title: 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.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA.
authors.forename: Foram N
authors.initials: FN
authors.lastname: Ashar
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Moes
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA.
authors.forename: Ann Z
authors.initials: AZ
authors.lastname: Moore
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, 7000 Fannin St, Houston, TX 77030, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Grove
authors.affiliation: Benjamin Leon Center for Geriatric Research and Education and Department of Medicine, Florida International University, 11200 SW 8 St, Miami, FL 33174, USA.
authors.forename: Paulo H M
authors.initials: PHM
authors.lastname: Chaves
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 4200 Fifth Ave, Pittsburgh, PA 15260, USA.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
authors.affiliation: Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Matteini
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Bandeen-Roche
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, 7000 Fannin St, Houston, TX 77030, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Walston
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA.|Department of Medicine, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
mesh_terms: D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D004272:DNA, Mitochondrial; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D015577:Geriatric Assessment / Q000706:statistics & numerical data; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009026:Mortality; D016017:Odds Ratio; D011159:Population Surveillance; D011446:Prospective Studies; D011795:Surveys and Questionnaires; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial