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BACKGROUND: Mosaic chromosomal alterations (mCAs) served as a novel indicator of genomic aging. We aimed to investigate the association of expanded mCAs (cell fraction ≥ 10%) with all-cause and cause-specific mortality, and to examine the joint effect of expanded mCAs and frailty index (FI), an indicator of phenotypic aging, on mortality in two large prospective cohorts.METHODS: A total of 100,237 participants in the China Kadoorie Biobank (CKB) and 456,283 participants in the UK Biobank (UKB) were included, followed till Dec 31, 2023, and Nov 30, 2022, respectively. MoChA pipeline was used to detect expanded mCAs events and the subtypes. FIs were calculated using previously validated equations, with 28 items included in the CKB and 49 items in the UKB, and categorized participants into three groups: robust, prefrail, and frail. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to examine the associations of the expanded mCAs and joint categories of frailty-mCAs with all-cause and cause-specific mortality by using Cox proportional hazards models. The combined effect values of two cohorts were estimated using random-effects models by meta-analysis.RESULTS: The prevalence of expanded mCAs in the CKB and UKB was 2.2% and 3.4%, respectively. After a median follow-up of 17.2 years in the CKB and 13.7 years in the UKB, expanded mCAs carriers had a higher risk of all-cause (HRs [95% CIs]: 1.20 [1.16, 1.24]) and risks of cause-specific mortality (HRs [95% CIs]: 1.27 [1.21, 1.34], 1.13 [1.02, 1.25], and 1.24 [1.12, 1.37] for death from cancers, circulatory diseases, and respiratory diseases, respectively). Such associations largely did not overlap with FI, especially for all-cause and cancer mortality. Joint analyses revealed that individuals with lower frailty level but with expanded mCAs had a comparable and even higher risk of cancer mortality compared to those with higher frailty level but without mCAs. Similar pattern was also found in terms of adjusted 10-year cancer mortality rates.CONCLUSIONS: Our findings suggested that expanded mCAs were significantly associated with all-cause and cause-specific deaths and could serve as a complement to the FI in providing a more comprehensive perspective on mortality risk, especially for cancer mortality.