Blood protein biomarkers predict future disability risk in very old adults

Japan has one of the world's fastest-aging populations, but maintaining independence into very old age remains a growing public health challenge. Nearly 60% of Japanese adults aged 85 years and older already receive support through the national Long-Term Care Insurance system, highlighting the need to identify people at risk before disability develops. Although routine blood tests can detect many age-related diseases, reliable biomarkers that predict future disability in the oldest-old have remained elusive. Identifying such markers could enable earlier interventions that help older adults remain active and independent for longer.

Addressing this challenge, a research team led by Associate Professor Yusuke Osawa from the Graduate School of Health Management, Keio University, Japan, along with Professor Yasumichi Arai from the Faculty of Nursing and Medical Care at the same university, and Dr. Luigi Ferrucci, Scientific Director of the Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, USA, analyzed blood samples from community-dwelling adults aged 85–89 years using an unbiased, data-driven screen of circulating proteins. Using machine learning and multivariable statistical analyses, they evaluated 29 plasma proteins for associations with future disability and mortality before independently validating the findings in the Italian Invecchiare in Chianti (InCHIANTI) aging study. The study was published online, in the journal GeroScience on June 27, 2026.

The discovery analysis included 230 disability-free participants from the Kawasaki Aging Well-being Project (KAWP), who were followed for approximately 4.5 years. Higher levels of beta-2-microglobulin (B2M) and cystatin C were consistently associated with a greater likelihood of developing disability. Each increase in these biomarkers was associated with significantly higher disability risk (hazard ratio 1.35 for B2M and 1.42 for cystatin C), even after accounting for age, sex, kidney function, lifestyle factors, and other potential confounders.

To determine whether the findings extended beyond one population, the researchers examined participants in the InCHIANTI study, which followed older adults in Italy for up to 15 years. Elevated B2M and cystatin C levels were again associated with greater disability risk, particularly among participants aged 80 years and older. In contrast, proteins initially linked with mortality-including epidermal growth factor and interferon gamma-induced protein 10-were not replicated, indicating that the disability-related biomarkers were the study's most consistent findings.

"Because B2M and cystatin C are already measurable using standard clinical assays, they have the potential to become practical tools for identifying older adults who may benefit from preventive support," says Dr. Osawa.

The two proteins also provide important biological insights. Both are associated with kidney function, while B2M additionally reflects chronic low-grade inflammation, or "inflammaging," which is increasingly recognized as a driver of age-related decline. Together, these processes may contribute to the gradual loss of physical function that ultimately leads to dependence on long-term care.

"Our findings suggest that preserving healthy aging requires attention not only to diseases but also to the biological processes that precede disability," explains Prof. Arai. "Earlier identification of people at higher risk could create opportunities for timely interventions such as exercise, nutritional support, and rehabilitation before irreversible decline occurs."

Overall, the study identifies B2M and cystatin C as promising blood-based biomarkers of future disability in very old adults. Their validation across Japanese and Italian cohorts supports their potential use in earlier risk stratification in rapidly aging societies. Such an approach may help shift healthcare from reactive treatment toward proactive prevention, enabling more older adults to maintain their independence while reducing the growing burden on long-term care systems worldwide.