Species-level Torque teno virus abundance is associated with immune impairment, epigenetic aging markers, and clinical vulnerability in hospitalized older adults: the VIROMA study

Torque teno viruses (TTVs) are ubiquitous components of the human virome whose replication is tightly regulated by host immunity. While elevated total TTV load has been associated with increased mortality in older adults, the clinical relevance of species-level virome composition remains unclear. We profiled the circulating anellovirome in 251 hospitalized older adults using amplicon-based whole-genome sequencing and investigated associations with frailty, cognitive impairment, mortality, immune remodeling, and epigenetic aging. Reduced TTV species evenness was associated with 1-year mortality ( p = 0.013, FDR = 0.052); however, differences in species composition accounted for less than 1% of the total variance (PERMANOVA: Ružička R 2 = 0.0079, p = 0.021, FDR = 0.035; Bray–Curtis R 2 = 0.0082, p = 0.035, FDR = 0.035), indicating that host-related factors rather than distinct clinical phenotypes primarily shaped the virome. Following multivariable adjustment, differential abundance analyses identified TTV19 enrichment in patients with 1- and 3-year mortality, frailty, and cognitive impairment, alongside TTV9 enrichment in frail patients. Bootstrap resampling confirmed a stable association between TTV19 and cognitive impairment (logFC = 2.39, 95% CI 0.59–5.43) and between TTV9 and frailty (logFC = 2.26, 95% CI 0.11–9.86). Conversely, multivariable Cox models showed no significant association between TTV19 abundance and 1-year or 3-year mortality, and only a nominal association with seven-year mortality (HR 1.10, 95% CI 1.01–1.19) that did not pass multiple testing correction. Species-specific associations with DNA methylation–estimated immune cell subsets further supported links between selected TTV species and immune remodeling. TTV19 log-abundance showed a positive nominal association with Age Acceleration GrimAge ( p = 0.024, FDR = 0.072), and with DNAm-estimated inflammatory and vascular markers. Overall, these findings suggest that the circulating anellovirome primarily reflects systemic vulnerability rather than disease-specific signatures in late life. A limited subset of viral species may represent candidate correlates of immune dysregulation and biological aging requiring further validation.