When you think about things that you can’t live without, your iPhone or the internet may top the list :-) But really, oxygen tops all of our ‘can’t live without it’ lists. A minute without it will remind you of just how important it is to every cell in your body.
Have you ever wondered, though, how your cells can survive for a few minutes without oxygen — or how your body manages when oxygen levels are lower than normal? It turns out that we have an innate system that detects when oxygen levels are low and turns on other genes that can help cells survive when precious O2 is not readily available.
The Nobel Prize in medicine has just been awarded to three scientists who discovered how cells manage oxygen and know when levels are low. This article covers one piece in this O2 puzzle that they figured out and delves into some of the genetic variants involved in this process.
The hypoxia-inducible factor-1 alpha (HIF1A) gene codes for a transcription factor, which regulates the rate at which certain other genes get transcribed.
So what is a transcription factor, and why is HIF-1a so important?
Genes code for proteins; your cells need to know which genes need to be translated into the proteins needed at that instance. Basically, a transcription factor is like a switch that can turn on or off the transcription of genes. There are a couple of thousand different transcription factors in the human genome.
HIF-1a (hypoxia-inducible factor-1 alpha) responds to the amount of oxygen available to the cell. Hypoxia refers to a state where there isn’t enough oxygen available.
Thus when there isn’t enough oxygen available at a cellular level, the HIF-1a transcription factor can change the transcription rate for the genes that code for proteins involved in oxygen and glucose transport. It switches on the genes needed for resolving the problems of low oxygen.
When oxygen levels are low (hypoxia), cells and tissues need to respond quickly. Oxygen is normally used in the process that cells use to make energy or ATP. (Yes, your cells have a backup route of anaerobic glycolysis which works without oxygen, but this isn’t as efficient for making ATP.)
Thus, when oxygen levels drop, the HIF-1a levels rise, kicking off a bunch of processes.
One way that HIF-1a helps your body respond to the lack of oxygen is by stimulating the growth of more blood vessels. It also stimulates the production of red blood cells by increasing erythropoietin (EPO) expression.
The first thing that comes to mind with low oxygen levels may be high altitudes. As you go up a mountain in Colorado – or in the Himalayas – oxygen levels decrease. Anyone who has flown out to Colorado to ski at Breckenridge (or worse, A-basin), knows how bad you can feel if you don’t take the time to adjust more slowly to the altitude. (Spend that first night in Denver. Seriously… it takes time to adjust.)
Another way that oxygen levels can drop in your body is during aerobic exercise. You know… like when it is New Years’ Day and you decided to join the gym and run on the treadmill — for the first time in a year. Your muscles are suddenly using up the oxygen faster than you can suck it in, leaving you gasping and feeling like you’re going to die.
On a cellular or tissue level, hypoxia can occur in a number of situations. First, inflammation can cause hypoxia in a specific area of the body. For example, a joint that is inflamed due to arthritis will have a low supply of oxygen. Other conditions that cause hypoxia include heart disease, stroke, and kidney disease. HIF-1a levels are increased in all of these chronic inflammatory conditions. [ref] [ref][ref]
Cancer cells grow really rapid and need a lot of oxygen. Thus, they need more blood vessels to bring in the O2 and they need nutrients.
HIF-1a is often upregulated or increased in cancer and helps to promote the growth of tumors by creating more blood vessels to bring in the oxygen. It is sometimes tested as a marker to predict the aggressiveness of the tumor.
Getting more specific, one study showed that HIF-1a is increased in >90% of colon, lung, and prostate cancers. In addition to causing an increase in blood vessel formation (angiogenesis) to carry oxygen to the tumors, HIF-1a also decreases a cell’s DNA repair mechanism. This increases the rate of mutation in a cell, which is a big problem in tumor cells. Additionally, HIF-1a increases glucose transport, thus providing more energy to the cancer cells. [ref][ref]
When you have a normal amount of oxygen available, known as normoxia, the HIF1a protein is still produced in cells, but it is constantly being degraded by prolyl hydroxylases (PHDs). These PHDs are oxygen sensors, altering HIF-1a and degrading it when there is plenty of oxygen present in the cell. [ref]
Researchers have recently developed ways of inhibiting PHDs, thus allowing HIF-1A to be upregulated under normal oxygen conditions. These PHD (prolyl hydroxylase) inhibitors may be used for regenerating damaged tissue (increased blood vessel formation) or for treating specific types of anemia (stimulates red blood cell production).
The flip side of encouraging HIF-1a under normoxia is that you really don’t want to encourage cancer growth. So these PHD inhibitors are only used in specific conditions.
In addition to being activated by hypoxia, HIF-1a can also be activated by cytokines, growth factors, hormones, and cancer genes. For example, the growth factor IGF-1 can increase HIF1a. Estrogen can also increase HIF-1a, such as in the thickening of the endometrium each month for premenopausal women.[ref][ref][ref]
Interestingly, tamoxifen, which is used to treat estrogen-positive breast cancer, works in part by reducing HIF-1a levels.[ref]
Cytokines are inflammatory molecules that the body produces as part of the immune response. They are signals to increase inflammation. Specifically, the cytokine TNF-alpha causes an increase in HIF-1a. [ref] This is one connection between inflammatory conditions, such as arthritis or atherosclerosis, and higher HIF-1a levels. [ref]
The HIF1A gene codes for HIF-1a.
There are two really well studies HIF1A genetic variants that generally increase the amount of HIF-1a that is available in cells. As you might imagine, this may increase the risk of cancer. On the other hand, it is associated with advantages in athletic training and decreased risk of certain inflammatory conditions.
Check your genetic data for rs11549465 Pro582Ser (23andMe v4, v5; AncestryDNA):
Check your genetic data for rs11549467 Ala588Thr (23andMe v4, v5; AncestryDNA):
In contrast to the above variants that increase HIF1a activity, some genetic variants decrease activity a little.
Check your genetic data for rs2057482 (23andMe v5; AncestryDNA):
There are natural ways to both inhibit HIF1a and increase HIF1a. I’m listing both here – you can decide which way is best for your body right now. Another reason for listing both is that if you are trying to increase HIF1a, you may not want to take an inhibitor of HIF1a at the same time. For example, if you are taking resveratrol (inhibitor) while also trying to increase HIF1a through Wim Hof breathing, you may not get the expected benefits. Space them out :-)
Intermittently raising HIF1a may have benefits for your body. Just like exercise causes stress on the body at the moment, the benefits afterward outweigh the short-term stress on the body. Similarly, intermittently raising HIF-1a levels could be of benefit in certain situations.
Just like it sounds, intermittent hypoxia is when you subject your body to low oxygen levels for a period of time (usually minutes) and then go back to either normal oxygen or added oxygen (hyperoxia).
Intermittent hypoxia has been shown to reduce fasting blood glucose levels and decrease LDL cholesterol in people with prediabetes. The study used patients who were middle-aged and older and subjected them to sessions of four cycles of 5 minutes of hypoxia followed by either normal oxygen or hyperoxia. [ref]
Intermittent hypoxia is also being used for recovery after spinal injury. [ref] It has been shown to lower cholesterol levels, decrease depression (animal study), and increase neurogenesis. [ref][ref][ref]
There is a saying for athletes, ‘live high, train low’, which uses the idea that changes in altitude and oxygen levels will affect performance. This is based on the changes in HIF-1a which causes an increase in EPO and red blood cells. Research does show that changing the oxygen content of the air – either through intermittent hypoxia or continuous hypoxia – can increase red blood cell production. [ref]
Timing and dose are vital with intermittent hypoxia therapy. Chronic intermittent hypoxia at night is called sleep apnea and has many negative consequences. In fact, sleep apnea is a risk factor for diabetes, obesity, and cardiovascular disease. [ref][ref] So while a little intermittent hypoxia can be a good thing, chronic hypoxia every single night is bad.
So how can you do intermittent hypoxia therapy? There are athletic training facilities with expensive equipment to do it. And there are YouTube videos that have some odd DIY ideas. I’ll let you discover it on your own.
The Wim Hof method of breathwork uses a hyperventilation phase (increased oxygen) and a then a hypoventilation phase where you hold your breath. The hypoventilation phase should cause hypoxia and raise HIF1a.
Noopept is a nootropic peptide that has been around for a few decades. Surprisingly (to me), noopept increases the DNA binding activity of HIF-1, possibly through the inhibition of PHD. [ref]
Heavy menstrual bleeding:
A recent study showed that women with heavy menstrual bleeding have lower levels of endometrial HIF1a during their periods. HIF1a is thought to increase the rate of endometrial repair, and thus low levels of HIF1a cause more and longer bleeding.[ref] Theoretically, increasing hypoxia and increasing HIF-1a in the uterus should shorten menstrual bleeding.
Hyperbaric oxygen therapy:
Many wellness clinics now offer hyperbaric oxygen therapy as a way of increasing the oxygen levels in your body. Basically, you lie down in a pressurized chamber that contains 90 – 95% oxygen. It is often used for wound repair.
Hyperbaric oxygen therapy has been shown to increase HIF1a in wound healing.[ref] But it has also been shown to decrease HIF1a in chronic, inflammatory driven conditions. [ref] Why the two opposite effects? One study explains that the ‘hyperoxia-hypoxia paradox’ from hyperbaric oxygen therapy is that repeated hyperoxia increases reactive oxygen species in the cell. This, in turn, activates anti-oxidant defense systems in the cell as well as increasing HIF-1a. [ref]
The effects of hyperbaric oxygen therapy in either inducing or decreasing HIF-1a may then depend on whether you have a chronic, inflammatory condition or not.
In chronic disease states, it may be beneficial to decrease HIF-1a if it is elevated due to inflammation.
Apigenin is a plant flavone that is found in many different fruits and vegetables at low levels. Plants that are highest in apigenin include parsley, celery, and chamomile tea. It has been shown to inhibit HIF-1a and has been shown to have anti-tumor activity. [ref]
Nicotinamide riboside or NMN:
Low NAD+ levels cause an increase in HIF-1a due to mitochondrial stress. Increasing NAD+ through NMN or NR may decrease HIF-1a if it is elevated due to mitochondrial stress. [ref][ref]
Here is a good video on how chronic hypoxia causes cellular energy.
If you aren’t familiar with Wim Hof, here is a good intro video: