Causal Inference Approaches Reveal Associations Between LDL Oxidation, NO Metabolism, Telomere Length and DNA...

Area of Science:

• Biogerontology
• Molecular Biology
• Cardiovascular Science

Background:

• Genomic instability is a hallmark of aging.
• Metabolic factors influencing vascular aging require further elucidation.
• The MARK-AGE study previously identified genomic instability markers in aging.

Purpose of the Study:

• To investigate the impact of LDL oxidation (LDLox) and nitric oxide metabolites (NOx) on genomic instability markers.
• To assess the causal relationship between LDLox, NOx, and key indicators of genomic instability.

Main Methods:

• Analysis of a MARK-AGE cohort (1326 subjects, aged 35-75).
• Utilized Inverse Probability of Treatment Weighting (IPTW) for causal inference.
• Measured telomere length, initial DNA integrity, and DNA damage post-irradiation in mononuclear leukocytes.

Main Results:

• LDLox showed a statistically significant association with telomere shortening.
• NOx demonstrated a significant impact on DNA integrity.
• The effects of LDLox and NOx on genomic instability markers exceeded those of established vascular aging determinants like HDL cholesterol.

Conclusions:

• LDL oxidation and nitric oxide metabolism are significant contributors to genomic instability.
• Even minor alterations in LDLox and NOx levels have a meaningful impact on aging markers.
• These findings provide novel insights into the metabolic underpinnings of vascular aging and genomic instability.