Two people born on the same day can face very different health trajectories. While chronological age is fixed, biological age—how quickly the body’s systems decline—varies widely. Scientists have long used epigenetic clocks to estimate this pace, but what these clocks actually capture inside the body has remained unclear.
Now, researchers in the United States have analyzed blood samples from more than 3,200 participants in the US Health and Retirement Study to decode what five of the most commonly used epigenetic clocks are really picking up. Their findings, published in the journal Nature Aging, reveal that each clock is associated with distinct molecular processes, from energy use to immune response.
What are epigenetic clocks?
Epigenetic clocks are mathematical models based on DNA methylation—chemical modifications that alter gene activity without changing the underlying genetic code. These clocks are widely used in aging research to link biological aging to disease, physical decline, and mortality risk.
“Aging isn’t just about the number of candles on your birthday cake—it’s also about what’s happening inside your cells,” said T. Em Arpawong, a research associate professor of gerontology at the USC Leonard Davis School, in a press release. But until now, the specific biological signals behind each clock’s readings were unknown.
Five clocks, five windows into aging
The team compared the five clocks with gene activity in the blood samples. They found that the clocks were linked to different aspects of aging: some were more closely tied to how the body uses energy and how cells grow, while others reflected immune activity and inflammation. Despite these differences, the clocks shared common features, particularly changes involving the immune system, metabolism, and cell-to-cell communication.
“This helps open the ‘black box’ of biological aging clocks,” said senior author Eileen Crimmins, also at USC Leonard Davis. “We can now see which molecular processes are associated with their readings.”
The findings could help researchers choose the most appropriate clock for their studies. For example, a clock that tracks immune function might be better suited for research on infections or autoimmune diseases, while one linked to metabolism could inform studies on diabetes or obesity.
New tools for better predictions
Based on their results, the team developed new measurements called transcriptomic aging gene scores (TAGS). In several cases, TAGS outperformed the clocks alone in predicting frailty, walking speed, heart disease, diabetes, lung disease, and mortality.
These advances come as European researchers are also exploring biological aging. For instance, a blood test developed in Edinburgh shows how molecular markers can aid diagnosis. Similarly, European scientists are using ground data to better understand environmental impacts on health.
The study’s authors emphasize that biological age is not a fixed destiny. Lifestyle factors, medical care, and environmental exposures can influence the pace of aging. As research progresses, epigenetic clocks and TAGS may become valuable tools for personalized medicine, helping clinicians identify individuals at higher risk of age-related diseases earlier.
“We’re moving toward a more precise understanding of aging,” Crimmins said. “This is not just about extending lifespan, but about extending the years of healthy life.”
