Association of mitochondrial DNA levels with frailty and all-cause mortality

Abstract

Mitochondrial function is altered with age and variants in mitochondrial DNA (mtDNA) modulate risk for several age-related disease states. However, the association of mtDNA copy number, a readily available marker which reflects mitochondrial depletion, energy reserves, and oxidative stress, on aging and mortality in the general population has not been addressed. To assess the association between mtDNA copy number and two primary outcomes--prevalent frailty and all-cause mortality--we utilize data from participants who were from two multicenter, multiethnic, community-based, prospective studies--the Cardiovascular Health Study (CHS) (1989-2006) and the Atherosclerosis Risk in Communities (ARIC) study (1987-2013). A total of 4892 participants (43.3% men) from CHS and 11,509 participants (44.9% men) from ARIC self-identifying as white or black were included in the analysis. mtDNA copy number, the trait of interest, was measured using a qPCR-based method in CHS and an array-based method in ARIC from DNA isolated from whole blood in participants from both cohorts. In race-stratified meta-analyses, we observe a significant inverse association of mtDNA copy number with age and higher mtDNA copy number in women relative to men. Lower mtDNA copy number was also significantly associated with prevalent frailty in white participants from CHS (OR 0.91, 95% CI 0.85-0.97). Additionally, mtDNA copy number was a strong independent predictor of all-cause mortality in an age- and sex-adjusted, race-stratified analysis of 16,401 participants from both cohorts with a pooled hazard ratio of 1.47 (95% CI 1.33-1.62) for the lowest quintile of mtDNA copy number relative to the highest quintile. Key messages: Mitochondrial DNA (mtDNA) copy number is associated with age and sex. Lower mtDNA copy number is also associated with prevalent frailty. mtDNA copy number is a significant predictor of all-cause mortality in a multiethnic population.

Figure 1. Frailty components in CHS

Association between age, sex and collection site adjusted mitochondrial copy number and frailty components in white samples (top panel) and black samples (bottom panel) from CHS. MtDNA copy number is expressed in terms of standard deviation units. Participants were scored as being at risk (1) or not at risk (0) for each characteristic of frailty. Overall frailty was scored in terms of number of characteristics that each participant was at risk for—robust 0 characteristics, pre-frail 1-2 characteristics and frail >2 characteristics. Effect size estimates are reported as prevalence ratios (details in Methods).

Figure 2. Kaplan-Meier survival curves by quintiles of mtDNA copy number

Kaplan-Meier estimates for all-cause mortality by quintile of mtDNA copy number were calculated for both race groups in CHS and ARIC. Table indicates the total number of people in the model at each time point.

Figure 3. Meta-analysis of effects mtDNA copy number on mortality

Effects of highest copy quintile of copy number relative to lowest quintile from race stratified analyses in each cohort were meta-analyzed using an inverse-variance weighted approach. Model 1 was the baseline model adjusted for age, sex and collection site. Model 2 was more stringent model that included age, sex, collection site, BMI, HDL, total cholesterol, hypertension, and smoking status as covariates, and excluded samples with prevalent CHD, diabetes or previous history of MI.