Small RNA molecules can accurately predict survival in older adults

As people age, it becomes harder to know who is on track for healthy years ahead and who may be at higher risk for serious decline. A new study suggests that part of the answer may already be circulating in the bloodstream.

Research led by Duke Health, in collaboration with the University of Minnesota, has found that small RNA molecules known as piRNAs can accurately predict whether older adults are likely to survive at least two more years.

The findings, published February 25 in Aging Cell, suggest that a simple blood test could one day help identify survival risks earlier and guide treatment strategies to promote healthy aging.

"The combination of just a few piRNAs was the strongest predictor of two-year survival in older adults-stronger than age, lifestyle habits, or any other health measures we examined," said Virginia Byers Kraus, M.D., Ph.D., senior author of the study and professor in the departments of Medicine, Pathology and Orthopaedic Surgery at Duke University School of Medicine. "What surprised us most was that this powerful signal came from a simple blood test," Kraus said.

The team measured piRNAs in blood samples from adults aged 71 and older and discovered that lower levels of certain piRNAs were strongly linked with longer survival. Past studies have shown these small bits of RNA regulate development, regeneration and the immune system.

To conduct the study, researchers used causal artificial intelligence and machine learning approaches to analyze 187 clinical factors and 828 different small RNAs in more than 1,200 blood samples. The samples were drawn from a large North Carolina-based cohort established in a previous Duke-led study. Survival outcomes were determined by linking participants to national mortality records.

Advanced statistical modeling revealed that a group of six piRNAs alone predicted two‑year survival with accuracy as high as 86%. The team confirmed the findings in a second, independent group of older adults.

Participants who lived longer consistently had lower levels of specific piRNAs, echoing a pattern in simple organisms, wherein reducing these molecules can extend lifespan. Kraus said the findings suggest piRNAs may directly influence longevity.

We know very little about piRNAs in the blood, but what we're seeing is that lower levels of certain specific ones is better. When these molecules are present in higher amounts, it may signal that something in the body is off‑track. Understanding why could open new possibilities for therapies that promote healthy aging."

Virginia Byers Kraus, M.D., Ph.D., senior author of the study and professor in the departments of Medicine, Pathology and Orthopaedic Surgery, Duke University School of Medicine

The study also compared piRNAs with more familiar health indicators. For predicting short‑term survival, piRNAs outperformed age, cholesterol, physical activity, and more than 180 other clinical measures. For longer-term survival, lifestyle factors became more influential, but piRNAs continue to provide valuable insight into underlying biology.

Kraus said the team's next steps include studying whether treatments, lifestyle changes, or medications-including emerging drug classes like GLP-1 based therapies-might alter piRNA levels. They also plan to compare piRNA levels in blood with levels inside tissues to better understand how these molecules function.

"These small RNAs are like micromanagers in the body, helping control many processes that affect health and aging," Kraus said. "We are only beginning to understand how powerful they are. This research suggests we should be able to identify short-term survival risk using a practical, minimally invasive blood test-with the ultimate goal of improving health as we age."

In addition to Kraus, study authors include Sisi Ma, Syeda Iffat Naz, Xin Zhang, Christopher G Vann, Melissa C Orenduff, William E Kraus, Steven Shen, Janet L Huebner, Ching-Heng Chou, Erich Kummerfeld, Harvey Jay Cohen, Constantin F Aliferis.

This work was funded by the National Institutes of Health (U54AG07604), the National Institute on Aging (R01AG054840, P30-AG028716) the National Center for Advancing Translational Sciences (UL1TR002494), and the National Heart, Lung and Blood Institute (1UM1TR004405).