Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA Integrity Within the MARK-AGE Study
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Laboratory Methods
2.3. Statistical Analysis
2.3.1. General Statistical Analysis—Causal Algorithm
2.3.2. Setting the Thresholds for the Intervention Variables
2.3.3. Setting the Confounding Variables and Validating the Estimated Effects
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
CST | Critically short telomeres |
References
- Kovacic, J.C.; Moreno, P.; Nabel, E.G.; Hachinski, V.; Fuster, V. Cellular Senescence, Vascular Disease, and Aging. Circulation 2011, 123, 1900–1910. [Google Scholar] [CrossRef]
- Dantas, A.P.; Jiménez-Altayó, F.; Vila, E. Vascular Aging: Facts and Factors. Front. Physiol. 2012, 3, 325. [Google Scholar] [CrossRef] [PubMed]
- Nawrot, T.S.; Staessen, J.A.; Holvoet, P.; Struijker-Boudier, H.A.; Schiffers, P.; Van Bortel, L.M.; Fagard, R.H.; Gardner, J.P.; Kimura, M.; Aviv, A. Telomere Length and Its Associations with Oxidized-LDL, Carotid Artery Distensibility and Smoking. Front. Biosci. (Elite. Ed.) 2010, 2, 1164–1168. [Google Scholar] [CrossRef]
- Gradinaru, D.; Borsa, C.; Ionescu, C.; Prada, G.I. Oxidized LDL and NO Synthesis—Biomarkers of Endothelial Dysfunction and Ageing. Mech. Ageing Dev. 2015, 151, 101–113. [Google Scholar] [CrossRef]
- Valeanu, A.; Margina, D.; Weber, D.; Stuetz, W.; Moreno-Villanueva, M.; Dollé, M.E.T.; Jansen, E.H.; Gonos, E.S.; Bernhardt, J.; Grubeck-Loebenstein, B.; et al. Development and Validation of Cardiometabolic Risk Predictive Models Based on LDL Oxidation and Candidate Geromarkers from the MARK-AGE Data. Mech. Ageing Dev. 2024, 222, 111987. [Google Scholar] [CrossRef]
- Bürkle, A.; Moreno-Villanueva, M.; Bernhard, J.; Blasco, M.; Zondag, G.; Hoeijmakers, J.H.J.; Toussaint, O.; Grubeck-Loebenstein, B.; Mocchegiani, E.; Collino, S.; et al. MARK-AGE Biomarkers of Ageing. Mech. Ageing Dev. 2015, 151, 2–12. [Google Scholar] [CrossRef] [PubMed]
- Montpetit, A.J.; Alhareeri, A.A.; Montpetit, M.; Starkweather, A.R.; Elmore, L.W.; Filler, K.; Mohanraj, L.; Burton, C.W.; Menzies, V.S.; Lyon, D.E.; et al. Telomere Length. Nurs. Res. 2014, 63, 289–299. [Google Scholar] [CrossRef] [PubMed]
- Barnes, R.P.; Fouquerel, E.; Opresko, P.L. The Impact of Oxidative DNA Damage and Stress on Telomere Homeostasis. Mech. Ageing Dev. 2019, 177, 37–45. [Google Scholar] [CrossRef]
- Vaiserman, A.; Krasnienkov, D. Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives. Front. Genet. 2021, 11, 630186. [Google Scholar] [CrossRef]
- Yu, H.J.; Byun, Y.H.; Park, C.-K. Techniques for Assessing Telomere Length: A Methodological Review. Comput. Struct. Biotechnol. J. 2024, 23, 1489–1498. [Google Scholar] [CrossRef]
- Hewitt, G.; Jurk, D.; Marques, F.D.M.; Correia-Melo, C.; Hardy, T.; Gackowska, A.; Anderson, R.; Taschuk, M.; Mann, J.; Passos, J.F. Telomeres Are Favoured Targets of a Persistent DNA Damage Response in Ageing and Stress-Induced Senescence. Nat. Commun. 2012, 3, 708. [Google Scholar] [CrossRef]
- Thum, T.; Borlak, J. LOX-1 Receptor Blockade Abrogates OxLDL-Induced Oxidative DNA Damage and Prevents Activation of the Transcriptional Repressor Oct-1 in Human Coronary Arterial Endothelium. J. Biol. Chem. 2008, 283, 19456–19464. [Google Scholar] [CrossRef] [PubMed]
- Folkes, L.K.; O’Neill, P. Modification of DNA Damage Mechanisms by Nitric Oxide during Ionizing Radiation. Free Radic. Biol. Med. 2013, 58, 14–25. [Google Scholar] [CrossRef] [PubMed]
- Giampieri, E.; Remondini, D.; Bacalini, M.G.; Garagnani, P.; Pirazzini, C.; Yani, S.L.; Giuliani, C.; Menichetti, G.; Zironi, I.; Sala, C.; et al. Statistical Strategies and Stochastic Predictive Models for the MARK-AGE Data. Mech. Ageing Dev. 2015, 151, 45–53. [Google Scholar] [CrossRef]
- Matthews, D.R.; Hosker, J.P.; Rudenski, A.S.; Naylor, B.A.; Treacher, D.F.; Turner, R.C. Homeostasis Model Assessment: Insulin Resistance and ?—Cell Function from Fasting Plasma Glucose and Insulin Concentrations in Man. Diabetologia 1985, 28, 412–419. [Google Scholar] [CrossRef] [PubMed]
- Stuetz, W.; Weber, D.; Dollé, M.E.T.; Jansen, E.; Grubeck-Loebenstein, B.; Fiegl, S.; Toussaint, O.; Bernhardt, J.; Gonos, E.S.; Franceschi, C.; et al. Plasma Carotenoids, Tocopherols, and Retinol in the Age-Stratified (35-74 Years) General Population: A Cross-Sectional Study in Six European Countries. Nutrients 2016, 8, 614. [Google Scholar] [CrossRef]
- Malavolta, M.; Piacenza, F.; Basso, A.; Giacconi, R.; Costarelli, L.; Pierpaoli, S.; Mocchegiani, E. Speciation of Trace Elements in Human Serum by Micro Anion Exchange Chromatography Coupled with Inductively Coupled Plasma Mass Spectrometry. Anal. Biochem. 2012, 421, 16–25. [Google Scholar] [CrossRef]
- Moreno-Villanueva, M.; Eltze, T.; Dressler, D.; Bernhardt, J.; Hirsch, C.; Wick, P.; von Scheven, G.; Lex, K.; Bürkle, A. The Automated FADU-Assay, a Potential High-Throughput in Vitro Method for Early Screening of DNA Breakage. ALTEX 2011, 28, 295–303. [Google Scholar] [CrossRef]
- Canela, A.; Vera, E.; Klatt, P.; Blasco, M.A. High-Throughput Telomere Length Quantification by FISH and Its Application to Human Population Studies. Proc. Natl. Acad. Sci. USA 2007, 104, 5300–5305. [Google Scholar] [CrossRef]
- Python Software Foundation Python Language Reference, Version 3.9.2. Available online: http://www.python.org (accessed on 17 July 2023).
- Sharma, A.; Kiciman, E. DoWhy: An End-to-End Library for Causal Inference. arXiv 2020, arXiv:2011.04216. [Google Scholar]
- National Cholesterol Education Program (NCEP) Expert Panel on Detection, Treatment of High Blood Cholesterol in Adults. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation 2002, 106, 3143–3421. [Google Scholar] [CrossRef]
- Jiménez-Maldonado, A.; García-Suárez, P.C.; Rentería, I.; Moncada-Jiménez, J.; Plaisance, E.P. Impact of High-Intensity Interval Training and Sprint Interval Training on Peripheral Markers of Glycemic Control in Metabolic Syndrome and Type 2 Diabetes. Biochim. Et Biophys. Acta (BBA)-Mol. Basis Dis. 2020, 1866, 165820. [Google Scholar] [CrossRef]
- Mach, F.; Baigent, C.; Catapano, A.L.; Koskinas, K.C.; Casula, M.; Badimon, L.; Chapman, M.J.; De Backer, G.G.; Delgado, V.; Ference, B.A.; et al. 2019 ESC/EAS Guidelines for the Management of Dyslipidaemias: Lipid Modification to Reduce Cardiovascular Risk. Eur. Heart J. 2020, 41, 111–188. [Google Scholar] [CrossRef]
- McEvoy, J.W.; McCarthy, C.P.; Bruno, R.M.; Brouwers, S.; Canavan, M.D.; Ceconi, C.; Christodorescu, R.M.; Daskalopoulou, S.S.; Ferro, C.J.; Gerdts, E.; et al. 2024 ESC Guidelines for the Management of Elevated Blood Pressure and Hypertension. Eur. Heart J. 2024, 45, 3912–4018. [Google Scholar] [CrossRef]
- MacKinnon, D.P.; Lamp, S.J. A Unification of Mediator, Confounder, and Collider Effects. Prev. Sci. 2021, 22, 1185–1193. [Google Scholar] [CrossRef]
- Pinchuk, I.; Kohen, R.; Stuetz, W.; Weber, D.; Franceschi, C.; Capri, M.; Hurme, M.; Grubeck-Loebenstein, B.; Schön, C.; Bernhardt, J.; et al. Do Low Molecular Weight Antioxidants Contribute to the Protection against Oxidative Damage? The Interrelation between Oxidative Stress and Low Molecular Weight Antioxidants Based on Data from the MARK-AGE Study. Arch. Biochem. Biophys. 2021, 713, 109061. [Google Scholar] [CrossRef] [PubMed]
- Moix, S.; Sadler, M.C.; Kutalik, Z.; Auwerx, C. Breaking down Causes, Consequences, and Mediating Effects of Telomere Length Variation on Human Health. Genome Biol. 2024, 25, 125. [Google Scholar] [CrossRef]
- Vasa, M.; Breitschopf, K.; Zeiher, A.M.; Dimmeler, S. Nitric Oxide Activates Telomerase and Delays Endothelial Cell Senescence. Circ. Res. 2000, 87, 540–542. [Google Scholar] [CrossRef] [PubMed]
- Keefer, L.K.; Wink, D.A. DNA Damage and Nitric Oxid. Adv. Exp. Med. Biol. 1996, 387, 177–185. [Google Scholar] [PubMed]
- Compton, S.A.; Elmore, L.W.; Haydu, K.; Jackson-Cook, C.K.; Holt, S.E. Induction of Nitric Oxide Synthase-Dependent Telomere Shortening after Functional Inhibition of Hsp90 in Human Tumor Cells. Mol. Cell Biol. 2006, 26, 1452–1462. [Google Scholar] [CrossRef]
- Hong, Y.; Quintero, M.; Frakich, N.M.; Trivier, E.; Erusalimsky, J.D. Evidence against the Involvement of Nitric Oxide in the Modulation of Telomerase Activity or Replicative Capacity of Human Endothelial Cells. Exp. Gerontol. 2007, 42, 904–910. [Google Scholar] [CrossRef]
- Chen, W.; Gardner, J.P.; Kimura, M.; Brimacombe, M.; Cao, X.; Srinivasan, S.R.; Berenson, G.S.; Aviv, A. Leukocyte Telomere Length Is Associated with HDL Cholesterol Levels: The Bogalusa Heart Study. Atherosclerosis 2009, 205, 620–625. [Google Scholar] [CrossRef]
- Liu, X.; Ma, T.; Yang, C.; Li, J.; Zhang, Y.; Zhao, Y. Persistent Dyslipidemia Increases the Longitudinal Changes in Telomere Length. Lipids Health Dis. 2023, 22, 173. [Google Scholar] [CrossRef]
- Williams, A.B.; Schumacher, B. P53 in the DNA-Damage-Repair Process. Cold Spring Harb. Perspect. Med. 2016, 6, a026070. [Google Scholar] [CrossRef]
- Belenichev, I.; Popazova, O.; Bukhtiyarova, N.; Savchenko, D.; Oksenych, V.; Kamyshnyi, O. Modulating Nitric Oxide: Implications for Cytotoxicity and Cytoprotection. Antioxidants 2024, 13, 504. [Google Scholar] [CrossRef]
- Calcerrada, P.; Peluffo, G.; Radi, R. Nitric Oxide-Derived Oxidants with a Focus on Peroxynitrite: Molecular Targets, Cellular Responses and Therapeutic Implications. Curr. Pharm. Des. 2011, 17, 3905–3932. [Google Scholar] [CrossRef]
- Inoue, T.; Inoue, K.; Maeda, H.; Takayanagi, K.; Morooka, S. Immunological Response to Oxidized LDL Occurs in Association with Oxidative DNA Damage Independently of Serum LDL Concentrations in Dyslipidemic Patients. Clin. Chim. Acta 2001, 305, 115–121. [Google Scholar] [CrossRef] [PubMed]
- Jiang, H.; Zhou, Y.; Nabavi, S.M.; Sahebkar, A.; Little, P.J.; Xu, S.; Weng, J.; Ge, J. Mechanisms of Oxidized LDL-Mediated Endothelial Dysfunction and Its Consequences for the Development of Atherosclerosis. Front. Cardiovasc. Med. 2022, 9, 925923. [Google Scholar] [CrossRef] [PubMed]
- Camici, G.G.; Shi, Y.; Cosentino, F.; Francia, P.; Lüscher, T.F. Anti-Aging Medicine: Molecular Basis for Endothelial Cell-Targeted Strategies—A Mini-Review. Gerontology 2011, 57, 101–108. [Google Scholar] [CrossRef]
- Jeong, J.; Juhn, K.; Lee, H.; Kim, S.-H.; Min, B.-H.; Lee, K.-M.; Cho, M.-H.; Park, G.-H.; Lee, K.-H. SIRT1 Promotes DNA Repair Activity and Deacetylation of Ku70. Exp. Mol. Med. 2007, 39, 8–13. [Google Scholar] [CrossRef] [PubMed]
Intervention Threshold Name | Sign | Intervention Threshold Value | % of Subjects |
---|---|---|---|
NOx_Q12.5 | ≥ | 14.885 μmol/L | 87.41 |
NOx_Q25 | ≥ | 18.875 μmol/L | 74.81 |
NOx_Q37.5 | ≥ | 22.295 μmol/L | 62.22 |
NOx_Q50 | ≥ | 25.92 μmol/L | 49.70 |
NOx_Q62.5 | ≥ | 29.72 μmol/L | 37.25 |
NOx_Q75 | ≥ | 34.35 μmol/L | 24.89 |
NOx_Q87.5 | ≥ | 41.845 μmol/L | 12.29 |
LDLox_Q12.5 | ≥ | 11.66 nmol MDA/mL | 87.56 |
LDLox_Q25 | ≥ | 13.705 nmol MDA/mL | 75.26 |
LDLox_Q37.5 | ≥ | 15.445 nmol MDA/mL | 62.75 |
LDLox_Q50 | ≥ | 17.59 nmol MDA/mL | 50.00 |
LDLox_Q62.5 | ≥ | 20.15 nmol MDA/mL | 37.41 |
LDLox_Q75 | ≥ | 23.24 nmol MDA/mL | 24.89 |
LDLox_Q87.5 | ≥ | 27.615 nmol MDA/mL | 12.59 |
Risk_NOx + LDLox_Q12.5 | ≥ | - | 76.32 |
Risk_NOx + LDLox_Q25 | ≥ | - | 56.33 |
Risk_NOx + LDLox_Q37.5 | ≥ | - | 40.27 |
Risk_NOx + LDLox_Q50 | ≥ | - | 26.17 |
Risk_NOx + LDLox_Q62.5 | ≥ | - | 15.76 |
Risk_NOx + LDLox_Q75 | ≥ | - | 7.69 |
Risk_NOx + LDLox_Q87.5 | ≥ | - | 1.73 |
HBP_systolic_stage1 | ≥ | 140 mmHg | 37.10 |
HBP_diastolic_stage1 | ≥ | 90 mmHg | 23.30 |
HBP_uncontrolled_stage1 | ≥ | Subjects with uncontrolled BP (at least stage 1) | 41.93 |
HBP_stage1 | ≥ | Subjects with both controlled and uncontrolled BP (at least stage 1) | 49.25 |
HDL-C_40_50 | < | 40 mg/dL (males) OR 50 mg/dL (females) | 3.39 |
HDL-C_60 | < | 60 mg/dL | 28.81 |
LDL-C_70 | ≥ | 70 mg/dL | 97.06 |
LDL-C_100 | ≥ | 100 mg/dL | 81.30 |
LDL-C_116 | ≥ | 116 mg/dL | 64.78 |
LDL-C_190 | ≥ | 190 mg/dL | 2.19 |
HOMA_1.9 | ≥ | 1.9 | 19.98 |
HOMA_2.9 | ≥ | 2.9 | 8.90 |
Confounder |
---|
Sex |
Chronological age |
BMI |
WTHR |
Alpha-carotene |
Beta-carotene |
Gamma-tocopherol |
Alpha-tocopherol |
Lycopene |
Retinol |
25-Hydroxy-Vitamin-D |
Fe |
Se |
Cu/Zn ratio |
Lifestyle factors/characteristics: current smoker (yes/no), previous smoker (yes/no), smoking years, consume_bread_brown, consume_bread_white, consume_bread_whole, consume_cake_pie, consume_candies_sweets, consume_cheese, consume_dairy_products, consume_eggs, consume_fish, consume_fries_fried_potatos, consume_fruit, consume_icecream_dessert, consume_meat, consume_other_supplements, consume_salty_snacks, consume_sausages, consume_vegetables, consume_vitamin_supplements, consume_white_rice, drink_beer_never, drink_cola_soft_never, drink_never_juice, drink_never_water, drink_other_alco_never, drink_wine_never, day_activities_bathing_dressing_self, day_activities_bending_kneeling, day_activities_lifting_groceries, day_activities_moderate, day_activities_one_stairs, day_activities_several_stairs, day_activities_vigorous, day_activities_walking_half_mile, day_activities_walking_hundred_yards, day_activities_walking_several_miles, lives_with_children, lives_with_friends, lives_with_relatives, lives_with_spouse, marital_status_never, marital_status_divorced, marital_status_widow, marital_status_married, housing_apartment, housing_house, housing_special, ip_education_Never, ip_education_university degree, ip_education_Finished elementary, ip_education_First stage, ip_education_Second stage, feel_calm_peaceful, feel_full_of_life, feel_happy_person |
Parameter | Median (IQR) |
---|---|
Chronological age, years | 55.563 (18.566) |
LDLox, nmol MDA/mL | 17.565 (9.46) |
NOx (NO2− + NO3−), μmol/L | 25.808 (15.505) |
CST, % | 19.733 (14.017) |
Initial DNA integrity, % | 75.874 (13.69) |
DNA damage after 3.8 Gy, % | 41.224 (12.551) |
HDL cholesterol, mg/dL | 70.49 (25.26) |
LDL cholesterol, mg/dL | 126.864 (41.151) |
HOMA-IR | 1.121 (0.953) |
Systolic BP, mmHg | 130 (26) |
Diastolic BP, mmHg | 80 (15) |
BMI, kg/m2 | 25.352 (5.371) |
WTHR | 0.906 (0.105) |
Intervention Threshold Name | % of Telomeres Shorter than 3 kb | Initial DNA Integrity (%) | DNA Damage After 3.8 Gy (%) |
---|---|---|---|
NOx_Q12.5 | 2.492 (p = 0.008) | 3.478 (p = 0.001) | −2.64 (p = 0.002) |
NOx_Q25 | 1.429 (p = 0.045) | 3.608 (p = 0.001) | −1.803 (p = 0.002) |
NOx_Q37.5 | 1.064 (p = 0.086; NS *) | 3.326 (p = 0.001) | −1.646 (p = 0.001) |
NOx_Q50 | 1.619 (p = 0.019) | 2.313 (p = 0.001) | −1.412 (p = 0.002) |
NOx_Q62.5 | 1.916 (p = 0.006) | 1.809 (p = 0.001) | −1.83 (p = 0.001) |
NOx_Q75 | 2.786 (p = 0.001) | 1.391 (p = 0.018) | −1.778 (p = 0.003) |
NOx_Q87.5 | 1.68 (p = 0.062; NS) | 0.215 (p = 0.406; NS) | −1.038 (p = 0.139; NS) |
LDLox_Q12.5 | 2.364 (p = 0.015) | −0.632 (p = 0.244; NS) | 1.495 (p = 0.051; NS) |
LDLox_Q25 | 2.45 (p = 0.002) | 1.069 (p = 0.055; NS) | 0.145 (p = 0.429; NS) |
LDLox_Q37.5 | 2.833 (p = 0.001) | 0.754 (p = 0.099; NS) | −0.317 (p = 0.301; NS) |
LDLox_Q50 | 2.705 (p = 0.001) | 1.065 (p = 0.027) | −0.689 (p = 0.109; NS) |
LDLox_Q62.5 | 1.556 (p = 0.021) | 1.249 (p = 0.013) | −0.856 (p = 0.077; NS) |
LDLox_Q75 | 1.618 (p = 0.039) | 0.957 (p = 0.064; NS) | −0.676 (p = 0.154; NS) |
LDLox_Q87.5 | 3.624 (p = 0.002) | 2.778 (p = 0.001) | −0.975 (p = 0.135; NS) |
Risk_NOx + LDLox_Q12.5 | 2.726 (p = 0.001) | 1.657 (p = 0.004) | −0.96 (p = 0.087; NS) |
Risk_NOx + LDLox_Q25 | 2.373 (p = 0.001) | 2.916 (p = 0.001) | −1.268 (p = 0.012) |
Risk_NOx + LDLox_Q37.5 | 3.205 (p = 0.001) | 2.542 (p = 0.001) | −1.074 (p = 0.035) |
Risk_NOx + LDLox_Q50 | 3.481 (p = 0.001) | 1.669 (p = 0.003) | −1.245 (p = 0.031) |
Risk_NOx + LDLox_Q62.5 | 2.335 (p = 0.019) | 1.536 (p = 0.026) | −2.17 (p = 0.003) |
Risk_NOx + LDLox_Q75 | 4.132 (p = 0.002) | 2.431 (p = 0.013) | −2.275 (p = 0.013) |
Risk_NOx + LDLox_Q87.5 | 5.434 (p = 0.03) | 2.566 (p = 0.124; NS) | −0.296 (p = 0.448; NS) |
HBP_systolic_stage1 | 0.003 (p = 0.476; NS) | 0.276 (p = 0.337; NS) | −0.787 (p = 0.114; NS) |
HBP_diastolic_stage1 | −0.511 (p = 0.321; NS) | 0.837 (p = 0.11; NS) | −0.276 (p = 0.342; NS) |
HBP_uncontrolled_stage1 | −0.338 (p = 0.355; NS) | 0.44 (p = 0.214; NS) | −0.231 (p = 0.352; NS) |
HBP_stage1 | −0.011 (p = 0.497; NS) | 0.589 (p = 0.152; NS) | −0.752 (p = 0.112; NS) |
HDL-C_40_50 | 1.487 (p = 0.218; NS) | 0.602 (p = 0.361; NS) | −2.102 (p = 0.1; NS) |
HDL-C_60 | 3.214 (p = 0.001) | 1.419 (p = 0.02) | 0.883 (p = 0.103; NS) |
LDL-C_70 | −1.153 (p = 0.303; NS) | −1.995 (p = 0.117; NS) | 0.191 (p = 0.461; NS) |
LDL-C_100 | −0.929 (p = 0.169; NS) | −1.869 (p = 0.006) | −0.373 (p = 0.278; NS) |
LDL-C_116 | −0.679 (p = 0.185; NS) | −1.001 (p = 0.052; NS) | −0.194 (p = 0.339; NS) |
LDL-C_190 | −0.218 (p = 0.472; NS) | 0.662 (p = 0.367; NS) | −2.634 (p = 0.089; NS) |
HOMA_1.9 | 0.549 (p = 0.293; NS) | 1.259 (p = 0.055; NS) | −0.939 (p = 0.095; NS) |
HOMA_2.9 | 0.312 (p = 0.427; NS) | 0.71 (p = 0.248; NS) | −0.251 (p = 0.395; NS) |
% of Telomeres Shorter than 3 kb | Initial DNA Integrity (%) | DNA Damage After 3.8 Gy (%) | |
---|---|---|---|
Age decade: 35–44 years (n = 295) Age median (IQR): 40.053 (4.524) | |||
LDLox, nmol MDA/mL | 0.148 (p = 0.011) | −0.04 (p = 0.493; NS *) | −0.041 (p = 0.479; NS) |
NOx, μmol/L | −0.001 (p = 0.991; NS) | 0.163 (p = 0.005) | −0.121 (p = 0.038) |
Age decade: 45–54 years (n = 350) Age median (IQR): 50.163 (4.215) | |||
LDLox, nmol MDA/mL | 0.121 (p = 0.023) | 0.041 (p = 0.44; NS) | 0.04 (p = 0.451; NS) |
NOx, μmol/L | 0.046 (p = 0.39; NS) | 0.177 (p = 0.001) | −0.085 (p = 0.113; NS) |
Age decade: 55–64 years (n = 353) Age median (IQR): 60.187 (5.169) | |||
LDLox, nmol MDA/mL | 0.077 (p = 0.147; NS) | 0.108 (p = 0.043) | −0.024 (p = 0.647; NS) |
NOx, μmol/L | 0.094 (p = 0.077; NS) | 0.07 (p = 0.19; NS) | −0.087 (p = 0.102; NS) |
Age decade: 65–74 years (n = 328) Age median (IQR): 70.062 (5.238) | |||
LDLox, nmol MDA/mL | 0.067 (p = 0.226; NS) | 0.077 (p = 0.162; NS) | −0.004 (p = 0.94; NS) |
NOx, μmol/L | −0.038 (p = 0.488; NS) | 0.208 (p < 0.001) | −0.154 (p = 0.005) |
% of Telomeres Shorter than 3 kb | Initial DNA Integrity (%) | DNA Damage After 3.8 Gy (%) | |
---|---|---|---|
LDLox, nmol MDA/mL | 0.109 (p < 0.001) | 0.053 (p = 0.054; NS) | 0 (p = 0.986; NS) |
NOx, μmol/L | 0.033 (p = 0.224; NS) | 0.152 (p < 0.001) | −0.103 (p < 0.001) |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Valeanu, A.; Margina, D.; Moreno-Villanueva, M.; Blasco, M.; Sikora, E.; Mosieniak, G.; Capri, M.; Breusing, N.; Bernhardt, J.; Schön, C.; et al. Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA Integrity Within the MARK-AGE Study. Antioxidants 2025, 14, 933. https://doi.org/10.3390/antiox14080933
Valeanu A, Margina D, Moreno-Villanueva M, Blasco M, Sikora E, Mosieniak G, Capri M, Breusing N, Bernhardt J, Schön C, et al. Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA Integrity Within the MARK-AGE Study. Antioxidants. 2025; 14(8):933. https://doi.org/10.3390/antiox14080933
Chicago/Turabian StyleValeanu, Andrei, Denisa Margina, María Moreno-Villanueva, María Blasco, Ewa Sikora, Grazyna Mosieniak, Miriam Capri, Nicolle Breusing, Jürgen Bernhardt, Christiane Schön, and et al. 2025. "Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA Integrity Within the MARK-AGE Study" Antioxidants 14, no. 8: 933. https://doi.org/10.3390/antiox14080933
APA StyleValeanu, 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), 933. https://doi.org/10.3390/antiox14080933