RESULTS AND DISCUSSION
First, we examined epigenetic clocks of monocyte cells from a 24‐week clinical trial of 12 participants (time since HIV diagnosis ranged from 13 to 29 years) that were randomized 1:1 to receive either adjunctive metformin (500 mg extended release increasing to 1000 mg at Week 4 until 24 weeks) or observation. The study design of the retrospective analysis of a 24 week adjunctive metformin clinical trial is shown in Figure Epigenetic clock estimates in monocytes (a) Overview of 24 week clinical trial (b, c) Monocyte subsets did not significantly differ in participants in the metformin and observation arms. (d) PCGrimAge was significantly decreased in the metformin arm, We observed no significant differences in the percent of total monocytes, classical CD14Next, we utilized the DNAm dataset to examine whether metformin impacted monocytes DNAm mitotic clocks constructed from CpGs that map to gene promoters marked by the polycomb repressive complex 2 (PRC2) in human embryonic stem cells that estimate the relative stem cell division rate (Beerman et al., We next retrospectively examined epigenetic age of CD8Epigenetic clock estimates in CD8Observational epigenetic clock studies have reported conflicting metformin results on reducing epigenetic aging estimates (Li et al., In summary, this brief report suggests adjunctive metformin in PLWH reduces mortality‐based epigenetic clocks in monocyte cells, potentially impacting accelerated and or accentuated aging—a major concern for PLWH due to increased age‐related comorbidities. It is crucial to further investigate metformin's cell‐type specific effects on monocytes through clinical trials. This report's limitations include a small sample size and the absence of follow‐up after metformin therapy to assess the durability of epigenetic clock changes in short‐lived monocyte cells. Our findings highlight the importance of pursuing more geroscience interventions that target biological aging in PLWH who stand to gain the most benefits and incorporating epigenetic clocks in clinical trials of metformin for aging to provide valuable insights into assessing treatment effects, understanding mechanisms, and longitudinal monitoring.