TTV Species Diversity as a Novel Biomarker of Immune Dysregulation in Aging

Abstract

Torquetenovirus (TTV) is a prevalent virus whose clinical significance remains unclear, potentially linked to immunosenescence. This study examines TTV species in relation to immune impairment, inflammation, and cellular stress response in aging. A subset of recruited age‐stratified individuals (RASIG) from the MARK‐AGE study was divided into three groups: Cohort 1 A (healthy young adults), Cohort 1B (older adults with mild immune decline), and Cohort 1 C (older adults with marked immune impairment). Analyses included TTV load, species diversity, lymphocyte subpopulations, inflammatory markers, Poly‐(ADP‐ribose) polymerase (PARP‐1) expression/activity. Alpha‐ and beta‐diversity analyses showed the highest TTV species diversity in Cohort 1 C, with significant cohort‐dependent differences and partially cohort‐specific clustering patterns. Increased TTV species number correlated with higher TTV load, elevated CMV IgG levels, and greater immune impairment risk. Specific TTV species were associated with CD4/CD8, and reduced T‐cell receptor excision circles, suggesting impaired T‐cell homeostasis. TTV viremia positively correlated with C‐reactive protein (CRP) and α2‐macroglobulin. PARP‐1 expression and activity increased in individuals with higher TTV diversity, particularly in the presence of TTV9 and TTV20. TTV load and species diversity are associated with immunosenescence, inflammation, and PARP‐1 activation suggesting their potential as biomarkers of age‐related immune decline. Longitudinal studies are needed to clarify underlying mechanisms.