Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA Integrity Within the MARK-AGE Study

Andrei Valeanu; Denisa Margina; María Moreno-Villanueva; María Blasco; Ewa Sikora; Grazyna Mosieniak; Miriam Capri; Nicolle Breusing; Jürgen Bernhardt; Christiane Schön; Olivier Toussaint; Florence Debacq-Chainiaux; Beatrix Grubeck-Loebenstein; Birgit Weinberger; Simone Fiegl; Efstathios S. Gonos; Antti Hervonen; Eline P. Slagboom; Anton de Craen; Martijn E.T. Dollé; Eugène H.J.M. Jansen; Eugenio Mocchegiani; Robertina Giacconi; Francesco Piacenza; Marco Malavolta; Daniela Weber; Wolfgang Stuetz; Tilman Grune; Claudio Franceschi; Alexander Bürkle; Daniela Gradinaru

doi:10.3390/antiox14080933

Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA Integrity Within the MARK-AGE Study

Andrei Valeanu
, Denisa Margina
, María Moreno-Villanueva
, María Blasco
, Ewa Sikora
, Grazyna Mosieniak
, Miriam Capri
, Nicolle Breusing
, Jürgen Bernhardt
, Christiane Schön
, Olivier Toussaint
, Florence Debacq-Chainiaux
, Beatrix Grubeck-Loebenstein
, Birgit Weinberger
, Simone Fiegl
, Efstathios S. Gonos
, Antti Hervonen
, Eline P. Slagboom
, Anton de Craen
, Martijn E.T. Dollé

Eugène H.J.M. Jansen, Eugenio Mocchegiani, Robertina Giacconi, Francesco Piacenza, Marco Malavolta, Daniela Weber, Wolfgang Stuetz, Tilman Grune, Claudio Franceschi, Alexander Bürkle, Daniela Gradinaru

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Résumé

Genomic instability markers are important hallmarks of aging, as previously evidenced within the European study of biomarkers of human aging, MARK-AGE; however, establishing the specific metabolic determinants of vascular aging is challenging. The objective of the present study was to evaluate the impact of the susceptibility to oxidation of serum LDL particles (LDLox) and the plasma metabolization products of nitric oxide (NOx) on relevant genomic instability markers. The analysis was performed on a MARK-AGE cohort of 1326 subjects (635 men and 691 women, 35–75 years old) randomly recruited from the general population. The Inverse Probability of Treatment Weighting causal inference algorithm was implemented in order to assess the potential causal relationship between the LDLox and NOx octile-based thresholds and three genomic instability markers measured in mononuclear leukocytes: the percentage of telomeres shorter than 3 kb, the initial DNA integrity, and the DNA damage after irradiation with 3.8 Gy. The results showed statistically significant telomere shortening for LDLox, while NOx yielded a significant impact on DNA integrity. Overall, the effect on the genomic instability markers was higher than for the confirmed vascular aging determinants, such as low HDL cholesterol levels, indicating a meaningful impact even for small changes in LDLox and NOx values.

langue originale	Anglais
Numéro d'article	933
journal	Antioxidants
Volume	14
Numéro de publication	8
Les DOIs	https://doi.org/10.3390/antiox14080933
Etat de la publication	Publié - août 2025

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10.3390/antiox14080933

antioxidants-14-00933Version finale publiée, 1 MBLicense: CC BY

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Valeanu, A., Margina, D., Moreno-Villanueva, M., Blasco, M., Sikora, E., Mosieniak, G., Capri, M., Breusing, N., Bernhardt, J., Schön, C., Toussaint, O., Debacq-Chainiaux, F., Grubeck-Loebenstein, B., Weinberger, B., Fiegl, S., Gonos, E. S., Hervonen, A., Slagboom, E. P., de Craen, A., ... Gradinaru, D. (2025). Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA Integrity Within the MARK-AGE Study. Antioxidants, 14(8), Article 933. https://doi.org/10.3390/antiox14080933

@article{671f8f80bd134a23ae8931cbde897bd0,

title = "Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA Integrity Within the MARK-AGE Study",

abstract = "Genomic instability markers are important hallmarks of aging, as previously evidenced within the European study of biomarkers of human aging, MARK-AGE; however, establishing the specific metabolic determinants of vascular aging is challenging. The objective of the present study was to evaluate the impact of the susceptibility to oxidation of serum LDL particles (LDLox) and the plasma metabolization products of nitric oxide (NOx) on relevant genomic instability markers. The analysis was performed on a MARK-AGE cohort of 1326 subjects (635 men and 691 women, 35{\textendash}75 years old) randomly recruited from the general population. The Inverse Probability of Treatment Weighting causal inference algorithm was implemented in order to assess the potential causal relationship between the LDLox and NOx octile-based thresholds and three genomic instability markers measured in mononuclear leukocytes: the percentage of telomeres shorter than 3 kb, the initial DNA integrity, and the DNA damage after irradiation with 3.8 Gy. The results showed statistically significant telomere shortening for LDLox, while NOx yielded a significant impact on DNA integrity. Overall, the effect on the genomic instability markers was higher than for the confirmed vascular aging determinants, such as low HDL cholesterol levels, indicating a meaningful impact even for small changes in LDLox and NOx values.",

keywords = "causal analysis, genomic instability markers, LDL oxidation, MARK-AGE, nitric oxide, vascular aging",

author = "Andrei Valeanu and Denisa Margina and Mar{\'i}a Moreno-Villanueva and Mar{\'i}a Blasco and Ewa Sikora and Grazyna Mosieniak and Miriam Capri and Nicolle Breusing and J{\"u}rgen Bernhardt and Christiane Sch{\"o}n and Olivier Toussaint and Florence Debacq-Chainiaux and Beatrix Grubeck-Loebenstein and Birgit Weinberger and Simone Fiegl and Gonos, \{Efstathios S.\} and Antti Hervonen and Slagboom, \{Eline P.\} and \{de Craen\}, Anton and Doll{\'e}, \{Martijn E.T.\} and Jansen, \{Eug{\`e}ne H.J.M.\} and Eugenio Mocchegiani and Robertina Giacconi and Francesco Piacenza and Marco Malavolta and Daniela Weber and Wolfgang Stuetz and Tilman Grune and Claudio Franceschi and Alexander B{\"u}rkle and Daniela Gradinaru",

note = "Publisher Copyright: {\textcopyright} 2025 by the authors.",

year = "2025",

month = aug,

doi = "10.3390/antiox14080933",

language = "English",

volume = "14",

journal = "Antioxidants",

issn = "2076-3921",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "8",

}

Valeanu, A, Margina, D, Moreno-Villanueva, M, Blasco, M, Sikora, E, Mosieniak, G, Capri, M, Breusing, N, Bernhardt, J, Schön, C, Toussaint, O , Debacq-Chainiaux, F, Grubeck-Loebenstein, B, Weinberger, B, Fiegl, S, Gonos, ES, Hervonen, A, Slagboom, EP, de Craen, A, Dollé, MET, Jansen, EHJM, Mocchegiani, E, Giacconi, R, Piacenza, F, Malavolta, M, Weber, D, Stuetz, W, Grune, T, Franceschi, C, Bürkle, A & Gradinaru, D 2025, 'Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA Integrity Within the MARK-AGE Study', Antioxidants, VOL. 14, Numéro 8, 933. https://doi.org/10.3390/antiox14080933

TY - JOUR

T1 - Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA Integrity Within the MARK-AGE Study

AU - Valeanu, Andrei

AU - Margina, Denisa

AU - Moreno-Villanueva, María

AU - Blasco, María

AU - Sikora, Ewa

AU - Mosieniak, Grazyna

AU - Capri, Miriam

AU - Breusing, Nicolle

AU - Bernhardt, Jürgen

AU - Schön, Christiane

AU - Toussaint, Olivier

AU - Debacq-Chainiaux, Florence

AU - Grubeck-Loebenstein, Beatrix

AU - Weinberger, Birgit

AU - Fiegl, Simone

AU - Gonos, Efstathios S.

AU - Hervonen, Antti

AU - Slagboom, Eline P.

AU - de Craen, Anton

AU - Dollé, Martijn E.T.

AU - Jansen, Eugène H.J.M.

AU - Mocchegiani, Eugenio

AU - Giacconi, Robertina

AU - Piacenza, Francesco

AU - Malavolta, Marco

AU - Weber, Daniela

AU - Stuetz, Wolfgang

AU - Grune, Tilman

AU - Franceschi, Claudio

AU - Bürkle, Alexander

AU - Gradinaru, Daniela

PY - 2025/8

Y1 - 2025/8

N2 - Genomic instability markers are important hallmarks of aging, as previously evidenced within the European study of biomarkers of human aging, MARK-AGE; however, establishing the specific metabolic determinants of vascular aging is challenging. The objective of the present study was to evaluate the impact of the susceptibility to oxidation of serum LDL particles (LDLox) and the plasma metabolization products of nitric oxide (NOx) on relevant genomic instability markers. The analysis was performed on a MARK-AGE cohort of 1326 subjects (635 men and 691 women, 35–75 years old) randomly recruited from the general population. The Inverse Probability of Treatment Weighting causal inference algorithm was implemented in order to assess the potential causal relationship between the LDLox and NOx octile-based thresholds and three genomic instability markers measured in mononuclear leukocytes: the percentage of telomeres shorter than 3 kb, the initial DNA integrity, and the DNA damage after irradiation with 3.8 Gy. The results showed statistically significant telomere shortening for LDLox, while NOx yielded a significant impact on DNA integrity. Overall, the effect on the genomic instability markers was higher than for the confirmed vascular aging determinants, such as low HDL cholesterol levels, indicating a meaningful impact even for small changes in LDLox and NOx values.

AB - Genomic instability markers are important hallmarks of aging, as previously evidenced within the European study of biomarkers of human aging, MARK-AGE; however, establishing the specific metabolic determinants of vascular aging is challenging. The objective of the present study was to evaluate the impact of the susceptibility to oxidation of serum LDL particles (LDLox) and the plasma metabolization products of nitric oxide (NOx) on relevant genomic instability markers. The analysis was performed on a MARK-AGE cohort of 1326 subjects (635 men and 691 women, 35–75 years old) randomly recruited from the general population. The Inverse Probability of Treatment Weighting causal inference algorithm was implemented in order to assess the potential causal relationship between the LDLox and NOx octile-based thresholds and three genomic instability markers measured in mononuclear leukocytes: the percentage of telomeres shorter than 3 kb, the initial DNA integrity, and the DNA damage after irradiation with 3.8 Gy. The results showed statistically significant telomere shortening for LDLox, while NOx yielded a significant impact on DNA integrity. Overall, the effect on the genomic instability markers was higher than for the confirmed vascular aging determinants, such as low HDL cholesterol levels, indicating a meaningful impact even for small changes in LDLox and NOx values.

KW - causal analysis

KW - genomic instability markers

KW - LDL oxidation

KW - MARK-AGE

KW - nitric oxide

KW - vascular aging

UR - https://www.scopus.com/pages/publications/105014496695

U2 - 10.3390/antiox14080933

DO - 10.3390/antiox14080933

M3 - Article

AN - SCOPUS:105014496695

SN - 2076-3921

VL - 14

JO - Antioxidants

JF - Antioxidants

IS - 8

M1 - 933

ER -

Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA Integrity Within the MARK-AGE Study

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