DNA methylation age of blood predicts future onset of lung cancer in the women's health initiative

Abstract

Lung cancer is considered an age-associated disease, whose progression is in part due to accumulation of genomic instability as well as age-related decline in system integrity and function. Thus even among individuals exposed to high levels of genotoxic carcinogens, such as those found in cigarette smoke, lung cancer susceptibility may vary as a function of individual differences in the rate of biological aging. We recently developed a highly accurate candidate biomarker of aging based on DNA methylation (DNAm) levels, which may prove useful in assessing risk of aging-related diseases, such as lung cancer. Using data on 2,029 females from the Women's Health Initiative, we examined whether baseline measures of “intrinsic epigenetic age acceleration” (IEAA) predicted subsequent lung cancer incidence. We observed 43 lung cancer cases over the nearly twenty years of follow-up. Results showed that standardized measures of IEAA were significantly associated with lung cancer incidence (HR: 1.50, P = 3.4×10−3). Furthermore, stratified Cox proportional hazard models suggested that the association may be even stronger among older individuals (70 years or above) or those who are current smokers. Overall, our results suggest that IEAA may be a useful biomarker for evaluating lung cancer susceptibility from a biological aging perspective.

Plasma proteomic signature of age in healthy humans

“…The “epigenetic clock,” a biomarker index that combines weighted information of a subset of DNA methylation sites raised great interest because it is both strongly associated with chronological age across multiple tissues and populations and independent of age, predicts multiple health outcomes, including cardiovascular disease, cancer, and mortality (Chen et al., 2016; Levine et al., 2015; Perna et al., 2016). These findings suggest that aging is associated with stereotyped and reproducible molecular changes that can potentially be used to identify individuals who are aging faster or slower than the average population.…”

Fountain of youth for squamous cell carcinomas? On the epigenetic age of non‐small cell lung cancer and corresponding tumor‐free lung tissues

“…Although accelerated DNAm age has been already described in various cancer samples4, 5, 11 and has been linked to lung cancer risk,25 our study is the first to report striking differences in DNAm age compared with that of the matched internal control tissues and to attribute reduced DNAm age to increased stem cell gene activity in SQC.…”

Life stress, glucocorticoid signaling, and the aging epigenome: Implications for aging-related diseases

“…This model has been recently supported by studies showing that lifetime stress and stress-related phenotypes may accelerate epigenetic aging (Boks et al, 2015;Brody et al, 2016a;Brody et al, 2016b;Simons et al, 2016;Wolf et al, 2015;Zannas et al, 2015a), a measure associated with several aging-related phenotypes (Horvath et al, 2014;Horvath and Ritz, 2015;Levine et al, 2015a;Levine et al, 2015b;Marioni et al, 2015a;Marioni et al, 2015b;Wolf et al, 2015). These findings have important implications, though we are by no means proposing that all stressrelated increases in aging-related disease can be attributed to epigenetic mechanisms.…”

“…Interestingly, epigenetic age acceleration is highly heritable in newborns but shows markedly decreased heritability later in life (Horvath, 2013), suggesting considerable sensitivity of this marker to environmental factors. Furthermore, cumulative evidence supports that accelerated epigenetic aging is associated with a number of aging-related and progeria-type phenotypes, including all-cause mortality in late life (Marioni et al, 2016;Marioni et al, 2015a), physical and cognitive impairment (Levine et al, 2015b;Marioni et al, 2015b;Wolf et al, 2015), cancer incidence and mortality (Zheng et al, 2016), frailty in older ages (Breitling et al, 2016), lung cancer in women (Levine et al, 2015a), Down syndrome , Parkinson's disease (Horvath and Ritz, 2015), and obesity (Horvath et al, 2014).…”