Infections Accelerate Cellular Aging by Shortening Telomeres, Review Finds

Infections are increasingly recognized as potential contributors to age-related diseases such as cardiovascular disease and dementia, but the biological mechanisms remain poorly understood. One candidate pathway is accelerated immunological aging, measurable through telomere length (TL). Telomeres are repetitive DNA sequences capping chromosomes that shorten with each cell division; critically short telomeres trigger cellular senescence or apoptosis. Shorter telomeres have been linked to Alzheimer's disease in both observational studies and Mendelian randomization analyses, making TL a plausible mechanistic bridge between infection and age-related decline.

This pre-registered systematic review (PROSPERO: CRD42023444854) searched six major databases from inception through May 2025, identifying 10,349 records and ultimately including 73 studies meeting eligibility criteria. Studies covered adults of any age and geographic region, with any infection type diagnosed via clinical records, serology, self-report, or genetic instruments (for Mendelian randomization designs). Outcomes were TL or telomere attrition measured by any established assay. Two independent reviewers screened studies, extracted data, and assessed risk of bias using the ROBINS-E tool, with GRADE used to evaluate overall evidence quality.

HIV dominated the literature, accounting for 35 of 73 studies. Among those with non-overlapping samples, 79% reported that HIV infection was associated with shorter telomeres or greater attrition compared to uninfected controls. This pattern held across multiple cell types and assay methods, suggesting a robust signal. Proposed mechanisms include chronic immune activation, elevated oxidative stress, and the direct cytopathic effects of HIV on CD4+ T-cells driving accelerated replicative turnover. Evidence for herpesviruses (CMV, HSV, EBV) and Human Papillomavirus was far more heterogeneous, with studies reporting both shorter and longer telomeres, precluding clear conclusions.

A key limitation across the field is methodological heterogeneity. Studies varied in telomere measurement assay (qPCR, Southern blot, FISH), tissue or cell type sampled (whole blood, leukocytes, specific lymphocyte subsets), and statistical adjustment for confounders including age, sex, smoking, and socioeconomic factors. Most studies (59 of 73) were cross-sectional, limiting causal inference. The ROBINS-E assessment classified most studies as high risk of bias, primarily due to unmeasured confounding. Meta-analysis was therefore unfeasible and a narrative synthesis was conducted instead.

The GRADE assessment rated overall evidence quality as very low. The authors conclude that while HIV presents a biologically plausible and reasonably consistent association with telomere shortening, the evidence base for other infections remains insufficient. Rigorous longitudinal studies with standardized telomere assays, prospective infection ascertainment, and comprehensive confounder adjustment are urgently needed — particularly for pathogens beyond HIV — to determine whether infections causally accelerate biological aging and whether this explains downstream risks of dementia and cardiovascular disease.