While modern antiretroviral therapy (ART) has transformed HIV from a fatal diagnosis into a manageable chronic condition, a critical challenge remains: people living with HIV experience accelerated biological aging and a higher burden of comorbidities. However, is this aging process uniform across all patient ages and tissues?
Research from the University of Pittsburgh, in collaboration with our team at VUGENE and the Epigenetic Clock Foundation, utilized a primate HIV model (SIV infection in rhesus macaques) to answer a key question: Does the age at which an individual is infected influence biological aging trajectories? Is this effect uniform, or does it vary across tissue types?
By applying epigenetic clocks based on DNA methylation (DNAme) and epigenome-wide association studies (EWAS) to both blood and solid tissue samples, this study’s insights are starting to redefine our understanding of virus-driven aging.
The vulnerability of the young
During late-stage SIV infection (4.4–12 months post-infection), young rhesus macaques (4–6 years) but not older macaques (15–22 years) exhibited significant epigenetic age acceleration (EAA) in their blood cells (PBMCs), based on 8 of 10 mammalian clocks. This suggests that late-stage SIV disproportionately accelerates biological aging in the circulating immune cells of younger hosts.
In young animals, epigenetic age correlated negatively with CD4+ T cell abundance in superficial lymph nodes and positively with systemic T-cell activation. Although older macaques did not show significant PBMC EAA, epigenetic age was positively associated with markers of inflammation, including CRP levels and monocyte activation.
Tissue-specific effects of SIV infection
To examine the impact of SIV on tissue aging, EAA was measured in six solid tissues using the third universal pan-mammalian epigenetic clock, a robust multi-tissue estimator. Young macaques showed higher EAA than older macaques in the cerebellum, heart, and spleen, whereas only the colon exhibited greater EAA in older animals. This finding is notable because the cerebellum and heart contain long-lived cells, which may be particularly vulnerable to HIV-associated effects in younger hosts over the long term.
A Paradoxical Finding
Although older macaques showed more severe disease progression early on, long-term biological aging was paradoxically more pronounced in the younger group, indicating that accelerated aging does not always correspond directly with initial disease severity.
Bioinformatics Beyond Analysis
The study employed 10 epigenetic clocks to estimate biological age, including primate-specific and pan-mammalian clocks. EAA was calculated as the difference between epigenetic and chronological age. Blood-based EAA was modeled as a function of age status (young vs. older animals), while tissue-specific EAA was modeled using days post-infection and chronological age. Associations were assessed using Spearman rank correlation.
Why does this matter?
SIV-driven aging is not uniform: it varies by tissue and depends on the host’s age at infection. Importantly, epigenetic age acceleration disproportionately affects younger hosts, highlighting the need for further studies to map long-term aging trajectories following infection. It also suggests exploring and adjusting for the biological age (epigenetic age) when performing data analysis between infected and control groups. These insights may help explain the origins of comorbidities in people living with HIV and inform strategies to mitigate virus-driven biological aging, ultimately improving protection and care for this population.
Jasinska, A.J., Sivanandham, R., Sivanandham, S., Xu, C., Gordevičius, J., Milčiūtė, M., Brooke, R.T., Sette, P., He, T., Brocca-Cofano, E., Policicchio, B.B., Nayak, K., Talwar, S., Annapureddy, H., Ma, D., Ribeiro, R.M., Apetrei, C. and Pandrea, I. Pathogenic SIV infection is associated with acceleration of epigenetic age in rhesus macaques. Journal of Clinical Investigation, 2025, 135(14).
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Written by: Liucija Vaicenavičiūtė
Cover image credits: Giovanni Cancemi / Adobe Stock
