Caffeine: The Genetics Behind Your Love/Hate Relationship
This two-part series takes a deep-dive into the genetics behind caffeine consumption, taste, metabolism, and side effects.
Part 1: Caffeine’s Unpleasant Side
Caffeine is prized the world over for its ability to increase alertness and reduce fatigue. On the other hand, it has also been known to produce side effects of increased heart rate, jitters, anxiety, and insomnia. The major method by which caffeine produces its effects is by influencing the adenosine signaling pathway. Understanding this pathway is essential for understanding the side effects that can result from excessive caffeine consumption and the role genes play in side effects such as insomnia and anxiety.
Adenosine: Your Battery Meter
Adenosine is used as an indicator of current energy stores, and when energy stores are depleted it signals to slow everything down so that energy stores can be replenished. Adenosine is made when you burn ATP, the body's main energy currency. High levels of adenosine indicate that ATP is being burned faster than it is being made, sending a signal that an ongoing activity must be slowed. Adenosine acts as a sort of battery manager, as your cell phone's battery is depleted, background apps are shut off in order to conserve battery power for only essential operations. High levels of adenosine are why you feel fatigue after an intense workout and they are also why you feel tired or sleepy as your bedtime nears.
While very high levels of adenosine produce potent feelings of fatigue, a baseline or basal level of adenosine in your cells allows for wakefulness. When adenosine levels drop below this baseline, you experience feelings of alertness. Just as high levels of adenosine signal a lack of fuel, low levels of adenosine signal an abundance of fuel. Fuel demanding to be used! This is how caffeine works its magic.
Caffeine Hacks Your Battery Meter
Caffeine, and the byproducts of its metabolism, bind to adenosine receptors, block adenosine from binding, and in so doing, trick the cell into thinking that adenosine levels are low. This is the signal that there is fuel to burn, so energy and activity are increased. There are several different adenosine receptors, but caffeine and its metabolites target two in particular — the A1 and A2A receptors. These receptors are just the first step in a long signaling chain, so their triggering produces a series of effects.
Genetic variants in the adenosine A1 and A2A receptors have also been associated with poor sleep in response to caffeine. Poor sleep can mean either a reduction in sleep quality, lots of tossing and turning, or reduction in sleep duration due to trouble staying asleep. The disruption of sleep produced by caffeine is not related to a person's ability to metabolize caffeine; instead, it is a function of the brain's initiation and control of sleep. In studies of individuals with nearly identical caffeine metabolism, and identical amounts of caffeine in their blood, people with caffeine-sensitive adenosine receptors suffered from worse sleep.
One of the downstream effects of caffeine binding involves the neurotransmitter dopamine and may play a role in producing feelings of anxiety. While dopamine has often been described as "the pleasure chemical,” the neurotransmitter is involved in both reward-seeking behaviors and pain-avoidance behaviors. Reward-seeking behaviors are encouraged by triggering feelings of pleasure when a task is accomplished or an item is obtained. On the other hand, pain-avoidance behavior can be promoted by triggering feelings of fear and anxiety.
For example, when a child commits to a lengthy search for the cookie jar and they find it, they enjoy pleasure sensations along with their cookie. Tenacity and commitment are encouraged. On the other hand, if a child were to accidentally come into contact with a hot stove during their cookie search, feelings of pain and fear would wash over them. By promoting anxiety when near the stove, the child would be protected from further injury.
Genetic variants in both the adenosine A2A receptor [ADORA2A] and the dopamine D2 receptor [DRD2] have been associated with feelings of anxiety and stress in response to caffeine.
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