University of Oulu

Kananen, L., Hurme, M., Bürkle, A. et al. Circulating cell-free DNA in health and disease — the relationship to health behaviours, ageing phenotypes and metabolomics. GeroScience 45, 85–103 (2023).

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

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Author: Kananen, Laura1,2,3,4; Hurme, Mikko3,4; Buerkle, Alexander5;
Organizations: 1Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
2Tampere Univ, Fac Social Sci Hlth Sci, Tampere, Finland.
3Tampere Univ, Gerontol Res Ctr, Tampere, Finland.
4Tampere Univ, Fac Med & Hlth Technol, Tampere, Finland.
5Univ Konstanz, Mol Toxicol Grp, Constance, Germany.
6BioTeSys GmbH, D-73728 Esslingen, Germany.
7Univ Namur, URBC Narilis, Rue Bruxelles 61, B-5000 Namur, Belgium.
8Univ Innsbruck, Res Inst Biomed Aging Res, Rennweg 10, A-6020 Innsbruck, Austria.
9IRCCS INRCA, Adv Technol Ctr Aging Res, Sci Technol Area, Ancona, Italy.
10Nestle Res, Nestle Inst Hlth Sci, EPFL Innovat Pk, CH-1015 Lausanne, Switzerland.
11Natl Hellen Res Fdn, Inst Biol Med Chem & Biotechnol, Athens, Greece.
12Polish Acad Sci, Nencki Inst Expt Biol, Lab Mol Bases Ageing, 3 Pasteur St, PL-02093 Warsaw, Poland.
13Carol Davila Univ Med & Pharm, Fac Pharm, Dept Biochem, Bucharest 020956, Romania.
14Ctr Hlth Protect, Natl Inst Publ Hlth & Environm RIVM, POB 1, NL-3720 BA Bilthoven, Netherlands.
15Straticell, Sci Pk Crealys,Rue Jean Sonet 10, B-5032 Les Isnes, Belgium.
16Univ Hohenheim, Inst Nutr Sci 140, D-70593 Stuttgart, Germany.
17German Inst Human Nutr Potsdam Rehbruecke DIfE, Dept Mol Toxicol, Nuthetal, Germany.
18Univ Vienna, Fac Chem, Dept Physiol Chem, A-1090 Vienna, Austria.
19Univ Hohenheim, Inst Nutr Med 180, D-70593 Stuttgart, Germany.
20Univ Hosp Halle, Dept Cardiothorac Surg, Ernst Grube Str 40, D-06120 Halle, Saale, Germany.
21Univ Bologna, DIMES Dept Expt Diagnost & Specialty Med, Interdept Ctr,Alma Mater Studiorum, Alma Mater Res Inst Global Challenges & Climate C, I-40126 Bologna, Italy.
22Leiden Univ Med Ctr, Sect Mol Epidemiol, Leiden, Netherlands.
23Unilever Sci & Technol, Beauty & Personal Care, Sharnbrook, Beds, England.
24VIB, Ctr Inflammat Res, Ghent, Belgium.
25Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium.
26Natl Inst Hlth & Welf, Helsinki, Finland.
27Univ Turku, Dept Publ Hlth, Turku, Finland.
28Turku Univ Hosp, Turku, Finland.
29Univ Turku, Ctr Populat Hlth Res, Turku, Finland.
30Univ Oulu, Fac Med, Computat Med, Oulu, Finland.
31Bioctr Oulu, Oulu, Finland.
32Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland.
33Univ Eastern Finland, Sch Pharm, NMR Metabol Lab, Kuopio, Finland.
34Tampere Univ, Fac Med & Hlth Technol, Dept Clin Chem, Tampere, Finland.
35Tampere Univ, Fac Med & Hlth Technol, Finnish Cardiovasc Res Ctr, Tampere, Finland.
36Fimlab Labs, Dept Clin Chem, Tampere, Finland.
37Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.
38Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.
39Univ Oulu, Oulu Univ Hosp, Med Res Ctr Oulu, Res Unit Internal Med, Oulu, Finland.
40Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.8 MB)
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Language: English
Published: Springer Nature, 2023
Publish Date: 2023-11-17


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.

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Series: GeroScience
ISSN: 2509-2715
ISSN-E: 2509-2723
ISSN-L: 2509-2715
Volume: 45
Issue: 1
Pages: 85 - 103
DOI: 10.1007/s11357-022-00590-8
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
3141 Health care science
Funding: Open access funding provided by Karolinska Institute. We also acknowledge the financial support provided by the European Commission through the FP7 large-scale integrating project "European Study to Establish Biomarkers of Human Ageing" (MARK-AGE; grant agreement No.: 200880). The Young Finns Study has been financially supported by the Academy of Finland: grants 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjo Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreements: No 848146 for To Aition and grant agreement 755320 for TAXINOMISIS, European Research Council (grant 742927 for MULTIEPIGEN project), Tampere University Hospital Supporting Foundation and Finnish Society of Clinical Chemistry. The Health 2000 Survey was funded by the National Institute for Health and Welfare Institution of Finland (KELA), the Local Government Pensions Institution nk/for-researchers/sample-collections/health-2000-and-2011-surveys). This analysis was supported financially by Yrjo Jahnsson Foundation Academy of Finland through its funding to the Centre of Excellence in Research of Ageing and Care (CoEAgeCare, grant numbers 326567 and 336670). M. Ala-Korpela was supported by a research grant from the Sigrid Juselius Foundation, Finland. J. Jylhava was supported by the Swedish Research Council (2018-02077), the Loo & Hans Osterman Foundation and the Strategic Research Program in Epidemiology at Karolinska Institutet.
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