As a computational epigeneticist and data architect of multi-omics datasets, Hayan Lee, PhD, Assistant Professor, Cancer Epigenetics Institute at Fox Chase Cancer Center, and physician-scientist Glenn S. Gerhard, MD, Professor and Chair, Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, with long-standing interest in the genetics of aging, are pioneering research to unravel the complex relationships between aging, epigenetics, and cancer.
Dr. Lee explained, “We design machine learning models to predict epigenetic and image biomarkers for early diagnostics and prognostics and recommend therapeutic options in cancer and neurodegenerative diseases.” While aging is widely recognized as a major risk factor for cancer, the actual determination of biological age is more complex than mere chronology since chronological age does not always reflect individual variations in the aging process. For example, someone who is chronologically 50 years old may have a biological age that is significantly younger or older. DNA methylation (DNAm), an essential epigenetic modifier that regulates gene expression, cell differentiation, and aging, is being used to estimate biological age.
To date, many DNAm-based epigenetic clocks have been developed to predict biological aging. Each clock has its value, but they often differ widely depending on their AI training architecture as well as the organ and assay technologies used.
Pursuing a more reliable “biological age predictor,” Dr. Lee, Dr. Gerhard, and colleagues developed two EnsembleAge clocks to smooth out these variances, harnessing the power of eight previously developed DNAm epigenetic clock models. Using advanced machine learning, the team “trained” their EnsembleAge clock models using DNA methylation data from nine organs in the Genotype-Tissue Expression (GTEx) dataset.
The results were striking: the EnsembleAge clocks achieved the lowest median absolute error (MeAE) across multiple organs and applications, indicating a practical value for predicting biological age and offering significant promise for identifying those at increased risk for age-related cancers such as breast, prostate, and colon cancer. Since treatments such as chemotherapy, radiation therapy, and immune checkpoint blockade (ICB) may accelerate epigenetic aging, DNA methylation clocks could serve as valuable biomarkers for guiding therapeutic decisions.
Previously, biological clocks focused on methylation data from the nuclear DNA. Now, Dr. Lee and Dr. Gerhard plan to exploit the epigenetics of mitochondrial DNA. Further motivation for this research is the dominant role that mitochondrial function has played in aging, and as the body’s energy “factory,” mitochondrial function diminishes as one grows older. “One application for a mitochondrial aging clock is it could be used to measure how older cancer patients may survive treatments,” said Dr. Lee. In addition, they are using long-read third-generation sequencing, where genomic and epigenomic information is directly decoded from native DNA molecules, enabling a more accurate determination of DNAm relative to the amplification-based methods that have been in widespread use.
Both Dr. Lee and Dr. Gerhard note that beyond general aging clocks, customized “clocks” for specific organs are essential to understanding the organ-specific aging process; thus, they are more effectively applicable to matching cancer types.
The commitment and relentless drive of clinician-scientists such as Dr. Lee and Dr. Gerhard represent the epitome of an elite NCI-designated Comprehensive Cancer Center. Through additional support from our partnership with Temple University Health System’s oncology research, treatment, and prevention programs, Fox Chase research makes a world of difference in Northeast Philadelphia and in all the communities that we serve—to deliver foundational scientific breakthroughs that transform cancer care and the lives of those affected by it.
Our EnsembleAge online clock service empowers individuals to track their biological/epigenetic age over time, mitigating the effect of variance and promoting healthy aging and a beneficial lifestyle. It is available at https://ensemble.epiclock.app/.
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