Genetic evidence ties higher blood caffeine levels to lower body fat and reduced type 2 diabetes risk. Digest
Caffeine is a widely consumed psychoactive substance, but its long-term metabolic effects are often hard to isolate because coffee, tea, and soft drink habits correlate with many other health-related behaviors. To address that problem, researchers used human genetics to ask whether long-term differences in blood caffeine levels relate to adiposity and cardiometabolic disease.
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The researchers applied a method called Mendelian randomization, which uses naturally occurring genetic differences to explore cause-and-effect relationships. Because inherited genetic variants are fixed at conception, they create natural groups that are largely not shaped by later habits or environmental factors. In this study, the researchers focused on two genetic variants near the CYP1A2 and AHR genes, which are involved in regulating how caffeine is metabolized in the body. The team then linked these caffeine-related differences to large genetic datasets containing information on body mass index (BMI, a weight-to-height measure), body fat, type 2 diabetes, and major cardiovascular diseases.
- People with genetic variants linked to higher predicted blood caffeine tended to have lower BMI.
- Higher genetically inferred blood caffeine levels were associated with lower whole-body fat mass, while lean mass, which includes muscle and organs, showed no meaningful change.
- Individuals with genetically predicted higher caffeine levels had a lower risk of type 2 diabetes.
- When the researchers examined possible pathways, they estimated that about 43% of the lower diabetes risk could be attributed to reductions in BMI.
- No strong links were found between higher predicted blood caffeine levels and major cardiovascular diseases, including ischemic heart disease, atrial fibrillation, heart failure, or stroke.
- The same genetic variants linked to higher caffeine levels were also associated with drinking less coffee and tea, likely because people who metabolize caffeine more slowly tend to consume less of it to achieve the same stimulant effects.
Slower caffeine breakdown keeps circulating levels elevated for longer periods, which may increase energy expenditure through caffeine-induced thermogenesis and fat oxidation. Experimental work suggests caffeine enhances mitochondrial activity, increases sympathetic nervous system signaling, and shifts brown fat tissue toward a more metabolically active state. Caffeine has also been shown to increase satiety and reduce energy intake in some settings. Over years, even small increases in daily energy expenditure and decreases in energy intake could meaningfully alter fat accumulation and downstream insulin signaling.
Because this genetic analysis reflects lifelong caffeine exposure rather than a specific intake level, it cannot indicate an effective dose, and its reliance on only two variants from mostly European datasets further limits precision. Even with these constraints, the study provides causal evidence linking sustained caffeine exposure to metabolic benefits. In episode #103, I synthesize extensive research to illuminate how the timing, brewing methods, and additives to coffee influence its health benefits and risks.