Abstract
Changes in the DNA methylation (DNAm) landscape have been implicated in aging and cellular senescence. To unravel the role of specific DNAm patterns in late-life survival, we performed genome-wide methylation profiling in nonagenarians (n=111) and determined the performance of the methylomic predictors and conventional risk markers in a longitudinal setting. The survival model containing only the methylomic markers was superior in terms of predictive accuracy compared with the model containing only the conventional predictors or the model containing conventional predictors combined with the methylomic markers. At the 2.55-year follow-up, we identified 19 mortality-associated (false-discovery rate <0.5) CpG sites that mapped to genes functionally clustering around the nuclear factor kappa B (NF-κB) complex. Interestingly, none of the mortality-associated CpG sites overlapped with the established aging-associated DNAm sites. Our results are in line with previous findings on the role of NF-κB in controlling animal life spans and demonstrate the role of this complex in human longevity.
Highlights
The influential role of genomic factors, such as DNA methylation (DNAm) in the course of development, aging and age-related pathologies is well established
The predictors remaining in the multivariate model, body mass index (BMI) and MiniMental State Examination (MMSE) test score, were used as the model factors in the assessment of the predictive accuracy of modeling
We ran the Ingenuity Pathway Analysis (IPA) network and pathway analyses from the genes harboring the 250 top-ranking CpG sites according to the 2.55year follow-up data
Summary
The influential role of genomic factors, such as DNA methylation (DNAm) in the course of development, aging and age-related pathologies is well established. The results of this study reveal that the DNAm regions associated with aging phenotypes are distinct from those associated with chronological age These findings suggest that the CpG sites involved in health-related outcomes in later life are largely regulated by sites other than the established agerelated DNAm regions [8]. Using an EWAS www.impactjournals.com/oncotarget approach, we have recently demonstrated that the CpG sites that are associated with aging-related inflammation, i.e., inflammaging [9] are largely different from the sites associated with age [5] This phenomenon is observable in regard to gene expression profiles and old age mortality. These findings underscore the complexity and unknown nature of the genomic factors that control the human health span and late-life events
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