Combined Impact of Telomere Length and Mitochondrial DNA Copy Number on Cognitive Function in Community-Dwelling Very Old Adults

Jeeyon, Lee; Kim, Jung-Ha; Lee, Duk Chul

doi:10.1159/000480427

Cited by 12 publications

(10 citation statements)

References 41 publications

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“…These aging-related neurodegenerative diseases have all underlying mitochondrial pathologies [57][58][59][60] and dysregulated ubiquitination pathways [61]. In particular, mtDNA-CN has been implicated in Alzheimer's disease [62][63][64] and cognitive function [65,66].…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Common pathways and complicated telomere-mitochondria interplay during human ageing were also suggested, although the relationship is still not completely understood [31]. A recent report investigating the combined impact of telomere length and mtDNAcn on cognitive function of communitydwelling very old adults proposed that the combination of the two parameters might be useful for monitoring cognitive decline in older people [7]. The promise of using mtDNAcn and TL as combined biomarkers of health and disease in the future prompted us to investigate their association in the framework of a genetically controlled study design, while also assessing co-twin similarities of monozygotic and dizygotic twin subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental evidence suggested that mitochondrial biogenesis could be modulated by the telomere – p53–PPARG (peroxisome proliferator-activated receptor γ) axis, and also by the telomerase enzyme, but the exact mechanisms are still unknown [ 7 , 48 , 49 ]. Along with in vitro and animal models aiming to reveal the molecular mechanisms underlying the associations of telomere and mitochondrial functions, recent population-based studies have started to investigate the connection between mtDNAcn and TL.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Their maintenance and shortening is a complex process which could be influenced by genetics and epigenetic mechanisms [3,4]. Several environmental factors might contribute to telomere shortening, including oxidative stress, inflammation or psychiatric conditions [5][6][7]. Telomere dysfunction and defects in telomere maintenance could contribute to a higher risk of many aging-related diseases [8], and as some studies found that telomere length (TL) of leukocytes could predict mortality [9,10] and longevity [11], it was suggested as a potential biomarker of biological aging [12,13], yet the exact relationship between TL and aging is not fully understood [14].…”

Section: Introductionmentioning

confidence: 99%

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Positive association and future perspectives of mitochondrial DNA copy number and telomere length – a pilot twin study

Melicher¹,

Illés²,

Littvay³

et al. 2019

aoms

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Introduction: Recent experimental and population studies have highlighted the existence of telomere-mitochondria interplay. Besides studies revealing the molecular mechanisms underlying the associations of telomere defects and mitochondrial functions, investigations of mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) in healthy and disease phenotypes have likewise begun, with the aim of gaining more insights about their relationship in humans. Material and methods: A total of 142 asymptomatic adult twins, comprising 96 monozygotic (MZ) and 46 dizygotic (DZ) twins (mean age: 50.54 ±15.43 years), members of the Hungarian Twin Registry, were included in the analysis. Applying the qPCR standard curve method, we investigated the relationship of mtDNA copy number, telomere length and clinical data, besides assessing co-twin similarities of MZ and DZ twins for their mtDNAcn and TL measures. Results: We found that twins were similar in their intraclass correlation coefficients irrespective of zygosity, suggesting a possibly more important role of common (shared) environmental factors compared to non-shared (unique) environmental and to a smaller degree also individual genetic influences. We confirmed a significant positive association between mtDNAcn and TL (r = 0.28, p < 0.01) in age-and sex-corrected analysis. Following bivariate estimates and correction with significant predictors, the independent positive associations were further verified. Conclusions: Our results extend the until now modest number of studies investigating mtDNAcn and TL simultaneously in humans. In addition, we are the first to examine the relationship between mtDNAcn and telomere length in MZ and DZ twin subjects.

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Mitochondria, its DNA and telomeres in ageing and human population

Zole

Ranka

2018

Biogerontology

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In the last decades, studies about ageing have become more essential as our population grows older. The incidence of age-related diseases increases, which pose challenges both for societies and individuals in terms of life quality and economic impact. Understanding ageing and ageing-related processes will help us to slow down or even prevent these diseases and provide opportunities for healthy ageing; additionally, we all want to live longer. Ageing is a consequence of the interaction between processes that occur over time and genetics interacting with various disease states and an individual's lifestyle. There are several hallmarks of ageing that are generally accepted, but neither of the theories appears to be fully satisfactory. The focus of this article is on two theories of ageing: telomere shortening and mitochondrial DNA (mtDNA) alterations and dysfunction. We discuss characteristic molecular features such as mitochondrial haplogroups, telomere length, mtDNA copy number and heteroplasmy, and how all these traits come together in the ageing population. The recent evidence shows the existence of a strong linkage between these two theories suggesting common molecular mechanisms and a complicated telomere-mitochondria interplay during the humans' ageing. However, this relationship is still not completely understood, which is why it needs more attention.

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Combined Impact of Telomere Length and Mitochondrial DNA Copy Number on Cognitive Function in Community-Dwelling Very Old Adults

Cited by 12 publications

References 41 publications

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

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

Positive association and future perspectives of mitochondrial DNA copy number and telomere length – a pilot twin study

Mitochondria, its DNA and telomeres in ageing and human population

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