Profiling an integrated network of cellular senescence and immune resilience measures in natural aging: a prospective multi-cohort study.

Background: Biological aging begins decades before the onset of age-related clinical conditions and is mediated by both cellular senescence and declining adaptive immune function. These processes are functionally related with the rate of senescent cell accumulation dependent upon a balance between induction and immune clearance. We previously showed that biomarkers in these domains can identify patients at-risk of surgery-related adverse events. Here, we describe evidence of clinical relevance in early aging and metabolic phenotypes in a general adult population.

Methods: We enrolled a total of 482 participants (ages 25-90) into two prospective, cross-sectional healthy aging cohorts. Expression of biomarkers of adaptive immune function and cellular senescence (SapereX) was measured in CD3+ T cells isolated from peripheral blood.

Findings: We established a network of biomarkers of adaptive immune function that correlate with cellular senescence and associate with early aging phenotypes. SapereX immune components associated with a decrease in CD4+ T cells, an increase in cytotoxic CD8+ T cells, and a loss of CD8+ naïve T cells (Pearson correlation 0.3-0.6). These components also associated with a metric of immune resilience, an ability to withstand antigen challenge and inflammation. In contrast, SapereX components were only weakly associated with GlycanAge (Pearson correlation 0.03-0.15) and commonly used DNA methylation clocks (Pearson correlation 0-0.25). Finally, SapereX biomarkers, in particular p16, were associated with chronic inflammation and metabolic dysregulation.

Interpretation: Measurement of SapereX biomarkers may capture essential elements of the relationship between cellular senescence and dysregulated adaptive immune function and may provide a benchmark for clinically relevant health decisions.