A proteomic signature of healthspan

Abstract The focus of aging research has shifted from increasing lifespan to enhancing healthspan(definition) to reduce the time spent living with disability. Despite significant efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. We developed a proteomics-based signature of healthspan (healthspan proteomic score (HPS)) using proteomic data from the Olink Explore 3072 assay in the UK Biobank Pharma Proteomics Project (53,018 individuals and 2920 proteins). A lower HPS was associated with higher mortality risk and several age-related conditions, such as COPD, diabetes, heart failure, cancer, myocardial infarction, dementia, and stroke. HPS showed superior predictive accuracy for these outcomes compared to other biological age measures. Proteins associated with HPS were enriched in hallmark pathways such as immune response, inflammation, cellular signaling, and metabolic regulation. The external validity was evaluated using the Essential Hypertension Epigenetics study with proteomic data also from the Olink Explore 3072 and complementary epigenetic data, making it a valuable tool for assessing healthspan and as a potential surrogate marker to complement existing proteomic and epigenetic biological age measures in geroscience-guided studies. Significance Despite substantial efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. The challenge lies in the need for long follow-up periods and large sample sizes of healthy individuals to observe aging outcomes. Therefore, developing surrogate biomarkers that can predict healthspan is crucial. We addressed this by developing a proteomics-based signature of healthspan, termed the Healthspan Proteomic Score (HPS), in a healthy cohort. We demonstrated its clinical, predictive, and biological validity in the UK Biobank and Essential Hypertension Epigenetics study, which represents a focused subset of the Finnish Twin Cohort. The HPS, serving as a surrogate marker of healthspan, is useful for gauging an individual’s biological health and monitoring the impact of geroscience-guided interventions.