ABSTRACT:
Loneliness is a psychosocial determinant increasingly recognised for its contribution to chronic disease, morbidity, and premature mortality. However, its causal influence on biological aging−indexed by leukocyte telomere length (LTL)−remains uncertain. Using UK Biobank data, we combined observational analyses, longitudinal G-methods, and both one-sample and two-sample Mendelian randomisation (MR) to clarify this relationship and assess its potential links with 30 chronic conditions. Across traditional and causal observational models, loneliness was not directly associated with reduced LTL but acted indirectly through elevated risks of several conditions, including asthma, bipolar disorder, cataract, chronic liver disease, hearing impairment, migraine, psychoactive substance misuse, and rheumatoid arthritis. Moreover, six conditions−anaemia, asthma, chronic liver disease, hearing loss, migraine, and peripheral arterial disease−modified the loneliness–LTL association, intensifying telomere shortening among individuals experiencing both loneliness and these comorbidities. Notably, some diseases served as both mediators and effect modifiers, suggesting a potential feedback loop that may compound vulnerability over time. Complementing these findings, two-sample MR provided genetic evidence supporting a direct causal effect of loneliness on shorter LTL (β = -0.025, 95% CI: -0.041 to -0.010, P = 0.0010), with no indication of reverse causality. Together, these convergent results indicate that loneliness contributes to accelerated cellular aging through intertwined direct and disease-mediated pathways. While MR captures the lifelong effect of genetic susceptibility to loneliness, G-methods quantify its observed impact over shorter exposure windows. These insights underscore loneliness and chronic disease as critical intervention targets to slow biological aging and reduce long-term public health burden.