A Pathogen Penalty? Associations Between Persistent Infections and Biological Aging in the US

BACKGROUND: Persistent infections, including cytomegalovirus (CMV), herpes simplex virus type 1 (HSV-1), Epstein-Barr Virus (EBV), and Helicobacter pylori (H. pylori), illicit chronic immune stimulation and may contribute to biological aging. While CMV has been associated with markers of biological aging in older adults, including immunosenescence, less is known about these associations earlier in adulthood or the role of other persistent infections. METHODS: Using data from a nationally representative U.S. cohort, we examined associations between CMV, HSV-1, EBV, and H. pylori infections (assessed at a median age of 28 years) and markers of biological aging, including epigenetic age acceleration (EAA) and cellular immunosenescence (measured approximately 10 years later). EAA was assessed via GrimAge, PhenoAge, and DunedinPACE clocks while immunosenescence was estimated using DNA methylation-based immune cell ratios. RESULTS: CMV infection and antibody concentrations were consistently associated with accelerated epigenetic aging and increased cellular immunosenescence measures. For example, CMV seropositivity was associated with 0.36 higher CD4 + memory: naive ratio (95% CI: .11, .62). H. pylori, HSV-1, and EBV demonstrated more limited but notable associations, particularly with EAA measures. For instance, increased EBV IgG was associated with higher GrimAge acceleration (GrimAgeAA) (β=0.006 years, 95% CI: .002, .01). Higher H. pylori IgG antibodies were unexpectedly associated with a higher CD4+/CD8 + cell ratio (β=0.002, 95% CI: .0002, .004). CONCLUSIONS: Persistent infections, particularly CMV, shape biological aging via DNA methylation aging and immunosenescence before midlife. Future research is needed to clarify how the timing and burden of these infections influence biological aging and immune function across the life course.