Epigenetic clocks are produced by identifying characteristic shifts in epigenetic marks with age, the decorations on the genome that control gene expression. It remains unclear as to the exact relationship between specific epigenetic marks and the underlying damage and dysfunction of aging, and so it remains unknown as to how comprehensively epigenetic clocks reflect the processes of aging: do all of the processes of aging contribute, or only some of them? If the latter, it will be hard to use epigenetic clocks to assess the quality of potential rejuvenation therapies. Removing that uncertainty will require a great deal of further work.
When epigenetic age is higher than chronological age, this is referred to as accelerated epigenetic age. It is thought to reflect a greater burden of the underlying cell and tissue damage that causes aging, but of course the uncertainty remains as to whether this is a full versus selective representation of the state of health for any given epigenetic clock - any given combination of epigenetic marks, in other words. Are there aspects of aging that contribute little to epigenetic age?
With that in mind, researchers here note that a first pass at analysis of cancer incidence and accelerated epigenetic age found little in the way of firm correlations. This is interesting, as (a) cancer risk is very robustly age-associated, (b) the risk of a number of other age-related conditions does correlate to accelerated epigenetic age, and (c) recent work suggests that incidence of serious mutational damage causes epigenetic change, so one might expect a greater pace of mutational damage to lead to both more cancer and more epigenetic aging.
Age is a prominent risk factor for most types of cancer. Cancer risk increases with age, in part, because genetic mutations that arise from DNA replication errors and exposure to environmental carcinogens accumulate as we get older. Aging also alters the epigenome, the chemical marks spread across DNA that help switch genes on or off by altering how the genome is packaged. For instance, the addition of a methyl group to DNA can play a role in compressing the nearby DNA sequence so it can no longer be accessed by the cell's machinery. Epigenetic modifications, including DNA methylation, have also been shown to contribute to the development of cancer. However, the potential impact of age-related epigenetic changes on cancer development has not been fully characterized.
It has been hypothesized that people whose epigenetic age is greater than their age in years - a phenomenon known as accelerated aging - may be at higher risk of age-related diseases, including cancer. However, previous studies linking accelerated epigenetic aging and cancer have produced mixed results. Now a team has taken a different approach. Instead of associating a person's risk of cancer with epigenetic clock estimates, they correlated it against genetic variations that are known to influence these algorithms.
The results did not show many clear relationships between the epigenetic aging clocks and risk for the various types of cancer studied. The most promising finding was an association between the GrimAge clock and colorectal cancer. The GrimAge clock was not designed to predict age alone, but also reflects the effects of smoking and other mortality-related epigenetic features. Thus, the interpretation of this association is not straightforward, as this clock may capture the effects of environmental or lifestyle factors on the epigenome. One caution is that epigenetic clocks have largely been developed based on how aging affects DNA methylation in blood cells. Much less is known regarding aging and epigenetics in other tissue types, including those prone to cancer.