Epigenetic Age: A Molecular Marker of Biological Wellbeing?

The widespread application of epigenetic age prediction has shown very high concordance between chronological age and predicted age; however, some individuals show large discrepancies between the two. These efforts have sparked a profusion of studies focused on determining the relationship between lifelong environmental exposures, biological age as measured by the epigenetic clock, and the presence of health and disease during aging.

Recent findings have shown epigenetic age acceleration in a number of diseases and disorders, though few studies have been able to determine whether this acceleration preceded, was concurrent with, or followed disease manifestation in late-onset diseases. For example, neurodegenerative disorders, such as a decline in cognitive function, episodic memory, and working memory, as well as neuropathological measures, such as diffuse and neurotic plaques and amyloid load have been associated with epigenetic age acceleration [86]. In addition, individuals with Down Syndrome, which has been associated with early cognitive decline, have an average epigenetic age 6.6 years older than their chronological age [87]. There have been many other studies showcasing deviations in the relationship between epigenetic age and chronological age in diseases such as Schizophrenia, PTSD, Parkinson’s Disease, and HIV [88-92]. In one case, however, researchers were able to show an association between lung cancer incidence and increased epigenetic age acceleration prior to diagnosis [93]. Together, these studies show there are particular diseases or disorders that associate with increased biological age, a relationship consistent with the toll diseases take on human health.

The connection between accelerated epigenetic age and poor health is further reinforced by work analyzing the association between epigenetic age acceleration and all-cause mortality. A longitudinal study found that an epigenetic age more than 5 years older than one’s chronological age was associated with a 21 % increased mortality rate [94]. The heritability of age acceleration, the degree to which is attributed to genetic composition, was also assessed in a parent-offspring cohort and revealed that approximately 40 % of the variation in age acceleration is due to genetic factors [94]. These results show that although a significant proportion of age-related methylation changes may be under a strong genetic influence, there is an even larger unknown non-genetic contribution to the variation in these events. These findings provided one of the first links between DNA methylation-predicted age and mortality, highlighting the potential clinical relevance of age-related DNA methylation.

More recently, another study investigated associations between epigenetic age and mortality in a cohort of 378 Danish twins, aged 30-82 years old. Upon resampling the 86 oldest twins in a 10-year follow-up, a mean 35 % higher mortality risk was associated with each 5-year increase in epigenetic age. Interestingly, through a separate intra-pair twin analysis, a 3.2 times greater risk for mortality per 5-year epigenetic age difference within twin pairs was observed for the epigenetically older twin, after controlling for familial factors [95]. This highlights, again, the link between mortality and DNA methylation-predicted age, exemplifying the capacity of DNA methylation to discriminate between biologically younger or older individuals independent of genetic sequence.

The described relationships, where the presence of disease is associated with acceleration in DNA methylation age, which in turn is associated with mortality, are highly suggestive that epigenetic age may be an excellent biomarker of human health. Future work will determine whether acceleration in biological ageing is reversible, and what factors might be involved in modifying the progression of ageing.

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