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

Ashar, Foram N.; Moes, Anna; Moore, Ann Zenobia; Grove, Megan L.; Chaves, Paulo H.M.; Coresh, Josef; Newman, Anne B.; Matteini, Amy M.; Bandeen‐Roche, Karen; Boerwinkle, Eric; Walston, Jeremy D.; Arking, Dan E.

doi:10.1007/s00109-014-1233-3

Cited by 197 publications

(169 citation statements)

References 37 publications

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“…10 In populationbased studies, higher mtDNA copy number in peripheral blood has been associated with lower risk of mortality. 11 This association was also observed in patients undergoing hemodialysis. 12 Regarding kidney function, higher mtDNA copy number in peripheral blood has been associated with lower risk of diabetes, a risk factor of CKD, and lower prevalence of albuminuria, a marker of kidney damage.…”

mentioning

confidence: 68%

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

Tin

Grams²,

Ashar

et al. 2016

JASN

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Mitochondrial dysfunction in kidney cells has been implicated in the pathogenesis of CKD. Mitochondrial DNA (mtDNA) copy number is a surrogate measure of mitochondrial function, and higher mtDNA copy number in peripheral blood has been associated with lower risk of two important risk factors for CKD progression, diabetes and microalbuminuria. We evaluated whether mtDNA copy number in peripheral blood associates with incident CKD in a population-based cohort of middle-aged adults. We estimated mtDNA copy number using 25 high-quality mitochondrial single nucleotide polymorphisms from the Affymetrix 6.0 array. Among 9058 participants, those with higher mtDNA copy number had a lower rate of prevalent diabetes and lower C-reactive protein levels and white blood cell counts. Baseline eGFR did not differ significantly by mtDNA copy number. Over a median follow-up of 19.6 years, 1490 participants developed CKD. Higher mtDNA copy number associated with lower risk of incident CKD (highest versus lowest quartile: hazard ratio 0.65; 95% confidence interval, 0.56 to 0.75; P,0.001) after adjusting for age, sex, and race. After adjusting for additional risk factors of CKD, including prevalent diabetes, hypertension, C-reactive protein level, and white blood cell count, this association remained significant (highest versus lowest quartile: hazard ratio 0.75; 95% confidence interval, 0.64 to 0.87; P,0.001). In conclusion, higher mtDNA copy number associated with lower incidence of CKD independent of traditional risk factors and inflammation biomarker levels in this cohort. Further research on modifiable factors influencing mtDNA copy number may lead to improvement in the prevention and treatment of CKD.

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mentioning

confidence: 68%

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

Tin

Grams²,

Ashar

et al. 2016

JASN

Self Cite

120

115

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“…However, robust evidence for the role of mitochondria in human health and aging is still lacking due to difficulty of assessing mitochondrial volume and function in vivo in large samples. Recently, relatively high‐throughput estimates of mitochondrial DNA copy number (mtDNA‐CN) have become feasible by quantitative PCR or extracting information from DNA microarray or sequencing data (Ashar et al ., 2015; Qian et al ., 2017). However, previous studies that attempted to relate mtDNA‐CN to phenotypes generally ignored technical factors that may contribute to variability in mtDNA‐CN and may lead to inconsistent and potentially biased estimates of association.…”

Section: Introduction Results Discussionmentioning

confidence: 99%

Influence of cell distribution and diabetes status on the association between mitochondrial DNA copy number and aging phenotypes in the InCHIANTI study

et al. 2017

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SummaryMitochondrial DNA copy number (mtDNA‐CN) estimated in whole blood is a novel marker of mitochondrial mass and function that can be used in large population‐based studies. Analyses that attempt to relate mtDNA‐CN to specific aging phenotypes may be confounded by differences in the distribution of blood cell types across samples. Also, low or high mtDNA‐CN may have a different meaning given the presence of diseases associated with mitochondrial damage. We evaluated the impact of blood cell type distribution and diabetes status on the association between mtDNA‐CN and aging phenotypes, namely chronologic age, interleukin‐6, hemoglobin, and all‐cause mortality, among 672 participants of the InCHIANTI study. After accounting for white blood cell count, platelet count, and white blood cell proportions in multivariate models, associations of mtDNA‐CN with age and interleukin‐6 were no longer statistically significant. Evaluation of a statistical interaction by diabetes status suggested heterogeneity of effects in the analysis of mortality (P < 0.01). The magnitude and direction of associations between mtDNA‐CN estimated from blood samples and aging phenotypes are influenced by the sample cell type distribution and disease status. Therefore, accounting for these factors may aid understanding of the relevance of mitochondrial DNA copy number to health and aging.

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“…Similar to what we found in a genetic mouse model of female obesity (88), we found that mtDNA copy number was reduced in fetal livers of female and male offspring from maternal HFD exposure, with levels not being further reduced by the addition of paternal obesity. In a number of tissues mtDNA copy is tightly associated with different types of cancer (49,57,58), cellular telomere length (82), and tissue-specific processes (15); therefore, disruption of mtDNA copy number is linked with a number of diseases and mortality (2,65). As offspring from female rodents fed high-calorie diets (before conception through to lactation) are smaller and have metabolic syndrome, similar to phenotypes reported in offspring generated in our study and others (35,52), reductions in mtDNA content in fetal tissues perhaps could be one of the mechanisms for a later predisposition to chronic disease.…”

Section: Alterations To Fetal Health From Combined Paternal and Matermentioning

confidence: 99%

When two obese parents are worse than one! Impacts on embryo and fetal development

McPherson

Bell

Zander-Fox

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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McPherson NO, Bell VG, Zander-Fox DL, Fullston T, Wu LL, Robker RL, Lane M. When two obese parents are worse than one! Impacts on embryo and fetal development. Am J Physiol Endocrinol Metab 309: E568 -E581, 2015. First published July 21, 2015; doi:10.1152/ajpendo.00230.2015.-The prevalence of overweight and obesity in reproductive-age adults is increasing worldwide. While the effects of either paternal or maternal obesity on gamete health and subsequent fertility and pregnancy have been reported independently, the combination of having both parents overweight/ obese on fecundity and offspring health has received minimal attention. Using a 2 ϫ 2 study design in rodents we established the relative contributions of paternal and maternal obesity on fetal and embryo development and whether combined paternal and maternal obesity had an additive effect. Here, we show that parental obesity reduces fetal and placental weights without altering pregnancy establishment and is not dependent on an in utero exposure to a high-fat diet. Interestingly combined parental obesity seemed to accumulate both the negative influences of paternal and maternal obesity had alone on embryo and fetal health rather than an amplification, manifested as reduced embryo developmental competency, reduced blastocyst cell numbers, impaired mitochondrial function, and alterations to active and repressive embryonic chromatin marks, resulting in aberrant placental gene expression and reduced fetal liver mtDNA copy numbers. Further understanding both the maternal cytoplasmic and paternal genetic interactions during this early developmental time frame will be vital for understanding how developmental programming is regulated and for the proposition of interventions to mitigate their effects. blastocyst; oocyte; sperm; embryo; fertility; infertility; obesity THE PREVALENCE OF OVERWEIGHT and obesity in reproductive-age adults is increasing worldwide (62). For example, in America it is estimated that 70.9% of males and 61.9% of women are classified as overweight/obese (62). The comorbidities associated with obesity have been well defined; however, until recently the impact on pregnancy and fetal development has been less recognized. Although the effects of either paternal or maternal obesity on gamete health and subsequent fertility and pregnancy have been reported independently, the combination of having both parents overweight/obese on fecundity and offspring health has received minimal attention. This information is essential, as the percentage of couples of reproductive age with both partners overweight/ obese is increasing and is the predominant situation in many countries (62).To date, there have only been three studies that have assessed the combined effects of maternal and paternal obesity on pregnancy and fetal health, two in human-assisted reproductive technology (ART) cohorts and one using a rodent high-fat diet model (41,67,76). These studies found no effect of maternal and paternal obesity on pregnancy establishment (41, 67, 76); however, when ...

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

Cited by 197 publications

References 37 publications

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

Influence of cell distribution and diabetes status on the association between mitochondrial DNA copy number and aging phenotypes in the InCHIANTI study

When two obese parents are worse than one! Impacts on embryo and fetal development

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