Researchers at McMaster University have identified, for the first time, a novel region of DNA and two associated genes connected to frailty, offering neurological and immune-related insights that might help explain why some older adults are more likely to be frail than others.
The McMaster team’s findings, published on April 22 in the journal npj Aging, fill an important gap by revealing genetic factors that contribute to the development of frailty. The discovery provides a biological connection to the condition and points toward new avenues for early detection and targeted intervention.
Frailty is a growing public health challenge driven by rapid population aging. It increases the risk of falls, disability, hospitalization, and early death, but its underlying biology has remained poorly understood.
“This research gives us new biological clues into why frailty develops. We identified a genetic region that has never been linked to frailty before,” says Sayem Borhan, the study’s lead author and assistant professor in the Department of Health Research Methods, Evidence and Impact at McMaster.
“Understanding how both the immune and brain systems influence frailty, opens the door to earlier screening and potentially more personalized approaches to supporting healthy aging.”
“Our hope is that these findings help researchers develop tools to identify at-risk individuals sooner. Frailty is complex and influenced by many factors, but genetics is one important piece of the puzzle,” adds Borhan, who is also a member of the McMaster Institute for Research on Aging (MIRA) and an affiliate scientist at the Research Institute of St. Joe’s Hamilton.
The research team conducted a type of study called a genome-wide association study (GWAS), which scans the complete DNA of many people to identify genetic variations. They used more than 8 million genetic variants from more than 23,000 participants in the Canadian Longitudinal Study on Aging (CLSA) and categorized participants as non-frail, pre-frail, or frail based on the clinically validated characteristics for frailty, which include grip strength, walking speed, exhaustion, weight loss, and physical activity.
The analysis found a genetic variant on a previously unknown region on chromosome 12, that is more common in people who are frail. This exact region has never been identified before. Two genes (PLXNC1 and SOCS2) linked to this region have been identified, which demonstrates the role of the brain and immune systems in frailty.
The study is one of the largest frailty genome-wide association studies completed in Canada and is the first to identify this specific genomic region. Together, these findings bring researchers closer to understanding the biology of frailty – an essential step toward earlier detection and better prevention strategies.
“The global phenomenon of a rapidly growing aging population challenges us all to find ways for healthy aging. Knowledge of the underlying biological mechanisms of aging is essential for finding these ways,” says Parminder Raina, last author of the study and a professor in the Department of Health Research Methods, Evidence and Impact at McMaster. Raina is the founding scientific director of MIRA and is the lead principal investigator of the CLSA.
Next steps for the research include validating these genetic findings in more diverse populations, investigating how the identified genes influence inflammation and brain function over time, and exploring whether these biological pathways can be targeted to prevent or delay frailty.
The team also hopes future work will support the development of early screening tools that help clinicians identify individuals at higher risk long before frailty affects their health or independence.