The interplay of circadian syndrome and biological aging in all-cause mortality: a stratified mediation analysis by cancer status

BACKGROUND: Circadian Syndrome (CircS) is a potent risk factor for adverse health outcomes. Its impact on biological aging, particularly among vulnerable populations like cancer survivors, and the pathways through which it influences mortality remain poorly understood. METHODS: We analyzed data from 10,191 adults in the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Mortality data was accessed from the NHANES-linked National Death Index database. CircS was defined as a score ≥ 4 based on seven components. Biological aging was quantified using Klemera-Doubal Method Biological Age, Phenotypic Age, and their age-acceleration derivatives. Nonlinear regression with restricted cubic splines was used to assess the association between CircS and biological aging, stratified by cancer history. Causal mediation analysis within a Cox proportional hazards framework was used to investigate the mediating role of biological aging in the association between CircS and all-cause mortality, stratified by cancer history. RESULTS: The population had a median age of 49 years, and median follow-up period of 90 months, with 48.5% were males. CircS was significantly associated with advanced biological age across all four metrics (P < 0.001). This association was non-linear in cancer-free individuals, with a steeper increase at higher scores, but was linear in cancer survivors. In cancer-free population, the association between CircS and mortality was largely mediated by biological aging (proportion mediated: 79.1-100%, (P < 0.001). In cancer survivors, biological aging played suppressor mediating effect, where a detrimental indirect effect through accelerated aging masked a slightly protective direct effect of CircS on mortality. CONCLUSION: CircS is associated with accelerated biological aging. Biological aging is a critical pathway linking CircS to mortality, especially among cancer survivors. These findings highlight the importance of circadian health in the aging process and suggest that biological age may be a potential therapeutic target for mitigating mortality risk, particularly in cancer survivors.