Adenosine is a natural chemical found ubiquitously in every cell of the human body. And it’s an important one: it induces sleep, it controls the circadian rhythm and fine-tunes neurotransmitter levels. In this article, we explore adenosine’s importance to health, factors that increase adenosine, and how the so-called adenosinergic pathway impacts health.
What Is Adenosine?
Adenosine is an endogenous nucleoside found in every cell of the body. One of its key roles is to control the sleep-wake cycle. It has a number of other physiological functions, including improving blood flow, protecting the heart, nerves, and other body parts from damage and disease, as well as balancing immune function [1, 2, 3, 4, 5, 6, 7, 8].
Adenosine is sometimes referred to as a “master regulator” because it is involved in such a wide range of activities in the body [9].
It is also used as a drug, primarily to treat irregular heartbeat (arrhythmias), in addition to pain and high blood pressure in the lungs (pulmonary hypertension) [10, 11, 12].
Owing to these diverse activities, it has critical effects on health and disease. Therefore, researchers have been exploring potential adenosine-receptor-based therapies to treat many different health problems such as infection, autoimmunity, and degenerative diseases since the 1960s [7, 13, 14, 15].
Adenosine: The Good
- Enables deep sleep and controls the sleep-wake cycle
- Balances immune responses and brain function
- Prevents excessive inflammation
- Lowers blood pressure
If you’re more interested in adenosine imbalances, their health consequences, and how to lower excessive adenosine activity and levels (especially if you’re constantly tired), take a look at this article.
Adenosine Metabolism
As a nucleoside, adenosine is made of an adenine base (a purine) attached to a sugar molecule (ribose).
It is formed either inside or on the surface of cells via the breakdown of nucleotides (the basic building blocks of DNA and RNA) or adenine phosphates: energy-rich adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP). Under normal conditions, adenosine is created from AMP (by the eventual breakdown of ATP) [16, 17, 18].
Adenosine triphosphate or ATP is known as the body’s “energy currency.” As ATP (energy) decreases, adenosine increases and tells the body to start conserving energy. In other words, adenosine builds up as the body uses up its energy reserves [19, 20].
Adenosine acts quickly and is rapidly broken down afterward. When administered intravenously, it has a half-life of around 10 seconds in human blood. Two enzymes break down adenosine [21, 22]:
- Adenosine kinase (ADK)
- Adenosine deaminase (ADA)
Under normal conditions, adenosine is primarily broken down by ADK, which maintains the relatively low levels of adenosine required by the body on a daily basis [9, 23].
ADK breaks adenosine down by to AMP, reducing its levels inside cells. A lack of ADK increases adenosine inside cells and has been associated with diabetes, epilepsy, and cancer. ADK gene mutations cause ADK deficiency, brain damage, and liver failure [9, 24].
Meanwhile, ADA is activated when adenosine levels become excessive. It converts adenosine to inosine, which in turn signals to the body to stop producing adenosine [9].
This process is extremely important because adenosine is required to regulate the immune system and prevent excessive immune reactivity and inflammation [25].
What Does Adenosine Do?
Adenosine and its receptors are involved in a wide variety of functions, including those of the circadian rhythm and the immune system [1, 2, 25].
This chemical also helps balance blood sugar levels, reduces inflammation and fat production, prevents insulin resistance, and controls body temperature and energy use. Its balanced levels and activity may help prevent diabetes and obesity [26, 27, 28, 29].
One of the most important functions of adenosine is sleep regulation. Adenosine is produced during both intense physical work and mental work. It slowly builds up in the body over the course of the day, eventually making you sleepy. As adenosine gradually attaches to adenosine receptors, it begins to promote muscle relaxation and tiredness, which is why you start to get tired later in the day [30, 31].
After you fall asleep, adenosine molecules start to be broken down. Adenosine needs to be active enough to get you into a state more restorative, deep sleep. Its levels will slowly decrease over the course of the night, eventually waking you up [30, 31, 2, 32, 33].
The body also produces adenosine in response to injury, inflammation, inadequate blood supply to an organ (ischemia), and cancer [34].
Initially, inflammation causes cells to release ATP, ADP, and other nucleotides that trigger a strong immune response. These need to be metabolized into anti-inflammatory adenosine to quell the immune overactivity [7, 35].
In other words, ATP first stimulates the immune system and adenosine stops the immune response. However, in cancer and certain immunodeficiency disorders, this stop signal is over-expressed allowing tumors or “opportunistic” infections to hide from the immune system [36].
Adenosine Receptors
Adenosine has four receptors – A1, A2A, A2B, and A3 – which enable it to achieve such a broad range of activities. Adenosine receptors are important for the everyday functions performed by many tissues in the body, including the brain, heart, and lungs. Adenosine levels determine the type of receptor it will be bind to, which molds the effect it will have on the body [37, 38, 39].
Here’s a rough breakdown of its diverse effects:
- Sleep: Adenosine increases in the brain during wakefulness and at night, it activates A1 and A2A receptors. This decreases brain activity and promotes sleep [40, 41, 42].
- Diabetes: Dysfunction of the A1 and A2B receptors play a role in diabetes [43, 44, 45].
- Neurodegenerative diseases: Blocking the A2A receptor can protect the brain from epilepsy, depression, Alzheimer’s disease, and Parkinson’s disease in animals [46, 47].
- Stress activates adenosine receptors. It increases ATP breakdown and adenosine, triggering the fight-or-flight response [37, 48].
- Serious diseases: Large amounts of adenosine are released during blood poisoning (sepsis) and the A2B receptor is activated to prevent further bacterial growth, inflammation, and death [49, 50, 51].
Functions of Adenosine
1) The Sleep-Wake Cycle
Adenosine builds up during the day and is broken down over the course of the night. This results in lower levels of adenosine in the morning. According to some researchers, people that do not break down adenosine as effectively may tend to feel more groggy in the morning [2, 31, 30].
The longer you’re awake, the more tired you feel, and the longer and deeper the following sleep will be – this is controlled by adenosine [30, 42].
Most of the effects that adenosine has on the sleep-wake cycle are due to changes in adenosine levels primarily within the basal forebrain, the area of the brain linked to cognition, pleasure, and motivation. Adenosine levels also fluctuate in the hippocampus – involved in storing memories, balancing emotions and stress – and in the cortex, which is crucial for complex cognitive tasks [52, 53, 54, 55].
Sleep is an active process during which much-needed cell growth, repair, and recovery occur. This happens in cycles of two distinct stages throughout the night: rapid eye movement sleep (REM) and non-REM sleep, also known as slow wave sleep (SWS) or “deep sleep.” As cycles repeat and sleep progresses, the REM stages get longer and the non-REM phases – the more restorative type of sleep – get shorter [56].
Circadian rhythms and zeitgebers determine the quality and quantity of sleep – when you sleep and the type of sleep likely to occur – REM versus non-REM. Adenosine can have important effects on your circadian clock [41].
Activation of adenosine receptors normally promotes more restorative non-REM slow wave sleep. However, if you are sleep deprived, it will enhance non-rapid-eye-movement (nonREM) sleep [30, 42].
Genetically modified mice without the A2A receptor had disrupted sleep/wake cycles. Moreover, blocking the A1 receptor in rats increased wakefulness and decreased both deep and REM sleep [57, 52].
These findings also explain why caffeine, which opposes adenosine’s effects, can have such detrimental effects on sleep, stress response, and circadian rhythm in the long run. In fact, anything that disrupts natural sleep-wake rhythms may influence the levels or activity of adenosine. To balance adenosine, a healthy circadian rhythm is essential.
2) Tissue Damage After Injury
Adenosine is always present in the body, but its levels increase when tissues are damaged or injured [8].
Adenosine is released to protect the brain or heart from further damage after the loss of blood flow due to a stroke or heart attack. In animal studies, adenosine increased three-fold within one minute of a stroke and its levels continued to rise thereafter [58, 59].
Since adenosine controls blood flow in the brain, increased adenosine helps prevent damage due to seizures and high blood pressure by increasing blood flow in the compromised area [60, 61, 62].
Similarly, increased adenosine is believed to protect the heart from damage caused by inadequate blood flow (ischemia), which is often caused by a heart attack. However, the effects were reduced in older mice [59, 63, 64, 65].
Surgeons sometimes take advantage of the protective effects of adenosine and adenosine receptor signaling to treat patients with frequent heart attacks. Adenosine is increased by temporarily reducing blood flow to the heart using either anesthetics or a balloon to physically deflate and then re-inflate the blood vessels connected to the heart [66, 67, 68, 69].
3) Inflammation
Adenosine protects the body from excessive immune responses by limiting the extent and duration of inflammation. This prevents inflammation from spiraling out of control [70].
In rats, activating the A2A receptor reduced the release of inflammatory molecules and increased the release of anti-inflammatory molecules by immune cells [71].
Autoimmune Disease
When the immune system is not “switched off” quickly enough, it over-activates and starts to attack normal tissues, which is what happens in autoimmune disorders.
When the stop signal from adenosine is not strong enough, some researchers argue, autoimmunity may result. More broadly, they believe that any deficiency in the adenosine pathway may contribute to autoimmune diseases [72, 73].
4) Brain Function
Adenosine may also have so-called neuroprotective abilities that rely on activating certain adenosine receptors in the brain, which promote sleep and arousal, enhance cognition and memory, and prevent nerve damage and degeneration [74, 6, 75, 76].
Therefore, adenosine receptors have become an important therapeutic approach for neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, epilepsy, and multiple sclerosis [76].
Chemical Signalling in the Brain
Adenosine is known as a neuromodulator, crucial for brain function. It regulates the production and release of neurotransmitters, including GABA, glutamate, and dopamine [77].
Adenosine levels can change rapidly in the brain, which allows the chemical to quickly activate or inhibit the release of neurotransmitters. Once released from brain cells, adenosine activates adenosine receptors to either increase or decrease other neurotransmitters [78, 28].
The effects of adenosine on signaling in the brain may continue over a long period of time or last for only a few minutes [79, 28, 80, 81].
Conditions such as Alzheimer’s and epilepsy are associated with overexpression of ADK and decreased adenosine [82, 83, 84, 85].
Mice genetically modified to overexpress ADK have low adenosine and develop seizures, sleep disturbances, cognitive issues, psychosis, and loss of dopamine function [83].
Owing to its influence on neurotransmitters like dopamine and glutamate, subtle adenosine disturbances can alter behavior and contribute to schizophrenia, as well as brain diseases like Parkinson’s. Adenosine imbalances may also blur the encoding of information in the brain, triggering symptoms of schizophrenia [86, 47, 6, 87].
Fine-tuning the Brain
The effects of adenosine on neurotransmitters aren’t a clear-cut increase or decrease. Adenosine is a neuromodulator, which means it can do both, depending on the receptors it activates [86]:
- A1 receptors block the release of neurotransmitters like dopamine and glutamate and calms activity in the brain
- A2A act in the opposite way and increase the release of these neurotransmitters. Activation of the A2 receptor by adenosine in rats also increased the release of noradrenaline and the fight-or-flight response [88].
Adenosine is uniquely positioned to fine-tune brain signals, coordinating excitatory and calming signals. It unites dopamine and glutamine and is sometimes called the “bioenergetic network regulator” of the brain [86].
In a way, adenosine works as the mastermind from the shadows of the nervous system, and it never received a lot of recognition until recently. Scientists are now realizing that adenosine carefully regulates complex neurotransmitters and whole-brain networks in various parts of the brain involved in [86]:
- Learning and memory
- Brain inflammation
- Brain development
- Motivation
- Feelings of reward
- Movement
In light of these recent discoveries, researchers are developing therapies intended to restore adenosine balance (by selectively affecting its receptors or breakdown). These therapies may be candidates for combating apparently different diseases linked to similar adenosine imbalances in the brain – like schizophrenia and Parkinson’s disease [89, 90, 91, 92].
5) Blood Vessels
Adenosine controls blood flow. Most blood vessels relax and expand (vasodilation) in response to adenosine, except those in the kidney [3, 4, 93].
By relaxing blood vessels, adenosine also lowers blood pressure. In animal studies, it decreased blood pressure but also caused large blood pressure fluctuations (via the A2A receptor) [94, 95].
In healthy people, adenosine injections first increased and then decreased blood pressure. Intravenous infusions caused no changes in some studies. In others, the effects were mixed – either increased or decreased blood pressure (systolic or diastolic). The infusions also increased heart rate and pulse pressure (the difference between systolic and diastolic blood pressure) [96, 97, 98].
Differences in responses were most likely due to the route of administration and adenosine dosage. Rapid injections cause more dramatic fluctuations in blood pressure whereas slower infusions might not trigger any major changes [96].
Moreover, side effects, such as headaches, nervousness, and flushing, limited the dose of adenosine that could be given to each person. And importantly, the effects of injected and naturally produced adenosine might substantially differ [96].
6) Pain Perception
Adenosine can help relieve pain, which is why it is often used as a painkiller after surgery or for severe nerve pain [99, 11].
Mice lacking the adenosine A1 receptor experienced increased pain and anxiety [100].
7) Metabolism & Weight
The link between adenosine (and its receptors) and obesity is still not fully understood since adenosine is involved so many different functions tied to obesity [29, 45].
Nonetheless, adenosine may prevent obesity by maintaining healthy glucose levels, suppressing fat storage (adipogenesis), reducing inflammation, and preventing insulin resistance [101, 45, 44].
Since obesity decreases the ability of insulin to clear sugar from the blood, adenosine may also help prevent diabetes [102, 103].
Factors that Increase Adenosine
The role of adenosine in health has not been fully explored. Before making any significant changes to your diet, supplements, or lifestyle, talk to your doctor to make sure you’re making the best health choices for you.
1) Exercise
Adenosine increases during exercise as ATP is consumed for energy. This may contribute to the feeling of sleepiness after physical exertion. So if you have trouble falling asleep and want to increase adenosine, some researchers recommend a trip to the gym [104, 105, 106, 107].
Whereas moderate exercise did not affect adenosine levels in the brains of rats, intense exercise increased adenosine as a result of ATP (energy) breakdown [104].
Increases in adenosine due to exercise may improve sleep quality [108].
2) Diet
Following a high-fat low-carb (ketogenic) diet can increase adenosine levels. The ketogenic diet alters energy metabolism and increases both ATP and adenosine [109].
A ketogenic diet restored normal adenosine levels in adenosine-deficient rats with epilepsy. The effects were lost when the rats switched back to a normal diet [110].
The increase in adenosine may be responsible for the antiepileptic (anti-convulsant) and brain-protecting effects of the diet [111].
3) ADA Blockers
Since ADA is the enzyme that breaks adenosine down, substances that block ADA could theoretically increase adenosine levels. Some natural ADA blockers include:
- Berberine [112]
- Curcumin [113]
- Stinging nettle [114]
- Naringenin, a bioactive compound found in citrus fruits [115]
- Increasing nitric oxide, which will also boost your blood flow and brain circulation
Cordycepin, an active compound from cordyceps mushrooms is chemically very similar to adenosine. It is also broken down by ADA and may have adenosine-like effects in the body [115].
