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

Abstract

Age is the predominant risk factor for late-onset Alzheimer's disease, and interventions that reduce biological age may be therapeutic. We previously reported that bezisterim, a novel anti-inflammatory insulin sensitizer, modulated epigenetic age acceleration (EAA) in a randomized, placebo-controlled, 7-month Alzheimer's disease trial. Building on prior evidence linking bezisterim-induced EAA changes to improved cognitive and functional outcomes, we conducted integrative analyses to elucidate underlying molecular mechanisms. Bezisterim significantly reduced EAA across 12 independent biological clocks, reinforcing its impact on validated aging biomarkers, and identifying targets predominantly involved in inflammation and cognition, including transcriptional regulators that orchestrate broader gene networks. Genome-wide methylation profiling revealed 2,154 genes with significant differential promoter methylation between bezisterim and placebo groups. Treatment increased promoter methylation - suggesting transcriptional repression - in 433 genes known to be associated with aging and disease processes, including microglial neuroinflammation, pro-inflammatory kinase activity, cognitive decline, lipid metabolism, and transcriptional regulation. Conversely, treatment-decreased methylation of 15 genes potentially improved autophagy, and increased anti-inflammatory phosphatases and macrophage polarization. Analyses were conducted to search for correlations between promoter methylation and the 31 previous clinical measures in bezisterim and placebo subjects. Significant correlations (72 bezisterim, 13 placebo) suggest that methylation differences contribute to observed clinical differences. The majority of the correlations in bezisterim subjects were associated with neurologic and metabolic improvements, and 12 of 72 were correlated with 2-5 clinical measures each, potentially emphasizing their contribution to clinical benefit. 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.