This study investigates the impact of living with HIV on the biological aging of the intestines, both in terms of systemic and tissue-specific aging, in people on antiretroviral therapy (ART). Using a systems biology approach, the researchers analyzed colon and ileal biopsies, blood samples, and stool specimens from 25 people living with HIV (PLWH) on ART and 23 people without HIV (PLWoH) as controls. The results show that PLWH exhibit accelerated biological aging in the colon, ileum, and blood compared to PLWoH, as measured by various epigenetic aging clocks. Specifically, PLWH had decreased levels of tight junction proteins in the intestines, increased microbial translocation, and higher levels of pro-inflammatory bacteria, such as *Catenibacterium* and *Prevotella*, while lower levels of anti-inflammatory bacteria, such as *Subdoligranulum* and *Erysipelotrichaceae*. These findings suggest that microbial dysbiosis and translocation contribute to the accelerated biological aging in PLWH. Additionally, the study found that specific bacterial genera in the colon, such as *Catenibacterium* and *Prevotella 2*, correlated strongly with greater accelerated aging, while others, like *Erysipelotrichaceae UCG-003* and *Alistipes*, correlated with slower aging. The study also revealed that SCFA-producing bacteria, particularly those producing butyrate, were associated with lower levels of HIV DNA and RNA, suggesting a potential role in HIV persistence. Finally, correlation networks identified links between specific microbial genera, microbe-related metabolites, and accelerated biological aging, highlighting the complex interplay between the gut microbiome, inflammation, and aging in PLWH on ART.This study investigates the impact of living with HIV on the biological aging of the intestines, both in terms of systemic and tissue-specific aging, in people on antiretroviral therapy (ART). Using a systems biology approach, the researchers analyzed colon and ileal biopsies, blood samples, and stool specimens from 25 people living with HIV (PLWH) on ART and 23 people without HIV (PLWoH) as controls. The results show that PLWH exhibit accelerated biological aging in the colon, ileum, and blood compared to PLWoH, as measured by various epigenetic aging clocks. Specifically, PLWH had decreased levels of tight junction proteins in the intestines, increased microbial translocation, and higher levels of pro-inflammatory bacteria, such as *Catenibacterium* and *Prevotella*, while lower levels of anti-inflammatory bacteria, such as *Subdoligranulum* and *Erysipelotrichaceae*. These findings suggest that microbial dysbiosis and translocation contribute to the accelerated biological aging in PLWH. Additionally, the study found that specific bacterial genera in the colon, such as *Catenibacterium* and *Prevotella 2*, correlated strongly with greater accelerated aging, while others, like *Erysipelotrichaceae UCG-003* and *Alistipes*, correlated with slower aging. The study also revealed that SCFA-producing bacteria, particularly those producing butyrate, were associated with lower levels of HIV DNA and RNA, suggesting a potential role in HIV persistence. Finally, correlation networks identified links between specific microbial genera, microbe-related metabolites, and accelerated biological aging, highlighting the complex interplay between the gut microbiome, inflammation, and aging in PLWH on ART.