Plasma proteins offer clues to biological aging and mortality risk

A new study published in Geromedicine has identified 17 plasma proteins associated with all-cause mortality in older adults and found that several of these proteins also track with measures of biological aging across multiple organ systems.

The research analyzed 4,265 proteins in blood samples from 1,025 older adults enrolled in the LonGenity study. Participants were followed for an average of 8.05 years. The researchers then independently evaluated their findings in 1,124 participants from the Baltimore Longitudinal Study of Aging.

The study addresses a central question in geroscience: why do people of the same chronological age often differ substantially in health, disease burden and resilience? While chronological age records the passage of time, biological age seeks to capture how rapidly the body and individual organs may be aging.

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

The analysis identified 17 proteins significantly associated with all-cause mortality. Several stood out because their relationships with mortality were also reflected in biological-age measures.

Higher levels of epidermal growth factor receptor, or ERBB1, and anthrax toxin receptor 2, or ANTXR2, were associated with lower mortality risk and younger biological age across multiple organ systems. In contrast, higher levels of macrophage inhibitory cytokine-1, also known as MIC-1 or GDF15, human epididymis protein 4, known as HE4, and insulin-like growth factor-binding protein 2, or IGFBP-2, were associated with higher mortality risk and older biological age across multiple organ systems.

The researchers also reported more specific associations. 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 may help researchers better understand the biological pathways that connect systemic stress, physiological homeostasis, chronic disease and aging. They also identify candidate biomarkers that could be investigated in future studies of healthy aging and longevity.

The study does not establish that these proteins cause aging or mortality. Nor does it provide a clinical blood test for predicting an individual's lifespan or disease outcome. Rather, it identifies statistical associations in two longitudinal cohorts and highlights proteins that warrant further mechanistic and clinical investigation.

The research involved investigators from Albert Einstein College of Medicine, Stony Brook University, the National Institute on Aging, Stanford University School of Medicine, Kannur University and collaborating institutions.

The article, "Exploring mortality-linked proteins: Understanding their association with biological aging, disease phenotypes, signaling pathways, and their implications for longevity," is available open access in Geromedicine.

Study at a glance

• Primary cohort: 1,025 older adults from the LonGenity study
• Validation cohort: 1,124 participants from the Baltimore Longitudinal Study of Aging
• Proteins assessed: 4,265 plasma proteins
• Mean follow-up: 8.05 years
• Main result: 17 plasma proteins significantly associated with all-cause mortality
• Key interpretation: Mortality-associated proteins also showed relationships with organismal and organ-specific biological-age measures