HMN 2026: How Changes in pace of epigenetic clocks over time may help predict mortality risk

The age on your driver’s license may not be the same age as the cells in your body. Scientists use something called an epigenetic clock, which looks at certain chemical tags in DNA to measure your biological age, or how fast your body is actually aging. This can differ from your chronological age, the number of years you have been alive. In a study published in Nature Aging, researchers examined whether changes over time in the biomarkers used for epigenetic clocks could improve the prediction of mortality risk.

After tracking a group of people in the Chianti region of Italy for 24 years who were part of the long-term InCHIANTI study, they found that faster increases in epigenetic clocks were strongly linked to a higher risk of death, regardless of how old the person was when the study began.

Tracking how biological age evolves over time can be a powerful addition to routine health checkups, offering a much clearer, deeper picture of someone’s overall well-being.

Mapping the age trajectory

DNA methylation is the process where a methyl group (–CH₃) is added to the C5 position of cytosine, one of the four nucleotide bases in DNA. This modification regulates gene expression in two main ways: it can recruit proteins involved in gene repression or block transcription factors from binding to DNA. It is known that DNA methylation can change in response to environmental factors and aging, and it is widely used as a biomarker in epigenetic clocks.

The science of understanding the biological mechanisms of aging, known as geroscience, presents a rather interesting hypothesis: aging itself is the main cause of many long-term diseases and physical problems later in life. If we can slow the rate at which the body ages, we might be able to delay or prevent these diseases and help people stay healthy for longer.

With techniques like DNA methylation-based epigenetic clocks, scientists can now determine how fast someone is biologically aging.

Most earlier research relied on single-time-point measurements of epigenetic clocks, which limited understanding of changes in these measures over time and their relationship to health outcomes. It also left a major question unanswered: Are differences in biological aging set early in life, or can they change with health and age?

To find an answer, the researchers of this study followed 699 adults, both men and women, with an average starting age of about 63 years old, from the late 1990s to January 2024. DNA samples from the participants were collected at two or three different time points—1998, 2007, and 2013—to see how each person’s biology evolved.

First, they looked for methylation tags in the DNA and fed that data into seven different scientific formulas for epigenetic clocks. These included first-generation clocks that match chronological age, second-generation clocks designed to predict a person’s risk of death and health problems, and the third-generation that measures the pace of aging.

The team compared DNA samples collected years apart to calculate each person’s yearly rate of change. This revealed the slope of their aging process—showing whether their biological clock was advancing faster or slower than expected. Then the slopes were compared with official death records to check whether the speed of the slope could help predict mortality risk.

The data revealed that people whose epigenetic clocks sped more quickly over time had a significantly higher risk of death. For some of the most advanced clocks, biological aging did not progress at a steady rate but instead accelerated further as participants grew older.

These findings show that shifts in epigenetic aging over time mirror changes in health and could act as sensitive markers for interventions aimed at extending healthy lifespan and longevity.

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