Blood Proteins Linked to Mortality Risk and Biological Aging Across Organ Systems

Biological age aims to capture these differences by reflecting how rapidly the body and individual organs may be aging relative to calendar time. Blood-based biomarkers are being studied to clarify this variation and its relationship to survival. New findings connect these areas, showing that plasma proteins associated with mortality also align with biological aging across multiple organ systems.

Researchers at Albert Einstein College of Medicine (New York, NY, USA) and collaborating institutions analyzed plasma proteins in older adults to identify molecular markers associated with all-cause mortality. They measured 4,265 proteins in blood samples from 1,025 LonGenity study participants, who were followed for an average of 8.05 years. The findings were then independently evaluated in 1,124 participants from the Baltimore Longitudinal Study of Aging.

Using Cox proportional-hazards models, the investigators examined relationships between plasma-protein levels and all-cause mortality. They then assessed whether mortality-associated proteins were also related to chronic disease burden and proteome-derived measures of biological age. These measures captured both whole-body aging and organ-specific biological-age estimates.

The analysis identified 17 plasma proteins significantly associated with all-cause mortality, several of which also showed associations with biological aging. Higher levels of epidermal growth factor receptor (ERBB1) and anthrax toxin receptor 2 (ANTXR2) were associated with lower mortality risk and younger biological age across multiple organ systems. Conversely, higher levels of macrophage inhibitory cytokine-1 (MIC-1/GDF15), human epididymis protein 4 (HE4), and insulin-like growth factor-binding protein 2 (IGFBP-2) were associated with higher mortality risk and older biological age across multiple organ systems.

Further analysis highlighted associations with whole-body and organ-specific aging. Elevated MIC-1/GDF15 was associated with older organismal biological age, while ERBB1 was associated with younger liver biological age. Key associations were independently replicated in the Baltimore Longitudinal Study of Aging cohort.

The findings were published in Geromedicine in the open-access article “Exploring mortality-linked proteins: Understanding their association with biological aging, disease phenotypes, signaling pathways, and their implications for longevity.” Participating institutions included Albert Einstein College of Medicine, Stony Brook University, the National Institute on Aging, Stanford University School of Medicine, Kannur University, and collaborating institutions. The study does not establish that these proteins cause aging or mortality, and it does not provide a clinical blood test for predicting lifespan or disease outcomes.

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