Independent impacts of aging on mitochondrial DNA quantity and quality in humans

Abstract

BackgroundThe accumulation of mitochondrial DNA (mtDNA) mutations, and the reduction of mtDNA copy number, both disrupt mitochondrial energetics, and may contribute to aging and age-associated phenotypes. However, there are few genetic and epidemiological studies on the spectra of blood mtDNA heteroplasmies, and the distribution of mtDNA copy numbers in different age groups and their impact on age-related phenotypes. In this work, we used whole-genome sequencing data of isolated peripheral blood mononuclear cells (PBMCs) from the UK10K project to investigate in parallel mtDNA heteroplasmy and copy number in 1511 women, between 17 and 85 years old, recruited in the TwinsUK cohorts.ResultsWe report a high prevalence of pathogenic mtDNA heteroplasmies in this population. We also find an increase in mtDNA heteroplasmies with age (β = 0.011, P = 5.77e-6), and showed that, on average, individuals aged 70-years or older had 58.5% more mtDNA heteroplasmies than those under 40-years old. Conversely, mtDNA copy number decreased by an average of 0.4 copies per year (β = −0.395, P = 0.0097). Multiple regression analyses also showed that age had independent effects on mtDNA copy number decrease and heteroplasmy accumulation. Finally, mtDNA copy number was positively associated with serum bicarbonate level (P = 4.46e-5), and inversely correlated with white blood cell count (P = 0.0006). Moreover, the aggregated heteroplasmy load was associated with blood apolipoprotein B level (P = 1.33e-5), linking the accumulation of mtDNA mutations to age-related physiological markers.ConclusionsOur population-based study indicates that both mtDNA quality and quantity are influenced by age. An open question for the future is whether interventions that would contribute to maintain optimal mtDNA copy number and prevent the expansion of heteroplasmy could promote healthy aging.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4287-0) contains supplementary material, which is available to authorized users.

STAMP: a multiplex sequencing method for simultaneous evaluation of mitochondrial DNA heteroplasmies and content

“…180 (99%) lymphoblasts possessed at least one heteroplasmy in mtDNA ( Figure S3B). Similar to our previous study on lymphoblast mtDNA (5), the number of mtDNA heteroplasmies identified in lymphoblasts was consistently greater than those of whole blood, at about 1 heteroplasmy of VAF≥1-2% (14,16), implying that mtDNA of lymphoblasts may enrich for pre-existing variants in somatic cells that are undetectable at a tissue level.…”

“…But only mtDNA heteroplasmy incidence showed a significant difference between these two age groups ( Figure 4G; Cohen's d=0.42, P=0.0055). The lack of a significant association of mtDNA content with age ( Figure 4H; Cohen's d=-0.12, P=0.44 for STAMP-CN; Cohen's d=-0.07, P=0.71 for qPCR-CN) might be due to insufficient statistical power, since only a mild annual decrease of 0.4 mtDNA copies (0.24% of the population average in 1511 individuals, P=0.0097) in blood was noted in our previous study (14).…”

“…With both mtDNA heteroplasmies and mtDNA content measured in the same sample, we then evaluated how age impacts these mtDNA characteristics in lymphoblast samples as compared to what we previously observed in mtDNA of blood samples, using the WGS dataset of the UK10K project (14).…”

“…Likewise, whole-genome sequencing (WGS) with deep and uniform coverage on mtDNA can be used to measure mtDNA copy number and low-fraction heteroplasmies in tissues (14,15). However, WES and WGS are not cost-effective for investigators to study mtDNA with a large sample size.…”

Measuring biological aging in humans: A quest

“…Studies that use multiple mitochondrial biomarkers have revealed only a slight intercorrelation between the markers and aging, suggesting that they tap into different biological dimensions (Lara et al, 2015;Larsen et al, 2012;Marrocco, Altieri, & Peluso, 2017;Xia, Chen, McDermott, & Han, 2017). Recent data support the hypothesis that mtDNA copy number and degree of heteroplasmy-assessed in human blood cells and in tissue biopsies-provide information on mitochondrial physiology that is relevant for aging and age-related diseases (McDermott et al, 2018;Moore et al, 2017;Zhang, Wang, Ye, Picard, & Gu, 2017). Both measurements can be utilized via PCR methods or, more recently, by derivation from genome sequencing data (Ding et al, 2015).…”