Circulating cell-free DNA in health and disease — the relationship to health behaviours, ageing phenotypes and metabolomics,GeroScience

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Circulating cell-free DNA in health and disease — the relationship to health behaviours, ageing phenotypes and metabolomics
GeroScience ( IF 5.3 ) Pub Date : 2022-07-21 , DOI: 10.1007/s11357-022-00590-8
Laura Kananen _{1,

2,

3} , Mikko Hurme ₃ , Alexander Bürkle ₄ , Maria Moreno-Villanueva ₄ , Jürgen Bernhardt ₅ , Florence Debacq-Chainiaux ₆ , Beatrix Grubeck-Loebenstein ₇ , Marco Malavolta ₈ , Andrea Basso ₈ , Francesco Piacenza ₈ , Sebastiano Collino ₉ , Efstathios S Gonos ₁₀ , Ewa Sikora ₁₁ , Daniela Gradinaru ₁₂ , Eugene H J M Jansen ₁₃ , Martijn E T Dollé ₁₃ , Michel Salmon ₁₄ , Wolfgang Stuetz ₁₅ , Daniela Weber ₁₆ , Tilman Grune _{16,

17,

18} , Nicolle Breusing ₁₈ , Andreas Simm ₁₉ , Miriam Capri ₂₀ , Claudio Franceschi ₂₀ , Eline Slagboom ₂₁ , Duncan Talbot ₂₂ , Claude Libert _{23,

24} , Jani Raitanen ₂ , Seppo Koskinen ₂₅ , Tommi Härkänen ₂₅ , Sari Stenholm _{26,

27} , Mika Ala-Korpela _{28,

29,

30} , Terho Lehtimäki _{31,

32,

33} , Olli T Raitakari _{27,

34,

35} , Olavi Ukkola ₃₆ , Mika Kähönen _{31,

32,

37} , Marja Jylhä ₂ , Juulia Jylhävä _{1,

2}

Affiliation

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Faculty of Social Sciences (Health Sciences), and Gerontology Research Center, Tampere University, Tampere, Finland.
Faculty of Medicine and Health Technology, and Gerontology Research Center, Tampere University, Tampere, Finland.
Molecular Toxicology Group, University of Konstanz, Konstanz, Germany.
BioTeSys GmbH, 73728, Esslingen, Germany.
URBC-Narilis, University of Namur, Rue de Bruxelles, 61, B-5000, Namur, Belgium.
Research Institute for Biomedical Aging Research, University of Innsbruck, Rennweg, 10, 6020, Innsbruck, Austria.
Advanced Technology Center for Aging Research, Scientific Technological Area, IRCCS INRCA, Ancona, Italy.
Nestlé Research, Nestlé Institute of Health Sciences, EPFL Innovation Park, 1015, Lausanne, Switzerland.
Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
Laboratory of the Molecular Bases of Ageing, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur street, 02-093, Warsaw, Poland.
Department of Biochemistry, Faculty of Pharmacy, "Carol Davila" University of Medicine and Pharmacy, 020956, Bucharest, Romania.
National Institute for Public Health and the Environment (RIVM), Centre for Health Protection, P.O. Box 1, 3720 BA, Bilthoven, The Netherlands.
Straticell, Science Park Crealys, Rue Jean Sonet 10, 5032, Les Isnes, Belgium.
Institute of Nutritional Sciences (140), University of Hohenheim, 70593, Stuttgart, Germany.
Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.
Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, 1090, Vienna, Austria.
Institute of Nutritional Medicine (180), University of Hohenheim, 70593, Stuttgart, Germany.
Department of Cardiothoracic Surgery, University Hospital Halle, Ernst-Grube Str. 40, 06120, Halle (Saale), Germany.
DIMES- Department of Experimental, Diagnostic and Specialty Medicine, Interdepartmental Center "Alma Mater Research Institute On Global Challenges and Climate Change (Alma Climate)", Alma Mater Studiorum, University of Bologna, 40126, Bologna, Italy.
Section of Molecular Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands.
Unilever Science and Technology, Beauty and Personal Care, Sharnbrook, UK.
Center for Inflammation Research, VIB, Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
National Institute for Health and Welfare, Helsinki, Finland.
Department of Public Health, University of Turku and Turku University Hospital, Turku, Finland.
Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.
Center for Life Course Health Research, University of Oulu, Oulu, Finland.
NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Finnish Cardiovascular Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.

Circulating cell-free DNA (cf-DNA) has emerged as a promising biomarker of ageing, tissue damage and cellular stress. However, less is known about health behaviours, ageing phenotypes and metabolic processes that lead to elevated cf-DNA levels. We sought to analyse the relationship of circulating cf-DNA level to age, sex, smoking, physical activity, vegetable consumption, ageing phenotypes (physical functioning, the number of diseases, frailty) and an extensive panel of biomarkers including blood and urine metabolites and inflammatory markers in three human cohorts (N = 5385; 17–82 years). The relationships were assessed using correlation statistics, and linear and penalised regressions (the Lasso), also stratified by sex.

cf-DNA levels were significantly higher in men than in women, and especially in middle-aged men and women who smoke, and in older more frail individuals. Correlation statistics of biomarker data showed that cf-DNA level was higher with elevated inflammation (C-reactive protein, interleukin-6), and higher levels of homocysteine, and proportion of red blood cells and lower levels of ascorbic acid. Inflammation (C-reactive protein, glycoprotein acetylation), amino acids (isoleucine, leucine, tyrosine), and ketogenesis (3-hydroxybutyrate) were included in the cf-DNA level-related biomarker profiles in at least two of the cohorts.

In conclusion, circulating cf-DNA level is different by sex, and related to health behaviour, health decline and metabolic processes common in health and disease. These results can inform future studies where epidemiological and biological pathways of cf-DNA are to be analysed in details, and for studies evaluating cf-DNA as a potential clinical marker.

中文翻译：

健康和疾病中的循环游离 DNA——与健康行为、衰老表型和代谢组学的关系

循环游离 DNA (cf-DNA) 已成为衰老、组织损伤和细胞应激的有前途的生物标志物。然而，人们对导致 cf-DNA 水平升高的健康行为、衰老表型和代谢过程知之甚少。我们试图分析循环 cf-DNA 水平与年龄、性别、吸烟、身体活动、蔬菜摄入、衰老表型（身体机能、疾病数量、虚弱）以及包括血液和尿液代谢物和三个人类队列中的炎症标志物（N = 5385；17-82 岁）。这些关系使用相关统计、线性和惩罚回归（套索）进行评估，也按性别分层。

男性的 cf-DNA 水平明显高于女性，尤其是吸烟的中年男性和女性，以及年长体弱的个体。生物标志物数据的相关统计显示，cf-DNA 水平随着炎症（C 反应蛋白，白细胞介素 6）升高而升高，同型半胱氨酸水平升高，红细胞比例和抗坏血酸水平降低。炎症（C-反应蛋白、糖蛋白乙酰化）、氨基酸（异亮氨酸、亮氨酸、酪氨酸）和生酮（3-羟基丁酸）被包含在至少两个队列的 cf-DNA 水平相关生物标志物概况中。

总之，循环 cf-DNA 水平因性别而异，并且与健康行为、健康衰退以及健康和疾病中常见的代谢过程有关。这些结果可以为未来的研究提供信息，详细分析 cf-DNA 的流行病学和生物学途径，并用于评估 cf-DNA 作为潜在临床标志物的研究。

更新日期：2022-07-22

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