Aging is an inevitable time-dependent decline in physiological organ function and a complex process occurring at multiple levels, contributing to the development of age-related diseases (Ferrucci et al., 2018). Among these, cancer is rapidly growing worldwide, which has become an important global health burden. It is predicted that approximately 60% of cancer incidence and 70% of cancer-related mortality will occur in people over the age of 65 (Pal et al., 2010), and aging has emerged as a major risk factor for the occurrence and development of cancer (Aunan et al., 2017).

To investigate the degree of aging in the health of subjects, there is heterogeneity in health status based on chronological age alone (Aunan et al., 2017), i.e., people with the same chronological age may not have the same aging-related symptom (Ferrucci et al., 2018). However, biological age has been shown to be a better indicator of remaining life expectancy than chronological age and can better reflect an individual's physiology and risk of age-related mortality (Levine, 2013; Liu et al., 2018). Up to date, biological age has been constructed by omics data (DNA methylation, metabolomics, proteomics, etc.), and clinical biomarkers (blood chemistry, hematology and anthropometry, etc.) (Hägg et al., 2019; Jylhävä et al., 2017; Li et al., 2023). Among these, biological age, called “phenotypic age”, calculated by Levine based on the association of chronological age and nine clinical biomarkers with aging-related mortality (Levine et al., 2018), might represent the characteristics of aging in the body at the cellular level (Belsky et al., 2018; Liu et al., 2018). In order to quantify the differences between individuals in biological aging, further research proposed Phenotypic Age Acceleration (PhenoAgeAccel), defined as the residual resulting from the regression of phenotypic age on chronological age. A few studies have shown that biological aging based on phenotypic age was related to increased risks of overall cancer, breast, lung, and colorectal cancers (Ma et al., 2023; Mak et al., 2023), as well as cancer mortality (Levine et al., 2018; Liu et al., 2018) However, there has been a lack of data on the relationship between biological aging based on phenotypic age and risk of site-specific cancers incidence and mortality. There are substantial evidences that adopting a healthy lifestyle (including but not limited to avoiding smoking and harmful alcohol consumption, maintaining a healthy weight and diet, being physically active) is a “best buy” strategy for preventing and managing cancer (Zhang et al., 2020). Several studies have shown that unhealthy lifestyle factors are associated with accelerated biological aging by different algorithms (Fan et al., 2021; Fiorito et al., 2019; Zhao et al., 2019). Therefore, we hypothesized that individuals with biological aging and maintaining healthy lifestyle may have reduced risks of cancer incidence and mortality.

In this study, we aimed to investigate the association between biological aging and risks of cancer incidence and mortality using data from the large population-based UK Biobank cohort, and further to explore whether the healthy lifestyle could weaken these risks.