James, Emma Naomi and Sagi-Kiss, Virag and Bennett, Mark and Mycielska, Maria Elzbieta and Karen-Ng, Lee Peng and Roberts, Terry and Matta, Sheila and Dokal, Inderjeet and Bundy, Jacob Guy and Parkinson, Eric Kenneth (2023) Dyskeratosis Congenita Links Telomere Attrition to \nAge-Related Systemic Energetics. JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, 78 (5). pp. 780-789. ISSN 1079-5006, 1758-535X
Full text not available from this repository. (Request a copy)Abstract
The underlying mechanisms of plasma metabolite signatures of human aging 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 (TCA) 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. 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 have similarities with age-related disease signatures in humans. Our results have implications for the role of telomere dysfunction in human aging in addition to its early diagnosis and the monitoring of anti-senescence therapeutics, especially those designed to improve telomere function.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DNA-DAMAGE; DYSFUNCTION; FIBROBLASTS; HOMEOSTASIS; SIGNATURE; ACTIVATOR; HEALTH; LENGTH; CELLS; SPAN; Cellular senescence; Citrate; Human aging; Metabolism; Telomeres |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Mar 2024 05:41 |
| Last Modified: | 20 Mar 2024 05:41 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60673 |
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