Stanford’s Wyss-Coray lab harnesses large-scale plasma proteomics and LASSO modeling to derive organ-specific ‘age gaps’ for 11 human organs. They identify organ-enriched plasma proteins and train age predictors on UK Biobank data (~45,000 participants). The resulting age gaps correlate with lifestyle factors, forecast incident diseases—from heart failure to Alzheimer’s—and reveal that youthful brain and immune profiles confer substantial longevity benefits.
Key points
Applied Olink plasma proteomics (~3,000 proteins) with GTEx‐defined organ enrichment to train LASSO regression models for 11 organ‐specific age predictions.
Calculated z-scored ‘age gaps’ that forecasted 15 incident diseases, including heart failure and Alzheimer’s, with hazard ratios up to 8.3 for multi‐organ aging.
Demonstrated that extreme brain and immune age gaps rival APOE genotype effects—aged brains triple Alzheimer’s risk and youthful profiles halve mortality risk.
Why it matters:
This plasma proteomics approach enables noninvasive tracking of organ health, offering personalized disease risk profiling and new targets for longevity interventions.
Q&A
What is an “age gap”?
How are organ-enriched proteins chosen?
Why use plasma proteomics for aging?
How do brain age gaps compare to APOE genotypes?
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Academy
Plasma Proteomics in Longevity Science
Introduction: Aging research seeks reliable, noninvasive biomarkers that reflect the biological age of organs and guide interventions to extend healthy lifespan. Plasma proteomics uses high-throughput assays to quantify thousands of proteins in blood, revealing molecular signatures of organ health and systemic aging.
What Is Proteomics?
Proteomics is the large-scale study of proteins, the functional molecules coded by genes. Unlike genomics or transcriptomics, proteomics measures the levels, modifications, and interactions of proteins, capturing dynamic changes that occur during aging, disease, or in response to environmental factors.
Why Plasma?
The bloodstream carries proteins released by every organ. By analyzing plasma, researchers can monitor multiple tissues simultaneously. Blood draws are routine and minimally invasive, making plasma proteomics ideal for longitudinal studies that track aging over time.
Organ-Enriched Protein Selection
- Gene Expression Atlas: Scientists use resources like the GTEx atlas to identify genes highly expressed in one organ compared to others.
- Protein Mapping: These organ-specific genes are mapped to their corresponding proteins measured in plasma assays.
- Biomarker Panels: Each organ receives a tailored set of plasma proteins, forming a panel that represents tissue-specific health markers.
Machine Learning and Age Gap Estimation
Researchers train regression models (commonly LASSO) on large cohorts with known ages. The model learns to predict chronological age from protein levels. An individual’s predicted age is compared to their real age; the difference is called the “age gap.” Positive gaps indicate accelerated aging, negative gaps indicate youthful organ profiles.
Interpreting Age Gaps
- Accelerated Organ Aging: Higher age gaps correlate with increased risk of diseases such as heart failure, chronic kidney disease, and Alzheimer’s.
- Youthful Organ Profiles: Lower age gaps in the brain and immune system are linked to longer survival and protection against dementia.
- Multi-Organ Aging: Accumulation of aged organs compounds mortality risk, guiding holistic health assessments.
Applications in Longevity Science
Personalized Risk Profiling: Age gaps offer individual disease prediction beyond genetics and standard blood tests. Clinicians can identify high-risk individuals early and tailor lifestyle or drug interventions.
Intervention Monitoring: Proteomic age gaps respond to medications, supplements, and lifestyle changes, enabling rapid assessment of anti-aging therapies.
Research Insights: Dissecting molecular drivers in organ aging panels uncovers new therapeutic targets, such as extracellular matrix components in the brain or inflammatory markers in the immune system.
Future Directions
Expanded proteomic platforms and integrated multi-omics will refine organ age estimates. Longitudinal sampling in diverse populations is essential to validate biomarkers and develop age-reversal treatments that improve healthspan globally.
