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DC Field | Value | Language |
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dc.contributor.author | James, EN | - |
dc.contributor.author | Sagi-Kiss, V | - |
dc.contributor.author | Bennett, M | - |
dc.contributor.author | Mycielska, ME | - |
dc.contributor.author | Karen-Ng, LP | - |
dc.contributor.author | Roberts, T | - |
dc.contributor.author | Matta, S | - |
dc.contributor.author | Dokal, I | - |
dc.contributor.author | Bundy, JG | - |
dc.contributor.author | Parkinson, EK | - |
dc.date.accessioned | 2023-01-23T17:52:55Z | - |
dc.date.available | 2023-01-23T17:52:55Z | - |
dc.date.issued | 2023-01-18 | - |
dc.identifier | ORCID iD: Terry Roberts https://orcid.org/0000-0002-6738-2176 | - |
dc.identifier | glad018 | - |
dc.identifier.citation | James, E.N. et al. (2023) 'Dyskeratosis Congenita links telomere attrition to age-related systemic energetics', The Journals of Gerontology: Series A, 0 (pre-proof, ahead of print), glad018, pp. 1 - 35. doi: 10.1093/gerona/glad018. | en_US |
dc.identifier.issn | 1079-5006 | - |
dc.identifier.uri | https://bura.brunel.ac.uk/handle/2438/25860 | - |
dc.description | Supplementary data: glad018_suppl_Supplementary_Material - docx file available online at: https://academic.oup.com/biomedgerontology/advance-article/doi/10.1093/gerona/glad018/6991261#supplementary-data . | - |
dc.description.abstract | Copyright © The Author(s) 2023. Underlying mechanisms of plasma metabolite signatures of human ageing and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis Congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, and DKC1) and progressive telomere attrition. We analyzed the effect of telomere attrition on senescence associated metabolites in fibroblast conditioned media and DC patient plasma. Samples were analyzed by gas chromatography/ mass spectrometry and liquid chromatography/ mass spectrometry. We showed extracellular citrate was repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo; leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, elevated citrate and senescence factors only weakly distinguished DC patients from controls, whereas elevated levels of other tricarboxylic acid cycle metabolites, lactate and especially pyruvate distinguished them with high significance. The DC plasma signature most resembled that of patients with loss of function pyruvate dehydrogenase complex mutations and that of older subjects but significantly not those of type 2 diabetes, lactic acidosis, or elevated mitochondrial reactive oxygen species (1-3). Additionally, our data are consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data has similarities with age-related disease signatures in humans. Our results have implications for the role of telomere dysfunction in human ageing in addition to its early diagnosis and the monitoring of anti-senescence therapeutics, especially those designed to improve telomere function. | en_US |
dc.description.sponsorship | The work was supported by the Dunhill Medical Trust (grant number R452/1115) and Barts and the London Charity (grant number MRD&U0004) and Euorpean Union H2020, grant number 633589. Karen-Ng Lee Peng received a Ph.D. scholarship (Hadiah Latihan Persekutuan) from the Malaysian Ministry of Education. | en_US |
dc.format.extent | 1 - 35 | - |
dc.format.medium | Print-Electronic | - |
dc.language | English | - |
dc.language.iso | en_US | en_US |
dc.publisher | Oxford University Press on behalf of The Gerontological Society of America | en_US |
dc.rights | Copyright © The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com | - |
dc.rights.uri | https://creativecommons.org/licenses/by-nc/4.0/ | - |
dc.subject | metabolism | en_US |
dc.subject | telomeres | en_US |
dc.subject | human ageing | en_US |
dc.subject | cellular senescence | en_US |
dc.subject | citrate | en_US |
dc.title | Dyskeratosis Congenita links telomere attrition to age-related systemic energetics | en_US |
dc.type | Article | en_US |
dc.identifier.doi | https://doi.org/10.1093/gerona/glad018 | - |
dc.relation.isPartOf | The Journals of Gerontology: Series A | - |
pubs.issue | 00 | - |
pubs.publication-status | Published online | - |
pubs.volume | 0 | - |
dc.identifier.eissn | 1758-535X | - |
dc.rights.holder | The Author(s | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
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FullText.pdf | Copyright © The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com | 1.86 MB | Adobe PDF | View/Open |
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