Accelerated biological aging may cause bowel cancer, study

They found limited evidence that accelerated epigenetic age is causally linked to other cancer types.

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Bowel cancer is a general term for cancer that begins in the large bowel. Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker.

What causes bowel cancer?

The exact causes of bowel cancer remain unclear. According to a new study by the University of Bristol, accelerated biological aging measured by an epigenetic clock may cause bowel cancer. The study offers evidence that biological age might play a causal role in increasing the risk of certain diseases.

Epigenetic markers are changes to DNA that might modify how our genes work and fluctuate as we age. An epigenetic marker called DNA methylation is regularly used to measure age. DNA methylation patterns on the genome have been displayed to relate closely with age. They can give experiences into ‘biological aging’ – how old our cells look contrasted with how old they are in years.

First author Fernanda Morales-Berstein, a Wellcome Trust Ph.D. A student in Molecular, Genetic, and Lifecourse Epidemiology at the MRC Integrative Epidemiology Unit, University of Bristol, said, “When an individual’s biological age is older than their chronological age, they are experiencing epigenetic age acceleration. As measured by DNA methylation-based predictors of age called epigenetic clocks, Epigenetic age acceleration has been associated with several adverse health outcomes, including cancer. But although epigenetics can be used to predict cancer risk or detect the disease early, it is still unclear whether accelerated epigenetic aging is a cause of cancer.”

Making a casual relationship between biological clocks and disease is challenging. It is pretty difficult to know whether biological aging increases the risk of disease or whether other independent factors raise the risk of disease and biological aging at the same time.

Scientists addressed this problem by using Mendelian randomization to mimic a randomized trial evaluating the effectiveness of changes in epigenetic aging as a cancer prevention strategy. The information was then used on known genetic variants associated with levels of epigenetic age acceleration to investigate this.

The team compared four established epigenetic clocks: Two were first-generation clocks that use patterns of DNA methylation strongly linked to chronological age. The others were second-generation clocks that use markers associated with an increased risk of age-related diseases or death. They measured biological aging and their genetically predicted associations with several types of cancer. 

However, they found limited evidence that accelerated epigenetic age is causally linked to breast, lung, ovarian, or prostate cancer. Scientists were surprised to see the result of bowel cancer.

One of the second-generation clocks, called GrimAge, suggested a 12% increased risk of bowel cancer with every additional year of biological age. These outcomes were additionally supported by a relationship between biological age acceleration and parental history of bowel cancer. Further examination recommended that evidence for the risk was more grounded for colon cancer than rectal cancer.

Scientists suggest that targeting this pathway via lifestyle changes or epigenetic-targeted therapies could help reduce this risk.

Senior author Dr. Rebecca Richmond, Vice-Chancellor’s Research Fellow in Molecular Epidemiology at Bristol’s MRC Integrative Epidemiology Unit, said“Our work provides potentially relevant findings for public health. If epigenetic age acceleration is a causal mediator between risk factors and bowel cancer, the clock may be a treatable intermediary when targeting the underlying risk factors is not feasible or too difficult to accomplish, particularly in populations at high risk. More research is needed to support our findings and evaluate whether epigenetic age acceleration can be modified by lifestyle or clinical interventions.”

Journal Reference:

  1. Fernanda Morales Berstein et al. Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study. DOI: 10.7554/eLife.75374