Joint association of frailty index and biological aging with all-cause and cause-specific mortality: a population-based longitudinal cohort study

Background: The role of frailty in all-cause, cardiovascular, and cancer mortality is debatable, and the modification effect of biological aging remains unclear. Therefore, we aimed to evaluate the joint association of frailty index and biological aging with all-cause and cause-specific mortality.
Methods: In this population-based cohort study, data were obtained from the National Health and Nutrition Examination Survey (NHANES) and National Death Index (NDI). Demographic variables were extracted, frailty index was constructed, and biological aging was calculated. All-cause deaths, cancer deaths, and cardiovascular disease (CVD) deaths were extracted as outcomes. Cox proportional hazards regression models were used to estimate the correlations, stratified subgroup analyses were used to figure out effect modifiers, and sensitivity analyses were used to confirm the robustness.
Results: A total of 22,729 NHANES participants were included in this study, with 6786 all-cause deaths, 1830 CVD deaths, and 1396 cancer deaths occurred during an average follow-up of 8.5 years over a total of 192,601 person-years. The hazard ratios (HRs) of delayed aging group for all-cause mortality, CVD mortality, and cancer mortality were 0.45 (95 % CI: 0.41–0.49), 0.39 (95 % CI: 0.34–0.45), and 0.54 (95 % CI: 0.46–0.63), respectively, compared to accelerated aging group (P for all comparisons < 0.001). Likewise, the frailty index score was positively associated with all-cause mortality (HR, 1.06 [95 % CI, 1.06–1.06] per 0.01 increase in the frailty index), cardiovascular (CVD) mortality (HR, 1.07 [95 % CI, 1.06–1.07] per 0.01 increase in the frailty index), and cancer mortality (HR, 1.04 [95 % CI, 1.03–1.04] per 0.01 increase in the frailty index). The associations of frailty index with all-cause mortality and CVD mortality were modified by biological aging (P for interaction = 0.044), but cancer mortality was not (P for interaction = 0.482).
Conclusions: Accelerated biological aging is associated with higher frailty index, whereas delayed biological aging is inversely associated with risk of all-cause mortality, CVD mortality, and cancer mortality. Biological aging is effect modification among the associations of frailty index with all-cause mortality and CVD mortality, but not for cancer mortality. These findings suggest that for people with high frailty index and acceleration biological aging, to lower frailty degree and decrease biological aging acceleration by approaches such as lifestyle modifications might be beneficial for individual's longevity and lifespan.