Persistent infection via HIV, herpesvirus, or a range of other pathogens capable of evading or subverting the immune system might reasonably be thought of as producing accelerated aging. The dysfunction produced by these infections usually centers around the immune system, but this in turn negatively affects the function of tissues and systems throughout the body. Aging is an accumulation of damage, and persistent infection produces forms of damage that overlap with those generated during the normal course of aging. Here, researchers discuss the range of mechanisms thought to be involved.
Many models of aging assume that processes such as cellular senescence or epigenetic alteration occur under sterile conditions. However, humans sustain infection with viral, bacterial, fungal, and parasite pathogens across the course of a lifetime, many of which are capable of long-term persistence in host tissue and nerves. These pathogens - especially members of the human virome like herpesviruses, as well as intracellular bacteria and parasites - express proteins and metabolites capable of interfering with host immune signaling, mitochondrial function, gene expression, and the epigenetic environment.
This paper reviews these and other key mechanisms by which infectious agents can accelerate features of human aging. This includes hijacking of host mitochondria to gain replication substrates, or the expression of proteins that distort the signaling of host longevity-regulating pathways. We further delineate mechanisms by which pathogen activity contributes to age-related disease development: for example, Alzheimer's amyloid-β plaque can act as an antimicrobial peptide that forms in response to infection.
Overall, because many pathogens dysregulate mTOR, AMPK, or related immunometabolic signaling, healthspan interventions such as low-dose rapamycin, metformin, glutathione, and NAD+ may exert part of their effect by controlling persistent infection. The lack of diagnostics capable of detecting tissue-resident pathogen activity remains a critical bottleneck. Emerging tools - such as ultrasensitive protein assays, cell-free RNA metagenomics, and immune repertoire profiling - may enable integration of pathogen detection into biological age tracking. Incorporating infection into aging models is essential to more accurately characterize drivers of senescence and to optimize therapeutic strategies that target both host and microbial contributors to aging.
Link: https://doi.org/10.1016/j.arr.2025.102865
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