Cell‐type specific impact of metformin on monocyte epigenetic age reversal in virally suppressed older people living with <scp>HIV</scp>

Abstract The anti‐diabetic drug metformin may promote healthy aging. However, few clinical trials of metformin assessing biomarkers of aging have been completed. In this communication, we retrospectively examined the effect of metformin on epigenetic age using principal component (PC)‐based epigenetic clocks, mitotic clocks, and pace of aging in peripheral monocytes and CD8 + T cells from participants in two clinical trials of virologically‐suppressed people living with HIV (PLWH) with normal glucose receiving metformin. In a small 24‐week clinical trial that randomized participants to receive either adjunctive metformin or observation, we observed significantly decreased PCPhenoAge and PCGrimAge estimates of monocytes from only participants in the metformin arm by a mean decrease of 3.53 and 1.84 years from baseline to Week 24. In contrast, we observed no significant differences in all PC clocks for participants in the observation arm over 24 weeks. Notably, our analysis of epigenetic mitotic clocks revealed significant increases for monocytes in the metformin arm when comparing baseline to Week 24, suggesting an impact of metformin on myeloid cell kinetics. Analysis of a single‐arm clinical trial of adjunctive metformin in eight PLWH revealed no significant differences across all epigenetic clocks assessed in CD8 + T cells at 4‐ and 8‐week time points. Our results suggest cell‐type‐specific myeloid effects of metformin captured by PC‐based epigenetic clock(definition) biomarkers. Larger clinical studies of metformin are needed to validate these observations and this report highlights the need for further inclusion of PLWH in geroscience trials evaluating the effect of metformin on increasing healthspan(definition) and lifespan.