circulation leaves less heme to be processed by HO-1 which means bilirubin, iron and carbon monoxide will also be released in lower quantities.
This could have a negative impact on the regulation of INOS by HO-1. It would also impair bile flow, delay wound healing, and mess up the gut.
During the anemia of chronic disease, chronic inflammation throws iron regulation out the door. As a result, serum levels of iron are depressed while the liver and kidney may become overloaded with iron.
Nowhere does this scenario play out more accurately than in Type 2 diabetes(7). People with Type 2 diabetes have lower plasma hemoglobin levels, lower HO-1 activity(8), and are prone to the anemia of chronic disease.
This is actually quite simple. Heme and iron are breakdown products of hemoglobin and being sedentary leads to lower hemoglobin levels(More on this in a bit). Less hemoglobin means less heme to stimulate HO-1 and lower iron storage in red blood cells to make heme proteins for other things like carrying oxygen, detoxification, and fighting bad guys.
While HO-1 is increased in newly diagnosed Type 2 diabetics(9), it’s levels decrease as the disease progresses(10, 11). This means that HO-1 can’t block INOS activity which will lead to chronic inflammation. While this phenomenon hasn’t been studied in depth, it makes sense that this drop in HO-1 activity may be a direct result of the anemia of chronic disease while promoting it at the same time.
Exercise: Hedging your bets against chronic inflammation
Exercise has been shown in numerous studies to have potent anti-inflammatory effects and is protective against chronic disease. Exercise at the appropriate intensity and volume acts as a mild stressor to the body. The body responds by, among other things, increasing HO-1 activity after a bout of cardiovascular exercise(12).
Cardiovascular exercise also has other beneficial effects that may improve HO-1 activity over the long run. During long term adaptation to cardiovascular exercise, the body increases its ability to carry and use oxygen by increasing heme proteins. One of the chronic responses to endurance exercise is an increase in blood hemoglobin(13, 14) and myoglobin(15).
This increase in hemoglobin may be responsible for the increased bile flow seen in people who regularly perform cardiovascular exercise. More heme as an adaptive response to cardiovascular exercise coupled with enhanced heme breakdown due to oxidative stress increases carbon monoxide which will have a beneficial effect on bile flow.
More heme proteins not only helps to make heme available for HO-1, it also increases the body’s stores of iron. Over 70% of the body’s iron stores are contained in hemoglobin, and having a little extra stored in a safe place for when it’s needed is great.
Iron is how we store, carry and utilize oxygen for energy: Without it none of those processes can occur. When inflammation causes a drop in red blood cell production, this impairs your ability to carry and use oxygen which causes fatigue.
The heme iron stored in hemoglobin and myoglobin may act as a sort of functional reserve for when infection sets in. INOS is also a heme protein and dependent on adequate heme iron to produce nitric oxide to fight pathogens. The cytochrome p450 enzymes that handle phase I detoxification are also heme proteins. Basically, with too little heme, you’re effectively screwed.
Both HO-1 and INOS are important players in the way the body deals with stress. HO-1 responds to oxidative stress by breaking down hemoglobin in to important players in maintaining redox balance.
INOS, on the other hand, functions as a weapon against foreign invaders. Both enzymes are dependent on adequate iron and one another to maintain homeostasis.
The nitric oxide created by INOS is great at taking down bacteria that are trying to gain a foothold in the body, but it’s also damaging to our tissues. HO-1 functions as a sort of brake on INOS, preventing it from getting out of hand and causing collateral damage to our own tissues.
Ideally, an adequate amount of heme should be available to help stimulate HO-1. One of the chronic adaptations to cardiovascular exercise is an increase in hemoglobin and myoglobin. Over 70% of the body’s iron stores are found in hemoglobin, so this adaptation likely provides a functional reserve in case of attack from a foreign invader.
In the anemia of chronic disease, this whole relationship is thrown out of balance. Without adequate iron, HO-1 can’t put the brakes on INOS and inflammation continues unabated. Eventually, this leads to lower heme which reduces HO-1 activity.
Over the long run, this will lead to low serum iron levels but iron overload in the liver and kidney. This is actually a feature of the anemia of chronic disease which brings up 2 questions. Is the anemia of chronic disease simply HO-1 deficiency and can you improve it without physical activity?
One of the primary factors keeping people who experience the anemia of chronic disease down is that they feel drained all day. Given irons role in transporting and utilizing oxygen for energy, it’s no surprise that the symptoms of anemia include fatigue, shortness of breath, and rapid heart rate. These are simply adaptations to low oxygen availability due to a lack of heme iron.
Physical activity has been a requirement for the vast majority of human history. Given the number of beneficial effects attributed to exercise as well as the numerous chronic conditions associated with not getting enough, it may be time to view exercise “recommendations” as minimum requirements for health.