Abstract
BACKGROUND: Systemic chronic inflammation occurs with age. The association of the leukocyte mitochondrial DNA copy number, a measure of mitochondrial function in aging, with the temporal profile of serum high-sensitivity C-reactive protein and mortality risk remains uncertain. The objectives of this study were to examine the association of the leukocyte mitochondrial DNA copy number with longitudinal high-sensitivity C-reactive protein levels and the association of the longitudinal high-sensitivity C-reactive protein levels with mortality risk. METHODS: This prospective cohort study included 3928 adults aged ≥ 55 years without systemic inflammation in the baseline examination of the Healthy Aging Longitudinal Study in Taiwan, which started in 2009. Each participant received leukocyte mitochondrial DNA copy number measurement using a fluorescence-based quantitative polymerase chain reaction at baseline, serum high-sensitivity C-reactive protein measurements at baseline and the follow-up examination five years later, and the ascertainment of all-cause death (until November 30, 2021). The relationships among the leukocyte mitochondrial DNA copy number, longitudinal serum high-sensitivity C-reactive protein levels, and time to all-cause mortality were examined using the joint longitudinal and survival modeling analysis. RESULTS: Of the 3928 participants (mean age: 69 years; 2060 [52%] were women), 837 (21%) died during follow-up. In the adjusted analysis, one standard deviation lower natural log-transformed baseline leukocyte mitochondrial DNA copy number was associated with an increase of 0.05 (95% confidence interval [CI], 0.02 to 0.08) standard deviation in serum high-sensitivity C-reactive protein in subsequent years. An increase of 1 standard deviation in instantaneous high-sensitivity C-reactive protein levels was associated with a hazard ratio (HR) for all-cause mortality of 1.22 (95% CI, 1.14 to 1.30). Similar results were obtained after further adjusting for baseline high-sensitivity C-reactive protein levels (HR [95% CI], 1.27 [1.16 to 1.38]) and after excluding those with serum high-sensitivity C-reactive protein above 10 mg/L (HR [95% CI], 1.21[1.11 to 1.31]) or 3 mg/L (HR [95% CI], 1.19 [1.06 to 1.31]) during follow-up. CONCLUSIONS: A lower leukocyte mitochondrial DNA copy number was associated with persistently higher high-sensitivity C-reactive protein levels. Moreover, these higher time-varying high-sensitivity C-reactive protein levels were instantaneously associated with a higher risk of death.