Reviewing the Epigenetic Clock as a Predictor of Age-Related Mortality and Disease

Epigenetic clocks are weighted combinations of the DNA methylation status of various locations on the genome, shown to reflect chronological or biological age. DNA methylation is an epigenetic marker involved in regulating the production of proteins from their blueprint genes, and these markers constantly shift in response to circumstances, a part of the feedback loop of cellular metabolism. Definitive references to the epigenetic clock, singular, usually mean the original clock established by Steve Horvath's team and called DNA methylation age. A fair amount of work has gone into characterizing the behavior of this clock, particularly the association of higher measured ages with age-related disease: as a general rule, at a given chronological age, people who manifest age-related disease tend to have a DNA methylation age that is higher than their chronological age. This is thought to reflect a faster pace of aging.

The challenge here is that no-one has a good idea as to what exactly these characteristic DNA methylation changes actually reflect, which underlying processes of aging cause them. Since the most important goal of any reliable metric of aging is to use it to assess potential rejuvenation therapies, and thereby greatly speed up the processes of development, this lack of knowledge is a problem. Researchers cannot be assured that any specific approach to rejuvenation will actually exhibit the desired lower DNA methylation age - there is no necessary reason for any specific cause of aging to be reflected in the chosen sites for DNA methylation. They could very well turn out to reflect just a few of the full spectrum of contributing processes of damage that lie at the root of aging.

There is considerable between-person variation in the rate of ageing, and individual differences in their susceptibility to disease and death. The identification of individuals at greatest risk of age-related diseases and death would provide important opportunities for targeting prevention and intervention. There is thus great interest in molecular targets as clinical biomarkers which accurately predict the risk of age-related diseases and mortality. These biomarkers, which include cellular senescence, genomic instability, telomere attrition, and mitochondrial dysfunction, appear to capture pivotal aspects of biological age and have been associated with a number of age-related diseases and mortality.

It is well established that as individuals age, there is a raft of molecular changes that occur within the cells and tissues. Changes in DNA methylation patterns have been shown to occur with ageing, and thus may be a fundamental mechanism that drives human ageing. Epigenetic biomarkers of ageing, otherwise known as the epigenetic clock, have been developed using DNA methylation measurements. Referred to specifically as 'DNA methylation age' (DNAmAge), they provide an accurate estimate of age across a range of tissues, and at different stages of life, and are some of the most promising biomarkers of ageing. DNAmAge has also permitted the identification of individuals who show substantial deviations from their actual chronological age, and this 'accelerated biological aging' has been associated with unhealthy behaviours, frailty, cancer, diabetes, cardiovascular diseases, dementia, and mortality risk.

An increasing number of studies have investigated the association between DNAmAge, longevity, age-related disease, and mortality, with a total of 23 studies included in this systematic review and all published from 2015 onwards. Our primary finding is that there is sufficient evidence to support an association between accelerated DNAmAge and an increased risk of all-cause mortality. However, it remains unclear whether these methylation changes at specific CpGs are driving ageing or are consequences of the ageing process (cellular ageing, underlying disease processes.