Daily Coffee Linked to Lower α-Klotho Levels in Large US Population Study

α-Klotho is a circulating protein predominantly produced in the kidney's distal convoluted tubules and is widely regarded as a biomarker of biological aging. Higher serum α-Klotho (SαKl) levels are associated with longevity, reduced cardiovascular disease risk, protection against chronic kidney disease, and lower rates of neurodegenerative disorders. Coffee, one of the world's most consumed beverages, contains caffeine and over 1,000 bioactive compounds. While coffee has been linked to reduced risk of type 2 diabetes, cardiovascular disease, and certain cancers, its specific effects on α-Klotho had not been well characterized.

This population-based cross-sectional study drew on five consecutive two-year NHANES cycles (2007–2016), ultimately analyzing 9,811 participants aged 40–79 after excluding individuals with missing α-Klotho data, incomplete dietary records, cancer diagnoses, pregnancy, and extreme energy intakes. Coffee consumption—total, caffeinated, and decaffeinated—was assessed via 24-hour dietary recall and quantified in grams per day using USDA food codes. SαKl levels were measured by ELISA from stored serum samples. Multivariable linear regression models were adjusted for age, sex, race/ethnicity, BMI, income, education, smoking, alcohol, physical activity, energy intake, eGFR, hypertension, CVD, and COPD. Generalized additive models and restricted cubic splines assessed nonlinearity.

The primary finding was a statistically significant L-shaped association between both total coffee and caffeinated coffee intake and SαKl levels. This pattern indicates that even low levels of caffeinated coffee consumption were associated with a sharp initial decline in SαKl, which then plateaued at higher consumption levels. An inflection point was identified via recursive algorithm in the piecewise linear regression. Females had higher mean SαKl levels (866.17 pg/mL) than males (828.32 pg/mL), and the L-shaped relationship was particularly pronounced among females and adults under age 60. Critically, decaffeinated coffee showed no significant association with SαKl levels across any model, strongly implicating caffeine—rather than other coffee constituents—as the primary mediator.

The results carry meaningful implications for longevity research. If caffeine intake suppresses α-Klotho levels, even at moderate consumption, this could partially offset some of the metabolic and cardiovascular benefits attributed to coffee. The authors propose that caffeine may interfere with Klotho expression through pathways involving oxidative stress, inflammation, or insulin signaling, though the exact mechanisms remain to be elucidated in experimental studies. Notably, this is one of the first large-scale population studies to specifically examine the coffee–α-Klotho relationship, building on prior evidence linking dietary caffeine inversely to Klotho concentrations.

Several important caveats temper these conclusions. The cross-sectional design precludes causal inference, and coffee intake was measured from a single 24-hour recall, which may not reflect habitual consumption. Residual confounding from unmeasured dietary or lifestyle factors remains possible. Despite these limitations, the robust sample size, thorough covariate adjustment, and consistent dose-response pattern strengthen the credibility of the observed association.