Cancer: The aging epigenome

A new approach helps to assess the impact of accelerated epigenetic aging on the risk of cancer.
  1. Brandon L Pierce  Is a corresponding author
  1. Departments of Public Health and Human Genetics, University of Chicago, United States
  2. Department of Human Genetics, University of Chicago, United States

Age is a prominent risk factor for most types of cancer, including breast, lung and colon cancers, which each have a large impact on public health (de Magalhães, 2013). 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 (Tomasetti et al., 2017).

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 (Flavahan et al., 2017; Saghafinia et al., 2018). However, the potential impact of age-related epigenetic changes on cancer development has not been fully characterized.

Previous studies have identified specific DNA methylation sites that are associated with age (Horvath and Raj, 2018). Researchers have developed algorithms, called ‘epigenetic clocks’, that use data from tens to hundreds of these methylation sites to estimate an individual’s ‘epigenetic age’. This includes the Horvath clock which predicts age using DNA methylation data from any tissue type (Horvath, 2013), and the Hannum clock which was designed to use data from blood cells (Hannum et al., 2013).

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 (Yu et al., 2020). However, previous studies linking accelerated epigenetic aging and cancer have produced mixed results. Now, in eLife, Fernanda Morales Berstein from the University of Bristol and co-workers (who are based at various institutes in the United Kingdom, the United States, Greece and Australia) report how they tackled this question using a different approach to most prior studies called Mendelian randomization (Morales Berstein et al., 2022). 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.

First, the team examined results from a previously conducted genome-wide association study which had analyzed the DNA of over 34,000 individuals to identify genetic variations that influence epigenetic clocks (McCartney et al., 2021). They used these results to select specific variants that predict the epigenetic age values measured by four common clocks (Horvath, Hannum, PhenoAge and GrimAge).

Next, Morales Berstein et al. used the Mendelian randomization method to find out if the variants that predict accelerated aging also affect the risk of several different types of cancer (breast, prostate, ovarian, colorectal and lung cancer). To do this the team obtained data from several large genome-wide association studies that had searched the genome of individuals for differences that predict cancer status; genetic variations related to the aging clocks were then extracted to see if they were also associated with an increased risk of cancer.

The results of Morales Berstein et al. 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 (Lu et al., 2019). Thus, the interpretation of this association is not straightforward, as this clock may capture the effects of environmental or lifestyle factors on the epigenome.

While the Morales Berstein et al. study did not show pervasive effects of epigenetic aging on cancer risk, their work is a critical contribution to cancer susceptibility research, as they have addressed an important question using rigorous methods, including Mendelian randomization. The primary strength of studies that use this approach is that they are less prone to certain types of biases that can affect observational research, such as confounding and reverse causation. Furthermore, it is important to acknowledge 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, such as the ones examined by Morales Berstein et al.

Future studies will likely use Mendelian randomization to address similar hypotheses for additional cancer types and a wider variety of epigenetic aging algorithms. As the size of genome-wide association studies increase and more clock-related genetic variants are discovered, this approach will gain more power to detect the effects of epigenetic aging on cancer and other age-related diseases.


Article and author information

Author details

  1. Brandon L Pierce

    Brandon L Pierce is in the Departments of Public Health and Human Genetics, University of Chicago, Chicago, United States

    For correspondence
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7829-952X

Publication history

  1. Version of Record published: April 28, 2022 (version 1)


© 2022, Pierce

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 1,904
    Page views
  • 226
  • 3

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Brandon L Pierce
Cancer: The aging epigenome
eLife 11:e78693.

Further reading

    1. Genetics and Genomics
    2. Medicine
    Xueyang Pan, Albert N Alvarez ... Hugo J Bellen
    Research Article

    Protein UFMylation downstream of the E1 enzyme UBA5 plays essential roles in development and endoplasmic reticulum stress. Variants in the UBA5 gene are associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder characterized by early-onset encephalopathy, movement abnormalities, global developmental delay, intellectual disability, and seizures. DEE44 is caused by at least 12 different missense variants described as loss of function (LoF), but the relationships between genotypes and molecular or clinical phenotypes remain to be established. We developed a humanized UBA5 fly model and biochemical activity assays in order to describe in vivo and in vitro genotype–phenotype relationships across the UBA5 allelic series. In vivo, we observed a broad spectrum of phenotypes in viability, developmental timing, lifespan, locomotor activity, and bang sensitivity. A range of functional effects was also observed in vitro across comprehensive biochemical assays for protein stability, ATP binding, UFM1 activation, and UFM1 transthiolation. Importantly, there is a strong correlation between in vivo and in vitro phenotypes, establishing a classification of LoF variants into mild, intermediate, and severe allelic strengths. By systemically evaluating UBA5 variants across in vivo and in vitro platforms, this study provides a foundation for more basic and translational UBA5 research, as well as a basis for evaluating current and future individuals afflicted with this rare disease.

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Nadja S Katheder, Kristen C Browder ... Heinrich Jasper
    Research Article

    Disruption of epithelial barriers is a common disease manifestation in chronic degenerative diseases of the airways, lung and intestine. Extensive human genetic studies have identified risk loci in such diseases, including in chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (IBD). The genes associated with these loci have not fully been determined, and functional characterization of such genes requires extensive studies in model organisms. Here, we report the results of a screen in Drosophila melanogaster that allowed for rapid identification, validation and prioritization of COPD risk genes that were selected based on risk loci identified in human genome-wide association studies (GWAS) studies. Using intestinal barrier dysfunction in flies as a readout, our results validate the impact of candidate gene perturbations on epithelial barrier function in 56% of the cases, resulting in a prioritized target gene list. We further report the functional characterization in flies of one family of these genes, encoding for nicotinic acetylcholine receptor subunits (nAchR). We find that nAchR signaling in enterocytes of the fly gut promotes epithelial barrier function and epithelial homeostasis by regulating the production of the peritrophic matrix. Our findings identify COPD associated genes critical for epithelial barrier maintenance, and provide insight into the role of epithelial nAchR signaling for homeostasis.