Caffeine Consumption and Interaction with ADORA2A, CYP1A2 and NOS1 Variants Do Not Influence Age at Onset of Machado-Joseph Disease.

BACKGROUND: The age at onset (AO) of Machado-Joseph disease (SCA3/MJD), a disorder due to an expanded CAG repeat (CAGexp) in ATXN3, is quite variable and the role of environmental factors is still unknown. Caffeine was associated with protective effects against other neurodegenerative diseases, and against SCA3/MJD in transgenic mouse models. We aimed to evaluate whether caffeine consumption and its interaction with variants of caffeine signaling/metabolization genes impact the AO of this disease. METHODS: a questionnaire on caffeine consumption was applied to adult patients and unrelated controls living in Rio Grande do Sul, Brazil. AO and CAGexp were previously determined. SNPs rs5751876 (ADORA2A), rs2298383 (ADORA2A), rs762551 (CYP1A2) and rs478597 (NOS1) were genotyped. AO of subgroups were compared, adjusting the CAGexp to 75 repeats (p < 0.05). RESULTS: 171/179 cases and 98/100 controls consumed caffeine. Cases with high and low caffeine consumption (more or less than 314.5 mg of caffeine/day) had mean (SD) AO of 35.05 (11.44) and 35.43 (10.08) years (p = 0.40). The mean (SD) AO of the subgroups produced by the presence or absence of caffeine-enhancing alleles in ADORA2A (T allele at rs5751876 and rs2298383), CYP1A2 (C allele) and NOS1 (C allele) were all similar (p between 0.069 and 0.516). DISCUSSION: Caffeine consumption was not related to changes in the AO of SCA3/MJD, either alone or in interaction with protective genotypes at ADORA2A, CYP1A2 and NOS1.

The risk of premature cardiac contractions (PAC/PVC) related to caffeine consumption among healthcare workers: A comprehensive review.

Background and Aims: Premature atrial contractions (PACs) and premature ventricular contractions (PVCs) are ectopic heart rhythm disorders with implications for cardiovascular health. This study explores the relationship between caffeine consumption and the risk of PACs and PVCs, with a focus on healthcare workers, such as doctors, nurses, pharmacists, and midwives, who often rely on caffeine to combat fatigue, especially during night shifts. Methods: A thorough review was conducted through PubMed, Scopus, Google Scholar, and Web of Science, utilizing a combination of MeSH terms and keywords. Studies examining the link between caffeine consumption and PACs and PVCs, particularly in healthcare workers, were included. Results: We found that caffeine shows various effects based on dosage and can impact arrhythmia risk. Individuals working long shifts, including healthcare professionals, are prone to increased caffeine intake, leading to higher cardiovascular risk. To mitigate these risks, tailored guidelines for caffeine consumption, flexible shift scheduling, and mental health support services are recommended. Promoting caffeine alternatives within healthcare institutions can be beneficial. Conclusion: Although caffeine may have potential benefits, its drawbacks, particularly concerning cardiovascular health, may surpass its advantages, especially when consumed in high doses. A multidisciplinary approach is crucial for healthcare workers' well-being and quality of patient care. Further research is required to refine and support these recommendations.

Antagonistic interaction between caffeine and ketamine in zebrafish: Implications for aquatic toxicity.

The coexistence of caffeine (CF) and ketamine (KET) in surface waters across Asia has been widely reported. Previous studies have implied that CF and KET may share a mechanism of action. However, the combined toxicity of these two chemicals on aquatic organisms remains unclear at environmental levels, and the underlying mechanisms are not well understood. Here we demonstrate that KET antagonizes the adverse effects of CF on zebrafish larvae by modulating the gamma-aminobutyric acid (GABA)ergic synapse pathway. Specifically, KET (10-250 ng L-1) ameliorates the locomotor hyperactivity and impaired circadian rhythms in zebrafish larvae induced by 2 mg L-1 of CF, showing a dose-dependent relationship. Additionally, the developmental abnormalities in zebrafish larvae exposed to CF are mitigated by KET, with an incidence rate reduced from 26.7% to 6.7%. The competition between CF and KET for binding sites on the GABA-A receptor (in situ and in silico) elucidates the antagonistic interactions between the two chemicals. Following a seven-day recovery period, the adverse outcomes of CF exposure persist in the fish, whereas the changes observed in the CF + KET groups are significantly alleviated, especially with KET at 10 ng L-1. Based on these results, it is imperative to further assess the environmental risks associated with CF and KET co-pollution. This pilot study underscores the utility of systems toxicology approaches in estimating the combined toxicity of environmental chemicals on aquatic organisms. Moreover, the nighttime behavioral functions of fish could serve as a sensitive biomarker for evaluating the toxicity of psychoactive substances.

Enhancing water stress tolerance of bread wheat during seed germination and seedling emergence: caffeine-induced modulation of antioxidative defense mechanisms.

Better crop stand establishment, a function of rapid and uniform seedling emergence, depends on the activities of germination-related enzymes, which is problematic when there is insufficient soil moisture. Different ways are in practice for counteracting this problem, including seed priming with different chemicals, which are considered helpful in obtaining better crop stand establishment to some extent through improved seed germination and seedling emergence. In this growth room experiment, caffeine was used as a seed priming agent to improve germination under moisture scarcity. Polyethylene glycol-8000 (18%) was added to Hoagland's nutrient solution to create drought stress (-0.65 MPa). The experiment was arranged in a completely randomized design (CRD), having four replications of each treatment. A newly developed wheat genotype SB-1 was used for the experimentation. Different doses of caffeine, i.e., 4 ppm, 8 ppm, 12 ppm, and 16 ppm, including no soaking and water soaking, were used as seed priming treatments. Water deficit caused oxidative stress and adversely affected the seed germination, seedling vigor, activities of germination enzymes, photosynthetic pigments, and antioxidative defense mechanism in roots and shoots of seedlings. Caffeine seed priming ameliorated the negative effects of water deficit on seed germination and seedling vigor, which was attributed to the reduction in lipid peroxidation and improvement in the activities of germination-related enzymes like glucosidase, amylase, and protease. Conclusively, seed priming with 12 ppm caffeine outperformed the other treatments and hence is recommended for better crop stand establishment under conditions of soil moisture deficit.

Coffee consumption and cardiometabolic health: a comprehensive review of the evidence.

This review provides a comprehensive synthesis of longitudinal observational and interventional studies on the cardiometabolic effects of coffee consumption. It explores biological mechanisms, and clinical and policy implications, and highlights gaps in the evidence while suggesting future research directions. It also reviews evidence on the causal relationships between coffee consumption and cardiometabolic outcomes from Mendelian randomization (MR) studies. Findings indicate that while coffee may cause short-term increases in blood pressure, it does not contribute to long-term hypertension risk. There is limited evidence indicating that coffee intake might reduce the risk of metabolic syndrome and non-alcoholic fatty liver disease. Furthermore, coffee consumption is consistently linked with reduced risks of type 2 diabetes (T2D) and chronic kidney disease (CKD), showing dose-response relationships. The relationship between coffee and cardiovascular disease is complex, showing potential stroke prevention benefits but ambiguous effects on coronary heart disease. Moderate coffee consumption, typically ranging from 1 to 5 cups per day, is linked to a reduced risk of heart failure, while its impact on atrial fibrillation remains inconclusive. Furthermore, coffee consumption is associated with a lower risk of all-cause mortality, following a U-shaped pattern, with the largest risk reduction observed at moderate consumption levels. Except for T2D and CKD, MR studies do not robustly support a causal link between coffee consumption and adverse cardiometabolic outcomes. The potential beneficial effects of coffee on cardiometabolic health are consistent across age, sex, geographical regions, and coffee subtypes and are multi-dimensional, involving antioxidative, anti-inflammatory, lipid-modulating, insulin-sensitizing, and thermogenic effects. Based on its beneficial effects on cardiometabolic health and fundamental biological processes involved in aging, moderate coffee consumption has the potential to contribute to extending the healthspan and increasing longevity. The findings underscore the need for future research to understand the underlying mechanisms and refine health recommendations regarding coffee consumption.

The Role of Hydrogen Bonding in the Raman Spectral Signals of Caffeine in Aqueous Solution.

The identification and quantification of caffeine is a common need in the food and pharmaceutical industries and lately also in the field of environmental science. For that purpose, Raman spectroscopy has been used as an analytical technique, but the interpretation of the spectra requires reliable and accurate computational protocols, especially as regards the Resonance Raman (RR) variant. Herein, caffeine solutions are sampled using Molecular Dynamics simulations. Upon quantification of the strength of the non-covalent intermolecular interactions such as hydrogen bonding between caffeine and water, UV-Vis, Raman, and RR spectra are computed. The results provide general insights into the hydrogen bonding role in mediating the Raman spectral signals of caffeine in aqueous solution. Also, by analyzing the dependence of RR enhancement on the absorption spectrum of caffeine, it is proposed that the sensitivity of the RR technique could be exploited at excitation wavelengths moderately far from 266 nm, yet achieving very low detection limits in the quantification caffeine content.

Caffeine Boosts Weight-Lifting Performance in Rats: A Pilot Study.

Caffeine is a well-described ergogenic aid used to enhance athletic performance. Using animal models can greatly increase our understanding of caffeine's mechanisms in performance. Here, we adapted an animal weight-lifting exercise model to demonstrate caffeine's ergogenic effect in rats. Male Wistar rats (315 ± 35 g) were randomly divided into two groups: one group received 5 mg·kg-1 of caffeine (0.5 mL; CEx; n = 5) and the other 0.9% NaCl (0.5 mL; PEx; n = 4) through an orogastric probe (gavage) one hour before exercise. Weight-lifting exercise sessions were performed over three subsequent days, and the number of complete squats performed was counted. Analyses of the area under the curve in all three experiments showed that the CEx group responded more to stimuli, performing more squats (1.7-, 2.0-, and 1.6-fold; p < 0.05) than the control group did. These three days' data were analyzed to better understand the cumulative effect of this exercise, and a hyperbolic curve was fitted to these data. Data fitting from the caffeine-supplemented group, CEx, also showed larger Smax and Kd (2.3-fold and 1.6-fold, respectively) than the PEx group did. Our study demonstrated an acute ergogenic effect of caffeine in an animal weight-lifting exercise model for the first time, suggesting potential avenues for future research.

Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition.

Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.

Graphene Multiplexed Sensor for Point-of-Need Viral Wastewater-Based Epidemiology.

Wastewater-based epidemiology (WBE) can help mitigate the spread of respiratory infections through the early detection of viruses, pathogens, and other biomarkers in human waste. The need for sample collection, shipping, and testing facilities drives up the cost of WBE and hinders its use for rapid detection and isolation in environments with small populations and in low-resource settings. Given the ubiquitousness and regular outbreaks of respiratory syncytial virus, SARS-CoV-2, and various influenza strains, there is a rising need for a low-cost and easy-to-use biosensing platform to detect these viruses locally before outbreaks can occur and monitor their progression. To this end, we have developed an easy-to-use, cost-effective, multiplexed platform able to detect viral loads in wastewater with several orders of magnitude lower limit of detection than that of mass spectrometry. This is enabled by wafer-scale production and aptamers preattached with linker molecules, producing 44 chips at once. Each chip can simultaneously detect four target analytes using 20 transistors segregated into four sets of five for each analyte to allow for immediate statistical analysis. We show our platform's ability to rapidly detect three virus proteins (SARS-CoV-2, RSV, and Influenza A) and a population normalization molecule (caffeine) in wastewater. Going forward, turning these devices into hand-held systems would enable wastewater epidemiology in low-resource settings and be instrumental for rapid, local outbreak prevention.

Ad libitum caffeine consumption, cognitive performance, and sleep in special forces soldiers during a 96-h combat exercise.

Introduction: This observational study investigated the effects of sleep deprivation and ad libitum caffeine consumption on cognitive performance, risk behavior, and mood among 28 Israeli Special Forces (SF) soldiers (mean age: 20.57 ± 0.92 years) during a 96-hour combat exercise. Methods: Actigraphy was used to monitor sleep and activity; cognitive function, risk-taking propensity, mood states, and self-reported sleepiness were assessed using the Psychomotor Vigilance Task (PVT), Evaluation of Risks Scale (EVAR), Profile of Mood States (POMS), Karolinska Sleepiness Scale (KSS); and caffeine consumption by questionnaire at 0, 50, and 96 hours. For analyses, participants were divided into Low (<400 mg) and High (≥400 mg) caffeine consumption groups. Results: The soldiers hiked 108.5 ± 0.52 km and slept for 12.7 ± 0.5 h, with a notable transition from multiple short sleep epochs in the initial 50 hours to a consolidated 5-hour sleep period subsequently. In the High caffeine group, PVT reaction time was faster (p = 0.024) compared to the Low caffeine group, with fewer premature response errors (p = 0.026). However, this group showed increased risk-taking (p = 0.037), particularly reduced Self-Control (p = 0.010). No significant impact of ad libitum caffeine intake on mood was observed. However, degradation over the course of the exercise in both groups in mood states, including anger, fatigue, tension, and vigor, was noted (p < 0.05). KSS scores increased significantly at 50 and 96 h (p < 0.001). Discussion: These results suggest that while caffeine enhances cognitive function, its ad libitum consumption did not consistently improve these measures in this cohort of SF soldiers. The study highlights the complex relationship between sleep deprivation and caffeine intake and their combined effects on soldiers' cognitive and behavioral functions, indicating a need for evidence-based caffeine use guidelines for using caffeine in military settings.

Effect of adenosinergic manipulations on amygdala-kindled seizures in mice: Implications for sudden unexpected death in epilepsy.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) results in more years of potential life lost than any neurological condition with the exception of stroke. It is generally agreed that SUDEP happens due to some form of respiratory, cardiac, and electrocerebral dysfunction following a seizure; however, the mechanistic cause of these perturbations is unclear. One possible explanation lies with adenosinergic signaling. Extracellular levels of the inhibitory neuromodulator adenosine rapidly rise during seizures, a countermeasure that is necessary for seizure termination. Previous evidence has suggested that excessive adenosinergic inhibition could increase the risk of SUDEP by silencing brain areas necessary for life, such as the respiratory nuclei of the brainstem. The goal of this investigation was to further clarify the role of adenosine in seizure-induced respiratory and electrocerebral dysfunction. METHODS: To determine the role of adenosine in postictal physiological dysregulation, we pharmacologically manipulated adenosine signaling prior to amygdala-kindled seizures in mice while recording electroencephalogram (EEG), electromyogram, and breathing using whole body plethysmography. The adenosinergic drugs used in this study included selective and nonselective adenosine receptor antagonists and inhibitors of adenosine metabolism. RESULTS: We found that high doses of adenosine receptor antagonists caused some seizures to result in seizure-induced death; however, counterintuitively, animals in these conditions that did not experience seizure-induced death had little or no postictal generalized EEG suppression. Inhibitors of adenosine metabolism had no effect on postictal breathing but did worsen some postictal electrocerebral outcomes. SIGNIFICANCE: The unexpected effect of high doses of adenosine antagonists on seizure-induced death observed in this study may be due to the increase in seizure severity, vasoconstriction, or phosphodiesterase inhibition caused by these drugs at high doses. These findings further clarify the role of adenosine in seizure-induced death and may have implications for the consumption of caffeine in epilepsy patients and the prevention of SUDEP.

Associations between prenatal caffeine exposure and child development: Longitudinal results from the Adolescent Brain Cognitive Development (ABCD) Study.

Objective: Though caffeine use during pregnancy is common, its longitudinal associations with child behavioral and physical health outcomes remain poorly understood. Here, we estimated associations between prenatal caffeine exposure, body mass index (BMI), and behavior as children enter adolescence. Method: Longitudinal data and caregiver-reported prenatal caffeine exposure were obtained from the ongoing Adolescent Brain and Cognitive Development (ABCD) SM Study, which recruited 11,875 children aged 9-11 years at baseline from 21 sites across the United States starting June 1, 2016. Prenatal caffeine exposure was analyzed as a 4-level categorical variable, and further group contrasts were used to characterize "any exposure" and "daily exposure" groups. Outcomes included psychopathology characteristics in children, sleep problems, and BMI. Potentially confounding covariates included familial (e.g., income, familial psychopathology), pregnancy (e.g., prenatal substance exposure), and child (e.g., caffeine use) variables. Results: Among 10,873 children (5,686 boys [52.3%]; mean [SD] age, 9.9 [0.6] years) with nonmissing prenatal caffeine exposure data, 6,560 (60%) were exposed to caffeine prenatally. Relative to no exposure, daily caffeine exposure was associated with higher child BMI (ß=0.08; FDR-corrected p=0.02), but was not associated with child behavior. Those exposed to two or more cups of caffeine daily (n=1,028) had greater sleep problems than those with lower/no exposure (ß>0.92; FDR-corrected p<0.04). Conclusion: Daily prenatal caffeine exposure is associated with heightened childhood BMI, and when used multiple times a day greater sleep problems even after accounting for potential confounds. Whether this relationship is a consequence of prenatal caffeine exposure or its correlated factors remains unknown.

Development of an HPLC method using relative molar sensitivity for the measurement of blood concentrations of nine pharmaceutical compounds.

We developed a reliable high-performance liquid chromatographic analysis method using a relative molar sensitivity (RMS) technique that does not require an authentic, identical reference analyte material to quantify blood serum carbamazepine, phenytoin, voriconazole, lamotrigine, meropenem, mycophenolic acid, linezolid, vancomycin, and caffeine levels for routine blood concentration measurements. Carbamazepine and caffeine were also used as non-analyte reference materials to calculate the RMS of each analyte. The RMS was calculated from the ratio of the slope of the calibration equation (analyte/non-analyte reference material), then used to quantify analytes in control serum samples spiked with carbamazepine, phenytoin, voriconazole, meropenem, mycophenolic acid, linezolid or vancomycin. In addition, the concentrations of these six drugs in control serum samples determined by the proposed RMS method agreed well with that obtained using a conventional method. The proposed RMS method is a promising tool for the clinical determination of nine drugs, given the accuracy, precision, and efficiency of quantifying these analytes.

Updating 'Data on the determination of human epidermis integrity in skin permeation experiments by electrical resistance' with Data on pig ear skin.

The data presented in this article are an update of the dataset provided by Musazzi et al. [1] and are related to the research article entitled "Equivalence assessment of creams with quali-quantitative differences in light of the EMA and FDA regulatory framework" [2]. In vitro permeation study (IVPT) is typically conducted using the method of Franz's diffusion cell for assessing the biopharmaceutical performance of topically applied products. While the human epidermis is considered the benchmark, various animal models (for instance, pig ear) have been accepted as a permeation membrane. Nonetheless, it is crucial to evaluate the integrity of the membrane to ensure the quality of the experiments. The methods employed for this assessment vary, and the outcomes are heavily reliant on the operational conditions, and the model membrane. The article contributes to the existing dataset by providing data on the electrical resistance values of pig ear skin samples and their correlation with the in vitro permeability fluxes of caffeine and benzoic acid. This data is utilized to determine a suitable cut-off for verifying the skin integrity of such an animal model. This information could be beneficial for facilitating critical or comprehensive analyses, contributing to the creation of a standard method.

Experimental evolution of S. cerevisiae for caffeine tolerance alters multidrug resistance and TOR signaling pathways.

Caffeine is a natural compound that inhibits the major cellular signaling regulator TOR, leading to widespread effects including growth inhibition. S. cerevisiae yeast can adapt to tolerate high concentrations of caffeine in coffee and cacao fermentations and in experimental systems. While many factors affecting caffeine tolerance and TOR signaling have been identified, further characterization of their interactions and regulation remain to be studied. We used experimental evolution of S. cerevisiae to study the genetic contributions to caffeine tolerance in yeast, through a collaboration between high school students evolving yeast populations coupled with further research exploration in university labs. We identified multiple evolved yeast populations with mutations in PDR1 and PDR5, which contribute to multidrug resistance, and showed that gain-of-function mutations in multidrug resistance family transcription factors Pdr1, Pdr3, and Yrr1 differentially contribute to caffeine tolerance. We also identified loss-of-function mutations in TOR effectors Sit4, Sky1, and Tip41, and show that these mutations contribute to caffeine tolerance. These findings support the importance of both the multidrug resistance family and TOR signaling in caffeine tolerance, and can inform future exploration of networks affected by caffeine and other TOR inhibitors in model systems and industrial applications.

Habitual coffee and tea consumption and risk of cataract: A prospective cohort study from the UK Biobank.

BACKGROUND: To study the association of habitual coffee and tea consumption with the risk of cataract. METHODS: This prospective cohort study enrolled UK Biobank participants between 2006 and 2010, and prospectively followed them up for cataract diagnosis. We examined the associations of self-reported intake of tea and coffee and the calculated combined caffeine intake, with the risk of incident cataract. Cox proportional hazards models were analyzed after adjusting for age, sex, race, diabetes, Townsend Index, income, education, smoking and alcohol status. RESULTS: A total of 444,787 UK Biobank participants aged from 37 to 73 years old who had no cataract at baseline were included. Coffee intake of 2-3 cups/day (HR 0.973, 95% CI 0.949-0.998) or tea intake of 4-6 cups/day (HR 0.962, 95% CI 0.934-0.990) or combination caffeine intake of 160.0-235.0 mg/day (HR 0.950, 95% CI 0.925-0.976) were linked with the lowest risk of incident cataract. Cox models with restricted cubic splines showed J-shaped associations of coffee, tea, and combined caffeine intake with the risk of cataract (all p for nonlinear <0.001). CONCLUSIONS: Moderate habitual consumption of coffee and tea is associated with a lower risk of cataract. To maximize the protective effect against cataract, it is advisable to control total caffeine intake from coffee and tea within a range of 160.0-235.0 mg/day.

Comparison of caffeine consumption behavior with plasma caffeine levels as exposure measures in drug-target Mendelian randomization.

Mendelian randomization is an epidemiological technique that can explore the potential effect of perturbing a pharmacological target. Plasma caffeine levels can be used as a biomarker to measure the pharmacological effects of caffeine. Alternatively, this can be assessed using a behavioral proxy, such as average number of caffeinated drinks consumed per day. Either variable can be used as the exposure in a Mendelian randomization investigation, and to select which genetic variants to use as instrumental variables. Another possibility is to choose variants in gene regions with known biological relevance to caffeine level regulation. These choices affect the causal question that is being addressed by the analysis, and the validity of the analysis assumptions. Further, even when using the same genetic variants, the sign of Mendelian randomization estimates (positive or negative) can change depending on the choice of exposure. Some genetic variants that decrease caffeine metabolism associate with higher levels of plasma caffeine, but lower levels of caffeine consumption, as individuals with these variants require less caffeine consumption for the same physiological effect. We explore Mendelian randomization estimates for the effect of caffeine on body mass index, and discuss implications for variant and exposure choice in drug target Mendelian randomization investigations.

Association of caffeine consumption with all-cause and cause-specific mortality in adult Americans with hypertension.

Coffee is an important beverage that is widely consumed, of which caffeine is the main active ingredient. However, the long-term relationship between caffeine consumption and mortality in hypertensive patients has rarely been studied. This study analyzed a cohort of 12,093 US adults from the National Health and Nutrition Examination Survey from 1999 to 2018. Caffeine consumption was divided into five groups: no intake, >0 to ≤100, >100 to ≤300, >300 to ≤400 and >400 mg/day. Using multivariable-adjusted Cox proportional hazards models, this study performed a 20-year follow-up analysis (1999-2018). In the fully adjusted model, all caffeine consumers had lower all-cause mortality compared with no intake, especially in the >300 to ≤400 mg/day group (hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.60-0.84). The result of restricted cubic spline also showed a nonlinear association between caffeine consumption and all-cause mortality. For cardiovascular disease, mortality decreased only at >400 mg/day (HR 0.63, 95% CI 0.47-0.85). For cancer, diabetes, and kidney disease, only >300 to ≤400 mg/day was significantly associated with decreased mortality: (HR 0.60, 95% CI 0.42-0.67), (HR 0.22, 95% CI 0.07-0.75), and (HR 0.32, 95% CI 0.10-0.96), respectively. Lower all-cause mortality was observed in non-Hispanic White, African American, population aged 40 or above, and people with a body mass index <25 kg/m2. Our findings indicate a nonlinear association between average caffeine consumption and all-cause mortality, suggesting that hypertensive patients may benefit from moderate caffeine intake.