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.

Reference
Title of original paper: Plasma proteins associated with disability and mortality risks in Japanese community-dwelling octogenarians
Journal: GeroScience
DOI: https://doi.org/10.1007/s11357-026-02377-7

About Keio University Global Research Institute (KGRI), Japan
The Keio University Global Research Institute (KGRI), established in November 2016, serves as a university-wide platform connecting faculties and graduate schools. It promotes interdisciplinary and international collaborative research that transcends academic and geographic boundaries, while disseminating research outcomes both domestically and globally.
In 2024, Keio University launched the Program for Forming Japan’s Peak Research Universities (J-PEAKS), funded by the Japan Society for the Promotion of Science (JSPS), under the vision of becoming a “research university that forges the common sense of the future.” Through this initiative, KGRI is strengthening research infrastructure to enhance interdisciplinary collaboration, promoting the societal implementation of research, and fostering a research ecosystem that enables collaboration across the university and with leading institutions in Japan and abroad.
Website: https://www.keio.ac.jp/en/org/kgri/

About Associate Professor Yusuke Osawa from Keio University
Dr. Yusuke Osawa is an Associate Professor at the Graduate School of Health Management, Keio University, Japan, and a Special Volunteer at the Translational Gerontology Branch, National Institute on Aging (NIA), USA. He earned his Ph.D. from the Graduate School of Health Management, Keio University, in 2011. His research focuses on aging epidemiology, particularly body composition, physical function, and biomarkers of disability and mortality in older adults through long-term cohort studies in Japan and the USA. In 2023, he received the Outstanding Poster Presentation Award at the 12th IAGG Asia/Oceania Regional Congress. More information is available on his faculty profile: https://www.k-ris.keio.ac.jp/html/100007234_en.html.

Funding information
This work was supported by JSPS KAKENHI (Grant Number, 21K10505, 24K02711, and 23H03337), Keio Global Research Institute Pre-Start-up Grant (T04EZ00011), Japan Agency for Medical Research and Development (Grant Number, 17jm0210051h0001, 23zf0127007h0002, 23ae0121041h0003), JST Research Complex Program (JP15667051), and grants from Kanagawa Institute of Industrial Science and Technology. Luigi Ferrucci and Julián Candia were supported entirely by the Intramural Research Program of the National Institute on Aging, NIH (USA). The InCHIANTI study was funded by grants from the National Institutes of Health (R01HL111271 and R21HL112662) and National Institute on Aging Contract 263MD9164 and was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. The InCHIANTI study baseline (1998–2000) was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-up 1 (2001–2003) was funded by the U.S. National Institute on Aging (Contracts: N.1-AG-1–1 and N.1-AG-1–2111); and the InCHIANTI Follow-ups 2 and 3 studies (2004–2010) were financed by the U.S. National Institute on Aging (Contract: N01-AG-5–0002) and supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland.