Estimation of Biological Aging Based on T Cell Differentiation Trajectories: Emerging and Future Avenues

Aarav M Bhasin^1*Ishaan K Marwaha^2*Lahiri S Nooka^3*

• ¹Johns Creek High School, Johns Creek, United States
• ²Pope High School, Marietta, United States
• ³The Westminster Schools, Atlanta, United States

The relationship between disease onset and chronological age varies by individual, driving the need for a more accurate, universal biomarker of biological aging. Among the emerging alternatives, the immune system represents a universal shared complex system that consistently shows aging-related decline across diverse individuals. Specifically, T cell dynamics, capturing both thymic involution and lifelong antigenic exposure, provides insight into immune system aging. While existing aging clocks, such as those based on DNA methylation (i.e., Horvath's and GrimAge), offer valuable predictions of biological age and disease risk, these methods are often limited in ability and cost to reflect real-time immune function. We also explore cutting-edge techniques to measure T cell states, such as flow cytometry, single-cell omics, CyTOF, and the potential of non-invasive retinal imaging, but these techniques also face such limitations. To account for the challenges with the above-mentioned methods, we propose the naive-to-exhausted T cell ratio as a promising, quantifiable metric of immune aging. The conceptual framework benchmarks the naive-to-exhausted T cell ratio against established epigenetic clocks, generating an "immune age curve" that offers clinicians and researchers a practical approach to integrate immune aging assessments into clinical and preventative care. To test our hypothesis, we conducted survival association analysis based on naive to exhausted T cells levels across all major cancers (including adrenal carcinoma (HR=0.19 (CI [0.082, .44]), p=1.92e-5), low-grade glioma (HR=0.47 (CI [0.33, 0.67]), p=2.4e-5), sarcoma (HR=0.52 (CI[0.35, 0.77], p=.000984)). The survival analysis shows that a higher ratio of naive to exhausted T cells is associated with significantly better overall survival rates, with Hazard Ratios (HR) ranging from 2.7e-9 to 0.7. These preliminary results support the predictive value of naive to exhausted T cell levels for biological aging across multiple organ systems and disease progression prediction.