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

Laura Kananen; Mikko Hurme; Alexander Bürkle; Maria Moreno-Villanueva; Jürgen Bernhardt; Florence Debacq-Chainiaux; Beatrix Grubeck-Loebenstein; Marco Malavolta; Andrea Basso; Francesco Piacenza; Sebastiano Collino; Efstathios S. Gonos; Ewa Sikora; Daniela Gradinaru; Eugene H.J.M. Jansen; Martijn E.T. Dollé; Michel Salmon; Wolfgang Stuetz; Daniela Weber; Tilman Grune; Nicolle Breusing; Andreas Simm; Miriam Capri; Claudio Franceschi; Eline Slagboom; Duncan Talbot; Claude Libert; Jani Raitanen; Seppo Koskinen; Tommi Härkänen; Sari Stenholm; Mika Ala-Korpela; Terho Lehtimäki; Olli T. Raitakari; Olavi Ukkola; Mika Kähönen; Marja Jylhä; Juulia Jylhävä

doi:10.1007/s11357-022-00590-8

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

Laura Kananen, Mikko Hurme, Alexander Bürkle, Maria Moreno-Villanueva, Jürgen Bernhardt, Florence Debacq-Chainiaux, Beatrix Grubeck-Loebenstein, Marco Malavolta, Andrea Basso, Francesco Piacenza, Sebastiano Collino, Efstathios S. Gonos, Ewa Sikora, Daniela Gradinaru, Eugene H.J.M. Jansen, Martijn E.T. Dollé, Michel Salmon, Wolfgang Stuetz, Daniela Weber, Tilman GruneNicolle Breusing, Andreas Simm, Miriam Capri, Claudio Franceschi, Eline Slagboom, Duncan Talbot, Claude Libert, Jani Raitanen, Seppo Koskinen, Tommi Härkänen, Sari Stenholm, Mika Ala-Korpela, Terho Lehtimäki, Olli T. Raitakari, Olavi Ukkola, Mika Kähönen, Marja Jylhä, Juulia Jylhävä

Research output: Contribution to journal › Article › Scientific › peer-review

16 Citations (Scopus)

18 Downloads (Pure)

Abstract

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.

Original language	English
Pages (from-to)	85–103
Journal	GeroScience
Volume	45
Issue number	1
Early online date	2022
DOIs	https://doi.org/10.1007/s11357-022-00590-8
Publication status	Published - 2023
Publication type	A1 Journal article-refereed

Funding

The Health 2000 Survey was funded by the National Institute for Health and Welfare (THL), the Finnish Centre for Pensions (ETK), the Social Insurance Institution of Finland (KELA), the Local Government Pensions Institution (KEVA) and other organisations listed on the survey website ( https://thl.fi/en/web/thl-biobank/for-researchers/sample-collections/health-2000-and-2011-surveys ). 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; Yrjö 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. This analysis was supported financially by Yrjö Jahnsson Foundation (Grant 20197181) and Juho Vainio Foundation to L. Kananen, and by the 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. Jylhävä was supported by the Swedish Research Council (2018–02077), the Loo & Hans Osterman Foundation and the Strategic Research Program in Epidemiology at Karolinska Institutet.

Keywords

Biomarker of ageing
Cell-free DNA
Frailty
Health behaviours
Metabolomics
Morbidity

Publication forum classification

Publication forum level 1

ASJC Scopus subject areas

Ageing
veterinary (miscalleneous)
Complementary and alternative medicine
Geriatrics and Gerontology
Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s11357-022-00590-8Licence: CC BY

s11357-022-00590-8Final published version, 1.69 MBLicence: CC BY

https://urn.fi/URN:NBN:fi:tuni-202208086281Licence: CC BY

Cite this

Kananen, L., Hurme, M., Bürkle, A., Moreno-Villanueva, M., Bernhardt, J., Debacq-Chainiaux, F., Grubeck-Loebenstein, B., Malavolta, M., Basso, A., Piacenza, F., Collino, S., Gonos, E. S., Sikora, E., Gradinaru, D., Jansen, E. H. J. M., Dollé, M. E. T., Salmon, M., Stuetz, W., Weber, D., ... Jylhävä, J. (2023). Circulating cell-free DNA in health and disease: the relationship to health behaviours, ageing phenotypes and metabolomics. GeroScience, 45(1), 85–103. https://doi.org/10.1007/s11357-022-00590-8

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

abstract = "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.",

keywords = "Biomarker of ageing, Cell-free DNA, Frailty, Health behaviours, Metabolomics, Morbidity",

author = "Laura Kananen and Mikko Hurme and Alexander B{\"u}rkle and Maria Moreno-Villanueva and J{\"u}rgen Bernhardt and Florence Debacq-Chainiaux and Beatrix Grubeck-Loebenstein and Marco Malavolta and Andrea Basso and Francesco Piacenza and Sebastiano Collino and Gonos, {Efstathios S.} and Ewa Sikora and Daniela Gradinaru and Jansen, {Eugene H.J.M.} and Doll{\'e}, {Martijn E.T.} and Michel Salmon and Wolfgang Stuetz and Daniela Weber and Tilman Grune and Nicolle Breusing and Andreas Simm and Miriam Capri and Claudio Franceschi and Eline Slagboom and Duncan Talbot and Claude Libert and Jani Raitanen and Seppo Koskinen and Tommi H{\"a}rk{\"a}nen and Sari Stenholm and Mika Ala-Korpela and Terho Lehtim{\"a}ki and Raitakari, {Olli T.} and Olavi Ukkola and Mika K{\"a}h{\"o}nen and Marja Jylh{\"a} and Juulia Jylh{\"a}v{\"a}",

note = "Funding Information: The Health 2000 Survey was funded by the National Institute for Health and Welfare (THL), the Finnish Centre for Pensions (ETK), the Social Insurance Institution of Finland (KELA), the Local Government Pensions Institution (KEVA) and other organisations listed on the survey website ( https://thl.fi/en/web/thl-biobank/for-researchers/sample-collections/health-2000-and-2011-surveys ). Funding Information: 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). Funding Information: 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; Yrj{\"o} Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; This project has received funding from the European Union{\textquoteright}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. Funding Information: This analysis was supported financially by Yrj{\"o} Jahnsson Foundation (Grant 20197181) and Juho Vainio Foundation to L. Kananen, and by the 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. Jylh{\"a}v{\"a} was supported by the Swedish Research Council (2018–02077), the Loo & Hans Osterman Foundation and the Strategic Research Program in Epidemiology at Karolinska Institutet. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2023",

doi = "10.1007/s11357-022-00590-8",

language = "English",

volume = "45",

pages = "85–103",

number = "1",

}

Kananen, L , Hurme, M, Bürkle, A, Moreno-Villanueva, M, Bernhardt, J, Debacq-Chainiaux, F, Grubeck-Loebenstein, B, Malavolta, M, Basso, A, Piacenza, F, Collino, S, Gonos, ES, Sikora, E, Gradinaru, D, Jansen, EHJM, Dollé, MET, Salmon, M, Stuetz, W, Weber, D, Grune, T, Breusing, N, Simm, A, Capri, M, Franceschi, C, Slagboom, E, Talbot, D, Libert, C, Raitanen, J, Koskinen, S, Härkänen, T, Stenholm, S, Ala-Korpela, M, Lehtimäki, T, Raitakari, OT, Ukkola, O, Kähönen, M , Jylhä, M & Jylhävä, J 2023, 'Circulating cell-free DNA in health and disease: the relationship to health behaviours, ageing phenotypes and metabolomics', GeroScience, vol. 45, no. 1, pp. 85–103. https://doi.org/10.1007/s11357-022-00590-8

TY - JOUR

T1 - Circulating cell-free DNA in health and disease

T2 - the relationship to health behaviours, ageing phenotypes and metabolomics

AU - Kananen, Laura

AU - Hurme, Mikko

AU - Bürkle, Alexander

AU - Moreno-Villanueva, Maria

AU - Bernhardt, Jürgen

AU - Debacq-Chainiaux, Florence

AU - Grubeck-Loebenstein, Beatrix

AU - Malavolta, Marco

AU - Basso, Andrea

AU - Piacenza, Francesco

AU - Collino, Sebastiano

AU - Gonos, Efstathios S.

AU - Sikora, Ewa

AU - Gradinaru, Daniela

AU - Jansen, Eugene H.J.M.

AU - Dollé, Martijn E.T.

AU - Salmon, Michel

AU - Stuetz, Wolfgang

AU - Weber, Daniela

AU - Grune, Tilman

AU - Breusing, Nicolle

AU - Simm, Andreas

AU - Capri, Miriam

AU - Franceschi, Claudio

AU - Slagboom, Eline

AU - Talbot, Duncan

AU - Libert, Claude

AU - Raitanen, Jani

AU - Koskinen, Seppo

AU - Härkänen, Tommi

AU - Stenholm, Sari

AU - Ala-Korpela, Mika

AU - Lehtimäki, Terho

AU - Raitakari, Olli T.

AU - Ukkola, Olavi

AU - Kähönen, Mika

AU - Jylhä, Marja

AU - Jylhävä, Juulia

N1 - Funding Information: The Health 2000 Survey was funded by the National Institute for Health and Welfare (THL), the Finnish Centre for Pensions (ETK), the Social Insurance Institution of Finland (KELA), the Local Government Pensions Institution (KEVA) and other organisations listed on the survey website ( https://thl.fi/en/web/thl-biobank/for-researchers/sample-collections/health-2000-and-2011-surveys ). Funding Information: 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). Funding Information: 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; Yrjö 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. Funding Information: This analysis was supported financially by Yrjö Jahnsson Foundation (Grant 20197181) and Juho Vainio Foundation to L. Kananen, and by the 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. Jylhävä was supported by the Swedish Research Council (2018–02077), the Loo & Hans Osterman Foundation and the Strategic Research Program in Epidemiology at Karolinska Institutet. Publisher Copyright: © 2022, The Author(s).

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - Biomarker of ageing

KW - Cell-free DNA

KW - Frailty

KW - Health behaviours

KW - Metabolomics

KW - Morbidity

U2 - 10.1007/s11357-022-00590-8

DO - 10.1007/s11357-022-00590-8

M3 - Article

AN - SCOPUS:85134675413

SN - 2509-2715

VL - 45

SP - 85

EP - 103

JO - GeroScience

JF - GeroScience

IS - 1

ER -

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

Abstract

Funding

Keywords

Publication forum classification

ASJC Scopus subject areas

UN SDGs

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