The ticking ‘epigenetic’ clock measures true biological age

Events that occur during our lifetimes have an accumulative impact on our bodies and chronological age does not always reflect biological age In The Portrait of Dorian Gray, the famous book by Oscar Wilde, the protagonist has a mysterious painting of himself tucked away in an attic reflecting decades of vice that was not obvious by looking at him directly. Similar to Gray, over time people can be of a certain chronological age, but events that cause trauma or harm to the body cause their biological age to differ.

Even if two individuals are identical twins with the same DNA, the one that prioritizes exercise and nutrition will have a younger biological age. The biological root of such differences includes epigenetics: how DNA is modified and regulated without changing its sequence. In some people, biological age is accelerated, which scientists have shown is related to alterations of certain epigenetic markers.

“People can be the same chronological age, but biologically they are different,” said Zhaoming Wang, PhD, St. Jude Department of Epidemiology and Cancer Control, whose research focuses on the relationship between epigenetics, aging and disease risk. “Epigenetic age is one way to measure biological age. We look at methylation markers on DNA that were previously selected and built into various epigenetic clocks to estimate biological age.”

By looking at epigenetic aging, scientists can learn things about people that may be obscure from simply observing their chronological age. This information could be useful to help people protect or improve their health. For example, those with accelerated aging are at higher risk for age-related chronic health conditions, such as cardiovascular disease. Once someone understands their increased risk, they can make changes to their lifestyles (e.g., exercise, diet and nutrition) to slow down the biological aging process and potentially start appropriate medical care to reduce that risk.

The first step, however, is to measure epigenetic age.

Measuring epigenetic age with methylation

DNA is the code for life. The cell transcribes that code from DNA into RNA using a suite of proteins which need to physically access the DNA. Therefore, certain chemical modifications either open DNA to be read by transcription machinery encompassing these proteins, or close and pack DNA so it is inaccessible, which prevents transcription. Scientists measure epigenetic age by looking at how those chemical modifications are distributed on DNA.

One major type of DNA modification is methylation, where small methyl groups are added to DNA. The methyl groups are hydrophobic (they avoid liquid), which forces DNA to close in the watery environment of the cell, hence reducing gene expression. That change in gene expression is one way these modifications impact biological age. Studying the pattern of methylation markers and how they relate to age led to the novel concept of an epigenetic clock – a way to measure age using these epigenetic markers.

“The first clock used DNA methylation markers to correlate directly with chronological age,” Wang said. “The chronological age-related biomarkers were selected by a statistical model and formed the Horvath clock. Since then, over a dozen clocks have been developed by colleagues in the same field.”

Epigenetic clocks differ due to the methodology used to create them. While the first-generation clock mostly equated chronological and biological age, the second-generation clocks that model biological age instead of chronological age demonstrate better predictive power of age-related health conditions and have a greater potential to be used as objective metrics measuring the efficacy of interventions aiming to remediate aging phenotypes.

“The emblematic second-generation epigenetic clock is PhenoAge,” Wang said. “PhenoAge is more reflective of physiological age because the creator incorporated blood chemistry, such as glucose levels, in its creation. These blood chemistry-based biomarkers are all age-related measures that go up or down as we age.”

By focusing on phenotypical age, PhenoAge provides people with a more relevant understanding of the practical realities of their aging process. When the PhenoAge was built, blood chemistry was collected. Its creator selected DNA methylation sites to predict PhenoAge, which encompasses a total of nine molecules (e.g., glucose) from the blood test.

Slowing epigenetic aging means more for childhood cancer survivors

The potential is huge, as all people have a vested interest in avoiding age-related disease. However, the highest potential may be for a group that collectively experiences significant epigenetic age acceleration: childhood cancer survivors. Pediatric cancer treatments often cause changes to DNA including long-term damage as a side effect of cancer treatment. Wang has focused his research on these at-risk individuals.

“Survivors appear much older biologically than the chronologically matched general population,” Wang explained. “They are different from the non-cancer population, as they experience a significant epigenetic age acceleration. They are so different that you cannot simply consider chronological age in this population. Ideally, we should use biological age when predicting the risk of future age-related disease onset.”

Though almost all childhood cancer survivors experience some epigenetic age acceleration, the experience is not the same across the whole group. Some have very minor inconveniences, while others age much faster and develop chronic conditions decades earlier than the general population.

Wang’s group investigates those differences using data from the St. Jude Lifetime Cohort Study (St. Jude LIFE) and the Childhood Cancer Survivors Study (CCSS). The studies are two of the largest examinations of childhood cancer survivors, uncovering new potential avenues to help them lead better lives.

• One of their early findings was that treatment exposures for pediatric malignancies have a major effect, published in the Journal of the National Cancer Institute. In that same study, unhealthy behaviors were also found to increase epigenetic age acceleration significantly in survivors. Modifiable behaviors may be a reasonable place to intervene. In addition, drug repurposing such as rapamycin and metformin are under active clinical investigation.
• Another source of unequal accelerated aging is a person’s DNA. In a Genome Medicine paper, Wang’s group uncovered some of the underlying genetic bases of epigenetic age acceleration. Two genomic regions are associated with accelerated aging: SELP and HLA. Both genes are implicated in age-related diseases, increasing confidence in the findings. For example, SELP is upregulated in Alzheimer’s disease.
• Genetics can also lead to one of the worst outcomes for survivors, a second cancer. In a The Lancet Oncology study including data from both St. Jude LIFE and the CCSS, Wang found cancer-predisposing variants in 60 well-established genes that are associated with cancer risk, which could help survivors and their health care providers to take proactive preventative action. Furthermore, age is one of the top risk factors for cancer. A genetic predisposition combined with epigenetic age acceleration may put survivors at an even greater risk of developing a second cancer. This hypothesis will be further tested.
• They also attempted to address the question of when epigenetic aging acceleration started in survivors in a JAMA Network Open study. Wang’s group found that epigenetic age acceleration differed across chronological age-defined subgroups. They evaluated children and adolescent survivors with young adult survivors as well as old adult survivors. By analyzing those groups, they uncovered that epigenetic age acceleration was associated with risk of early-onset obesity developed younger than 20 years of age, suggesting a potential early entry point for anti-aging intervention for survivors of childhood cancer.
• Wang collaborated with AnnaLynn Williams, PhD, a former St. Jude postdoc fellow to assess the link between the aging biomarkers and deficit accumulation index. The deficit accumulation index is an established clinical tool for measuring signs of aging. The collaborators compared survivors with low, medium and high deficit accumulation index, finding that deficit accumulation index and epigenetic age acceleration can be used interchangeably to measure biological aging in JAMA Network Open. Those with medium deficit accumulation index had moderately increased epigenetic age acceleration, and those with high deficit accumulation index experienced highly increased epigenetic age acceleration.
• Patient-reported outcomes and health related quality of life are important for survivorship research and care. Wang’s group published a study in Journal of the National Cancer Institute reporting that overall and domain-specific measures of health-related quality of life are associated with DNA methylation measures of aging biomarkers. This included measuring epigenetic age using multiple clocks and others DNA methylation predicted circulating plasma proteins and hormones.
• Survivors self-reporting a non-Hispanic Black ethnicity experience significantly higher epigenetic age acceleration after pediatric cancer treatment than survivors self-reporting a non-Hispanic white background. In a recent study published in JAMA Network Open, Wang’s group sought to understand what factors accounted for that difference. They found social determinants of health, such as the environment, economics, and community context patients live in, were at the core of the difference. “We found that educational attainment, personal household income and the area deprivation index accounted for some of the biological aging differences between the two populations,” Wang said. The findings suggest policies that address these social determinants of health could reduce epigenetic aging in the most vulnerable survivors.

Cumulatively, Wang’s work has demonstrated that addressing genetic, treatment-related, as well as social, behavioral and environmental factors promises to slow accelerated epigenetic aging and remediate aging phenotypes in childhood cancer survivors.

“Quantifying epigenetic age acceleration has been the first step,” Wang concluded. “Our next step is to find and test interventions that address each source of epigenetic age acceleration, so our survivors can live longer, healthier lives.”