Epigenetic biomarkers of ageing are predictive of mortality risk in a longitudinal clinical cohort of individuals diagnosed with oropharyngeal cancer

Abstract

Background Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between age predicted by these clocks and chronological age, termed “epigenetic age acceleration”, has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration and a DNA methylation-based mortality risk score with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000. We investigated two markers of intrinsic epigenetic age acceleration (IEAAHorvath and IEAAHannum), one marker of extrinsic epigenetic age acceleration (EEAA), one optimised to predict physiological dysregulation (AgeAccelPheno), one optimised to predict lifespan (AgeAccelGrim) and a DNA methylation-based predictor of mortality (ZhangScore). Cox regression models were first used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of epigenetic age acceleration with all-cause mortality in people with oropharyngeal cancer (n = 408; 105 deaths). The added prognostic value of epigenetic markers compared to a clinical model including age, sex, TNM stage and HPV status was then evaluated. Results IEAAHannum and AgeAccelGrim were associated with mortality risk after adjustment for clinical and lifestyle factors (HRs per standard deviation [SD] increase in age acceleration = 1.30 [95% CI 1.07, 1.57; p = 0.007] and 1.40 [95% CI 1.06, 1.83; p = 0.016], respectively). There was weak evidence that the addition of AgeAccelGrim to the clinical model improved 3-year mortality prediction (area under the receiver operating characteristic curve: 0.80 vs. 0.77; p value for difference = 0.069). Conclusion In the setting of a large, clinical cohort of individuals with head and neck cancer, our study demonstrates the potential of epigenetic markers of ageing to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors. Our findings have potential uses in both clinical and non-clinical contexts: to aid treatment planning and improve patient stratification.

Host fecal DNA specific methylation signatures mark gut dysbiosis and inflammation in children affected by autism spectrum disorder

“…Finally, we here calculated the epigenetic age of patients and controls by the analysis of HFD methylomes. Epigenetic age is a recently established biomarker of aging 48 . DNA methylation-based aging clocks is a composite measure of DNA methylation (DNAm) levels across specific CpG sites along the genome and may be calculated from methylome raw data using different computational tools 38 , 49 – 51 .…”

Biomarkers of ageing: Current state‐of‐art, challenges, and opportunities

“…65,72,[82][83][84] EAA is not only associated with risk of cancer but also the prognosis of cancer. [85][86][87][88][89][90] Independent of chronological age and traditional CVD risk factors, greater EAA was a promising predictor for incident fatal coronary heart disease, peripheral arterial disease, heart failure, and ischemic stroke outcome. 74,[91][92][93] Moreover, EAA was associated with higher risk for incident CVD events, and a predictor for dementia, 94 Alzheimer's Disease, 95 Parkinson's Disease, 96 and posttraumatic stress disorder (PTSD).…”

“…Longitudinal studies have further revealed an association between EAA and a higher risk of all‐cause mortality, 80,81 and specific leading causes of deaths, such as cancer‐related mortality and CVD‐related mortality in EAA 65,72,82–84 . EAA is not only associated with risk of cancer but also the prognosis of cancer 85–90 . Independent of chronological age and traditional CVD risk factors, greater EAA was a promising predictor for incident fatal coronary heart disease, peripheral arterial disease, heart failure, and ischemic stroke outcome 74,91–93 .…”

Metabolo-epigenetic interplay provides targeted nutritional interventions in chronic diseases and ageing

“…Further research is needed to understand how epigenetic age and DNA methylation clocks may help us anticipate, prevent, and overcome diseases related to ageing. Clearly, epigenetic clocks have a big potential as clinical biomarkers ( 115 , 116 ).…”