Influence of cell distribution and diabetes status on the association between mitochondrial <scp>DNA</scp> copy number and aging phenotypes in the In<scp>CHIANTI</scp> study

Moore, Ann Zenobia; Ding, Jun; Tuke, Marcus A.; Wood, Andrew R.; Bandinelli, Stefania; Frayling, Timothy M.; Ferrucci, Luigi

doi:10.1111/acel.12683

Cited by 28 publications

(29 citation statements)

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“…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).…”

Section: Mitochondrial Functionmentioning

confidence: 88%

“…Both measurements can be utilized via PCR methods or, more recently, by derivation from genome sequencing data (Ding et al, ). High mtDNA copy number is considered to be a proxy measure of mitochondrial volume/function, and high mtDNA copy number in blood is associated with better health and survival among older persons, but the direction of this association may be reversed in certain conditions, such as diabetes (Mengel‐From et al, ; Moore et al, ). Humans have detectable levels of mtDNA‐acquired point mutations in circulating cells and whole blood and, notably, the burden of mutations increase with aging even when measured in inducible pluripotent stem cells (Kang et al, ; Qian et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Measuring biological aging in humans: A quest

et al. 2019

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The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well‐established clinical guidelines. Physicians are often forced to engage in cycles of “trial and error” that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are “aging faster” to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.

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Section: Mitochondrial Functionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Measuring biological aging in humans: A quest

et al. 2019

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“…To validate mtDNA-CN measurements in the filtered GTEx data, we determined the association between mtDNA-CN and known correlated measures, including age, sex, and neutrophil count [18,20,21]. We observed a significant association with neutrophil count (p=5e-05), with higher neutrophil count associated with lower mtDNA-CN.…”

Section: Determination and Validation Of Mtdna-cn Metricmentioning

confidence: 94%

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

Yang

Castellani

Longchamps

et al. 2020

Preprint

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Mitochondrial DNA copy number (mtDNA-CN) can be used as a proxy for mitochondrial function and is associated with a number of aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect risk for diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated the relationships between mtDNA-CN measured in whole blood and gene expression from whole blood as well as 47 additional tissues. We evaluated associations between blood-derived mtDNA-CN and gene expression in whole blood for 418 individuals, correcting for known confounders and surrogate variables derived from RNA-sequencing. Using a permutation-derived cutoff (p<2.70e-6), mtDNA-CN was significantly associated with expression for 721 genes in whole blood, including nuclear genes that are required for mitochondrial DNA replication. Significantly enriched pathways included splicing (p=1.03e-8) and ubiquitin-mediated proteolysis (p=2.4e-10). Genes with target sequences for the mitochondrial transcription factor NRF1 were also enriched (p=1.76e-35). In non-blood tissues, there were more significantly associated genes than expected in 30 out of 47 tested tissues, suggesting that global gene expression in those tissues is correlated with mtDNA-CN. Pathways that were associated in multiple tissues included RNA-binding, catalysis, and neurodegenerative disease. We evaluated the association between mtDNA-CN and incident neurodegenerative disease in an independent dataset, the UK Biobank, using a Cox proportional-hazards model. Higher mtDNA-CN was significantly associated with lower risk for incident neurodegenerative disease (HR=0.73, 95% CI= 0.66;0.90). The observation that mtDNA-CN measured in whole blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Key pathways in maintaining cellular homeostasis, including splicing, RNA binding, and catalytic genes were significantly associated with mtDNA-CN, reinforcing the importance of mitochondria in aging-related disease. As a specific example, genes involved in neurodegenerative disease were significantly enriched in multiple tissues. This finding, validated in a large independent cohort study showing an inverse association between mtDNA-CN and neurodegenerative disease, solidifies the link between blood-derived mtDNA-CN, altered gene expression in both blood and non-blood tissues, and aging-related disease.

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“…Indeed, we Importantly, our results indicate that MT DNA abundance is negatively associated with increased age, higher frailty, increased smoking behaviour as well as increased BMI. We hypothesized that MT copy number may be diminished due to lower rates of replication with increasing age20,21 , due to oxidative stress induced by smoking22 , by low-grade inflammation and metabolic stress due higher BMI20 or due to prior health related conditions (as expressed by the frailty index)23,24 . Since individuals with a healthier lifestyle tend to have higher MT DNA abundance, we also observed a reduced incidence of hypertensive disorders such as portal hypertension and cardiomegaly as well as lower mortality in those individuals.…”

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Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance

Hägg¹,

Jylhävä²,

Wang³

et al. 2020

Preprint

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Somatically acquired whole chromosome loss in nucleated blood cells is an indicator of immune aging and genomic instability. However, little is known about aging, lifestyle and genetic factors influencing mitochondrial (MT) DNA abundance. In this study, MT DNA abundance was estimated from the weighted intensities of probes mapping to the MT genome in 295,150 participants from the UK Biobank. We found that abundance of MT DNA was significantly elevated in women compared to men, was negatively correlated with advanced age, more packyears, greater body-mass index, higher frailty index as well as elevated red and white blood cell count and, importantly, lower mortality. In addition, several biochemistry markers in blood related to cholesterol metabolism, ion homeostasis and kidney function were found to be significantly associated with MT DNA abundance. By performing a genome-wide association study, we identified 50 independent regions genome-wide significantly associated with MT DNA abundance which harbour multiple genes involved in the immune system, cancer as well as mitochondrial function. Using mixed effects models, we estimated the SNP-heritability of MT DNA abundance to be around 8%. To investigate the consequence of altered MT DNA abundance, we performed a phenome-wide association study and found that MT DNA abundance is involved in risk for leukaemia, hematologic diseases as well as hypertension. Thus, estimating MT DNA abundance from genotyping arrays has the potential to provide novel insights into age- and disease relevant processes, particularly those related to immunity and established mitochondrial functions.

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

Cited by 28 publications

References 8 publications

Measuring biological aging in humans: A quest

Measuring biological aging in humans: A quest

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance

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