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 Alzheimers 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 linking bezisterim-induced EAA changes with clinical outcomes. Thirty weeks of bezisterim treatment in patients with mild-to-moderate AD showed favorable trends for reduced EAA across 13 independent biological clocks versus placebo. The reduced EAA was predominantly associated with inflammation, cognition, and transcription factor genes that orchestrate broader gene networks. Genome-wide methylation profiling revealed 2581 genes with significant differential promoter methylation (DPM) between the bezisterim and placebo groups. We identified 447 of these as having potentially beneficial DPM based on expected expression related to published aging and AD activities; 179 were AD hub genes. In addition, more than 1000 bezisterim treatment-related, potentially beneficial differential promoter methylation (PBDPM) genes associated with microglial neuroinflammation, pro-inflammatory kinase activity, cognitive decline, lipid metabolism, and transcriptional regulation were correlated with directional improvement in individual neurologic and metabolic clinical measures. The observed changes in PBDPM genes might contribute to the previously reported clinical effects of bezisterim in AD. Bezisterim appears to exert pleiotropic effects through coordinated modulation of aging-related epigenetic programs, potentially counteracting epigenetic-driven neurodegenerative processes at the intersection of inflammation, metabolism, and transcriptional control.