Longitudinal change in mitochondrial heteroplasmy exhibits positive selection for deleterious variants.

A common feature of human aging is the acquisition of somatic mutations, and mitochondria are particularly prone to mutation due to their inefficient DNA repair and close proximity to reactive oxygen species, leading to a state of mitochondrial DNA heteroplasmy1,2. Cross-sectional studies have demonstrated that detection of heteroplasmy increases with participant age3, a phenomenon that has been attributed to genetic drift4-7. In this first large-scale longitudinal study, we measured heteroplasmy in two prospective cohorts (combined n=1405) at two timepoints (mean time between visits, 8.6 years), demonstrating that deleterious heteroplasmies were more likely to increase in variant allele fraction (VAF). We further demonstrated that increase in VAF was associated with increased risk of overall mortality. These results challenge the claim that somatic mtDNA mutations arise mainly due to genetic drift, instead demonstrating positive selection for predicted deleterious mutations at the cellular level, despite an negative impact on overall mortality.

Past or Present; Which Exposures Predict Metabolomic Aging Better? The Doetinchem Cohort Study.

People age differently. Differences in aging might be reflected by metabolites, also known as metabolomic aging. Predicting metabolomic aging is of interest in public health research. However, the added value of longitudinal over cross-sectional predictors of metabolomic aging is unknown. We studied exposome-related exposures as potential predictors of metabolomic aging, both cross-sectionally and longitudinally in men and women. We used data from 4 459 participants, aged 36-75 of Round 4 (2003-2008) of the long-running Doetinchem Cohort Study (DCS). Metabolomic age was calculated with the MetaboHealth algorithm. Cross-sectional exposures were demographic, biological, lifestyle, and environmental at Round 4. Longitudinal exposures were based on the average exposure over 15 years (Round 1 [1987-1991] to 4), and trend in these exposure over time. Random Forest was performed to identify model performance and important predictors. Prediction performances were similar for cross-sectional and longitudinal exposures in both men (R2 6.8 and 5.8, respectively) and women (R2 14.8 and 14.4, respectively). Biological and diet exposures were most predictive for metabolomic aging in both men and women. Other important predictors were smoking behavior for men and contraceptive use and menopausal status for women. Taking into account history of exposure levels (longitudinal) had no added value over cross-sectionally measured exposures in predicting metabolomic aging in the current study. However, the prediction performances of both models were rather low. The most important predictors for metabolomic aging were from the biological and lifestyle domain and differed slightly between men and women.

Epigenetic and Metabolomic Biomarkers for Biological Age: A Comparative Analysis of Mortality and Frailty Risk.

Biological age captures a person's age-related risk of unfavorable outcomes using biophysiological information. Multivariate biological age measures include frailty scores and molecular biomarkers. These measures are often studied in isolation, but here we present a large-scale study comparing them. In 2 prospective cohorts (n = 3 222), we compared epigenetic (DNAm Horvath, DNAm Hannum, DNAm Lin, DNAm epiTOC, DNAm PhenoAge, DNAm DunedinPoAm, DNAm GrimAge, and DNAm Zhang) and metabolomic-based (MetaboAge and MetaboHealth) biomarkers in reflection of biological age, as represented by 5 frailty measures and overall mortality. Biomarkers trained on outcomes with biophysiological and/or mortality information outperformed age-trained biomarkers in frailty reflection and mortality prediction. DNAm GrimAge and MetaboHealth, trained on mortality, showed the strongest association with these outcomes. The associations of DNAm GrimAge and MetaboHealth with frailty and mortality were independent of each other and of the frailty score mimicking clinical geriatric assessment. Epigenetic, metabolomic, and clinical biological age markers seem to capture different aspects of aging. These findings suggest that mortality-trained molecular markers may provide novel phenotype reflecting biological age and strengthen current clinical geriatric health and well-being assessment.

C-factor: a summary measure for systemic arterial calcifications.

BACKGROUND: Arterial calcification, the hallmark of arteriosclerosis, has a widespread distribution in the human body with only moderate correlation among sites. Hitherto, a single measure capturing the systemic burden of arterial calcification was lacking. In this paper, we propose the C-factor as an overall measure of calcification burden. METHODS: To quantify calcification in the coronary arteries, aortic arch, extra- and intracranial carotid arteries, and vertebrobasilar arteries, 2384 Rotterdam Study participants underwent cardiac and extra-cardiac non-enhanced CT. We performed principal component analyses on the calcification volumes of all twenty-six possible combinations of these vessel beds. Each analysis' first principal component represents the C-factor. Subsequently, we determined the correlation between the C-factor derived from all vessel beds and the other C-factors with intraclass correlation coefficient (ICC) analyses. Finally, we examined the association of the C-factor and calcification in the separate vessel beds with cardiovascular, non-cardiovascular, and overall mortality using Cox-regression analyses. RESULTS: The ICCs ranged from 0.80 to 0.99. Larger calcification volumes and a higher C-factor were all individually associated with higher risk of cardiovascular, non-cardiovascular, and overall mortality. When included simultaneously in a model, the C-factor was still associated with all three mortality types (adjusted hazard ratio per standard deviation increase (HR) > 1.52), whereas associations of the separate vessel beds with mortality attenuated substantially (HR < 1.26). CONCLUSIONS: The C-factor summarizes the systemic component of arterial calcification on an individual level and appears robust among different combinations of vessel beds. Importantly, when mutually adjusted, the C-factor retains its strength of association with mortality while the site-specific associations attenuate.