Bezisterim-associated anti-inflammatory epigenetic modulation of age acceleration and Alzheimer’s disease genes

Treatments with the ability to slow or reduce biological age have therapeutic potential in diseases of aging, including late-onset Alzheimer’s disease (AD). We previously reported that bezisterim, a novel anti-inflammatory insulin sensitizer, modulated epigenetic age acceleration (EAA) in a randomized, placebo-controlled, 30-week AD trial. Here, we expand on those findings through integrative mechanistic analyses and by linking bezisterim-induced EAA changes with clinical outcomes. Thirty weeks of bezisterim treatment in patients with mild-to-moderate AD significantly reduced EAA across 13 independent biological clocks versus placebo. The reduced EAA was predominantly associated with biomarkers of inflammation and cognition, including transcriptional regulators that orchestrate broader gene networks. Genome-wide methylation profiling revealed 2,154 genes with significant differential promoter methylation (DPM) between bezisterim and placebo groups. Among those DPM genes, increased promoter methylation was observed in 432 genes associated with microglial neuroinflammation, pro-inflammatory kinase activity, cognitive decline, lipid metabolism, and transcriptional regulation, whereas decreased methylation was observed in 15 genes that might increase autophagy and anti-inflammatory phosphatases, and might decrease macrophage polarization. Finally, separate correlational analyses among the bezisterim and placebo groups suggest that the observed changes in potentially beneficial DPM genes might contribute to the previously reported clinical effects of bezisterim in AD. Notably, the majority of correlations in bezisterim-treated patients were associated with neurologic and metabolic improvements; 11 of these DPMs were correlated with two to five clinical measures each. Bezisterim appears to exert pleiotropic effects through coordinated modulation of aging-related epigenetic programs, potentially counteracting neurodegenerative processes at the intersection of inflammation, metabolism, and transcriptional control.