The FOXO-Aging Axis: Epigenetic Insights and Chromatin Mechanisms.

Aging is frequently accompanied by profound alterations in the chromatin landscape, leading to widespread changes in transcriptional programs and cellular functions. Forkhead box O (FOXO) proteins, traditionally viewed as downstream effectors of insulin and stress-response signaling, are now emerging as dynamic chromatin regulators that integrate metabolic cues with epigenetic remodeling during aging. In this review, we first outline the major epigenetic and chromatin alterations associated with aging and then examine the emerging role of FOXO proteins as chromatin regulators in this context. We discuss evidence for FOXO pioneer activity and the structural features that facilitate chromatin engagement, followed by FOXO-mediated regulation through ATP-dependent chromatin remodeling and histone modifications, and consider how these mechanisms may shape age-associated chromatin states and cellular senescence. Finally, we discuss the current FOXO-targeting therapeutic strategies and the challenges of achieving isoform- and chromatin context-specific FOXO modulation. Collectively, this review provides a chromatin-centered perspective on the FOXO-aging axis and offers a conceptual framework for future translational and therapeutic studies.