Airborne Benzene Linked to Fatty Liver Disease Through Faster Biological Aging

Ambient benzene, a volatile organic compound that drifts out of vehicle exhaust pipes and industrial stacks into the air millions of people breathe every day, has long been known as a cause of blood disorders and cancer at high occupational doses. A new large-scale study now suggests that even the low concentrations found in ordinary urban air may be quietly reshaping the health of one of the body’s most metabolically demanding organs: the liver. Drawing on more than a decade of follow-up data from over 400,000 adults in the United Kingdom, researchers report that long-term residential exposure to benzene significantly increases the risk of developing non-alcoholic fatty liver disease, or NAFLD, and that a portion of that risk appears to travel through an unexpected biological route, the acceleration of aging itself.

NAFLD has become one of the most common chronic liver conditions in the world, affecting roughly a third of adults globally, with prevalence climbing steeply over the past two decades. The disease, characterized by the accumulation of fat in liver cells in people who drink little or no alcohol, is classically tied to obesity, insulin resistance, and metabolic syndrome. But those familiar culprits explain only part of the picture, and scientists have increasingly looked toward environmental exposures for missing pieces. Benzene was a natural candidate. Earlier work had linked low-level ambient benzene to elevated mortality in a national English cohort, and laboratory studies had shown that the chemical disrupts mitochondrial function, impairs fatty acid oxidation, and reprograms lipid metabolism, disturbances that closely mirror the core pathology of fatty liver disease.

The new investigation, published in iScience, harnessed the UK Biobank, a prospective cohort of roughly half a million community-dwelling adults recruited across 22 assessment centers since 2006. After exclusions, 401,472 participants entered the primary analysis, followed for a median of 12.4 years, during which 5,848 developed incident NAFLD. To estimate each participant’s exposure, the team linked geocoded home addresses to annual benzene concentrations generated at a one-kilometer resolution by the UK Department for Environment, Food and Rural Affairs atmospheric dispersion and chemical transport model, an exposure surface validated against ground monitoring with a coefficient of determination of about 0.82. For people who moved during follow-up, the researchers calculated time-weighted average concentrations across each address, a refinement that reduces exposure misclassification.

The headline result was striking. For each interquartile-range increment in benzene concentration, just 0.151 micrograms per cubic meter, the risk of developing NAFLD rose by 26 percent in fully adjusted Cox proportional hazards models, an association with a p-value on the order of 10 to the minus 40. When participants were sorted into exposure quartiles, those in the highest quartile faced a 54 percent higher risk than those in the lowest. The relationship was not strictly linear. A two-piecewise threshold analysis identified an inflection point near 0.3 micrograms per cubic meter, below which the association was modest and above which it grew markedly steeper, hinting that the liver’s defenses may be progressively overwhelmed as exposure climbs past a certain level.

Robustness was tested from multiple angles. The association held when death was treated as a competing event, when NAFLD was redefined using a combination of the hepatic steatosis index and hospital coding, and when the analysis was restricted to participants who had lived at the same address for at least ten years. Excluding early follow-up cases to guard against reverse causation changed little. In multipollutant models adjusting for nitrogen dioxide and fine and coarse particulate matter, the benzene effect was attenuated but remained significant, suggesting the chemical carries an independent signal even within the complex cocktail of urban air pollution. Subgroup analyses across ethnicity, smoking status, physical activity, and body mass index showed consistent directions of effect, with slightly stronger associations among current drinkers and people with diabetes.

Genetics entered the picture through a polygenic risk score built from 31 independent variants identified in large genome-wide association studies, including well-known NAFLD loci such as PNPLA3, TM6SF2, GCKR, and MBOAT7. Each standard-deviation increase in the score was associated with a 36 percent higher risk of NAFLD, and participants in the highest genetic-risk tertile faced a 44 percent greater risk than those in the lowest. Most provocatively, the joint analysis revealed that people carrying both high genetic risk and high benzene exposure had the highest incidence of all, a 73 percent elevation compared with the low-risk, low-exposure reference group. Formal tests showed the interaction departed significantly from additivity, with a relative excess risk due to interaction of 0.27, indicating that benzene and genetic susceptibility act synergistically rather than simply stacking their effects.

The mechanistic centerpiece of the study, however, was biological aging. The researchers computed four complementary aging indices from baseline blood biomarkers: PhenoAge, which integrates nine clinical markers through a Gompertz regression model; homeostatic dysregulation, which measures how far multiple physiological parameters deviate from a healthy reference distribution using Mahalanobis distance; allostatic load, a composite of twelve biomarkers reflecting cumulative physiological stress; and accelerated biological aging, the residual of biological age regressed on chronological age. Mediation analysis with 5,000 bootstrap resamples showed that accelerated biological aging mediated about 6.5 percent of the benzene-NAFLD association, with homeostatic dysregulation and allostatic load contributing smaller but directionally consistent shares of roughly 3.1 and 2.5 percent. PhenoAge alone showed no stable mediating effect.

That aging pathway is biologically plausible, and the surrounding literature helps explain why. Benzene is metabolized in the liver by the enzyme CYP2E1 into reactive intermediates such as benzoquinone and hydroquinone, which generate reactive oxygen species and erode mitochondrial antioxidant defenses. The resulting oxidative injury activates inflammatory signaling through NF-kappa-B and p38-MAPK, promotes lipid peroxidation, and disturbs hepatic energy metabolism. Occupational studies have shown that highly exposed workers carry epigenetic clocks averaging about 2.1 years ahead of their chronological age, along with shortened leukocyte telomeres and aberrant methylation at immune and metabolic gene sites. In mice, twelve weeks of low-dose benzene inhalation raised hepatic inflammatory cytokines more than twofold, cut mitochondrial membrane potential by 35 percent, and nearly doubled malondialdehyde, a marker of lipid peroxidation. Accelerated hepatocyte aging, in turn, is accompanied by impaired fatty acid oxidation and compensatory upregulation of fat-synthesis pathways, a recipe for lipid accumulation.

The team also pushed the findings toward prediction and external consistency. Among ten machine-learning algorithms, a gradient boosting machine performed best, achieving an area under the receiver-operating-characteristic curve of 0.753 in a held-out validation set, with Shapley additive explanations ranking PhenoAge acceleration as the single most important predictive feature, ahead of sex, body mass index, and benzene exposure itself. A nomogram derived from the model offers individualized risk estimation. In an independent analysis of 1,681 participants from the US National Health and Nutrition Examination Survey, higher urinary trans,trans-muconic acid, a benzene exposure biomarker, was associated with greater odds of hepatic steatosis, though the authors caution that this supportive result should not be regarded as definitive replication given differing exposure metrics and outcome definitions.

The study’s limitations are worth keeping in view. Benzene in ambient air travels with other volatile organic compounds such as toluene and xylene, whose contributions could not be fully disentangled, and NAFLD was ascertained primarily from hospital coding, which may miss early or non-hospitalized cases. Alcohol intake was captured through self-report, and the UK Biobank’s famously healthy volunteers may temper generalizability. Even so, the scale of the cohort, the rigor of the sensitivity analyses, and the convergence of genetic, aging, and exposure data make a compelling case that benzene deserves a place among the environmental risk factors for metabolic liver disease. The findings also carry a broader message for environmental health: aging-related pathways, not just traditional metabolic measures, may be essential to understanding how everyday chemical exposures inscribe themselves on long-term health, and air quality standards may need to consider the liver alongside the lungs and the heart.

Subject of Research: The association between long-term ambient benzene exposure and incident non-alcoholic fatty liver disease, mediated by accelerated biological aging.

Article Title: Long-term ambient benzene exposure increases incident NAFLD risk through accelerated biological aging

Article References: Li, Y., Peng, Z., Zhang, J., Cao, H., & Zhang, J. (2026). Long-term ambient benzene exposure increases incident NAFLD risk through accelerated biological aging. iScience, 29(10), Article 117035. https://doi.org/10.1016/j.isci.2026.117035

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117035

Keywords: benzene, NAFLD, fatty liver disease, air pollution, biological aging, UK Biobank, polygenic risk score, epigenetics, oxidative stress, mitochondrial dysfunction, environmental health, epidemiology